Home Silencing of circ_002136 sensitizes gastric cancer to paclitaxel by targeting the miR-16-5p/HMGA1 axis
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Silencing of circ_002136 sensitizes gastric cancer to paclitaxel by targeting the miR-16-5p/HMGA1 axis

  • Zhijian Kuang , Haitao Yang , Shu Cheng , Xiaolong Zhou , Lan Chen , Yuqing Zhang and Jie Zhang EMAIL logo
Published/Copyright: January 31, 2023
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Open Medicine
From the journal Open Medicine Volume 18 Issue 1

Abstract

The dysregulated expression of circRNA in gastric cancer (GC) induces paclitaxel (Tax) resistance of cancer cells, which in turn affects disease progression and prognosis. Here, we sought to investigate the role and mechanism of circ_002136 in Tax-resistant GC. In this study, we found the enriched circ_002136 level and the declined miR-16-5p level in Tax-resistant GC tissues and cells. Biologically, knockdown of circ_002136 elevated the Tax sensitivity of Tax-resistant GC cells, inhibited the cell motility properties, and simultaneously drove the apoptosis. Mechanically, circ_002136 promoted the HMGA1-mediated cellular Tax resistance and cell invasion by sponging miR-16-5p. Furthermore, circ_002136 silencing impeded the growth of Tax-resistant GC tumors in vivo. Overall, our study revealed a novel signaling pathway that could be used for future clinical applications, namely the circ_002136/miR-16-5p/HMGA1 axis to regulate the Tax resistance of GC cells.

Keywords: gastric cancer; circ_002136; miR-16-5p; HMGA1; paclitaxel

1 Introduction

Gastric cancer (GC) is a common gastrointestinal malignancy worldwide, with the leading incidence and death rates [1]. In 2020, it ranked fifth with over 1 million new cases worldwide and fourth with approximately 769,000 deaths (equivalent to 1 in every 13 tumor-related deaths) [2]. GC presents as a highly molecularly heterogeneous disease that progresses rapidly and, therefore, has a poor prognosis [3]. Chemotherapy combined with targeted therapy significantly prolongs survival and quality of life in patients with GC progression, e.g., paclitaxel (Tax) and platinum-based agents [4]. However, the emergence of acquired drug resistance hinders the effectiveness of chemotherapy and predisposes the patients to treatment failure. Therefore, a deeper understanding of the mechanisms of chemotherapy resistance may provide new ideas and approaches for GC treatment.

Paclitaxel (Tax) is a natural botanical antitumor agent derived from Taxus brevifolia [5]. It functions as a microtubule inhibitor, which induces apoptosis by inhibiting the movement of spindle microtubules and thus causing the cellular G2/M phase block [6]. Due to its unique pharmacological mechanism, paclitaxel is widely used in the clinical treatment of GC, lung cancer and other malignant tumors in the middle and late stages [7,8,9,10]. However, the appearance and development of drug resistance has largely restricted the therapeutic effect of paclitaxel. Similarly, the molecular mechanism of resistance to Tax in GC has not been elucidated.

Covalently closed circular RNA (circRNA) does not possess a linear RNA cap as well as a poly(A) tail structure and presents in the cell as a stable form of closed RNA molecule [11,12]. An increasing number of reports have shown that dysregulated circRNAs conferred oncogenic function in GC and were closely related to tumor chemoresistance [13]. For example, circRNA PVT1 contributed to Tax resistance in GC cells through the regulation of ZEB1 expression by acting as a sponge of miR-124-3p [14]. Nevertheless, the exact role of circRNAs in GC Tax resistance remains questionable. In the present study, we confirmed that circ_002136 was clearly upregulated in GC tissues, and its level correlated with the sensitivity of GC patients to Tax. Specifically, Tax-resistant GC patients had higher circ_002136 expression. Further studies evidenced that circ_002136 could actively sponge miR-16-5p to modulate HMGA1 levels, which in turn induced a Tax-resistant phenotype in GC cells. In the former report, it was presented that the interaction of circ_002136 with FUS, miR-138-5p, SOX13, and SPON2 could retard the growth of glioma [15]. Therefore, the aim of this study was to clarify the molecular mechanisms of circ_002136 in Tax-resistant GC. We hypothesized that circ_002136 interference could sensitize Tax-resistant GC cells to Tax through the miR-16-5p/HMGA1 axis and inhibit the growth and metastasis of Tax-resistant tumor cells, which may provide a new avenue for the treatment of patients with Tax-resistant GC.

2 Materials and methods

2.1 Patient and sample collection

Tumor tissue specimens (including 20 Tax-sensitive and 17 Tax-resistant tissues) and matched histologically normal tissue specimens located ≥5 cm from the margin of cancer were collected from 37 GC patients who underwent gastrectomy at our institution. The recruited patients signed an informed consent form before surgery. Fresh tissue specimens were harvested under aseptic conditions, rapidly frozen in liquid nitrogen, and stored in a −80°C refrigerator. Inclusion criteria included (1) individuals, aged 18–65 years, who were clinically confirmed diagnosed as GC by pathological examination; (2) individuals who did not administer any preoperative radiotherapy or chemotherapy; and (3) individuals with comprehensive clinicopathological data (including age, gender, degree of tumor differentiation, TNM stating, and lymph node staging).

  1. Ethics approval and consent to participate: This study was performed according to institutional guidelines and was approved by Ningbo Mingzhou Hospital Ethics Committee, which consistent with the Declaration of Helsinki.

2.2 Cell culture and construction of Tax-resistant cell lines

Two human GC cell lines (SGC7901 and BGC823) were acquired from the Cell Bank of the Chinese Academy of Sciences (Shanghai, China). The corresponding Tax-resistant GC cells (SGC7901/Tax and BGC823/Tax) were created by exposing parental cells to incremental amounts of Tax (Solarbio, China). All cells were grown in RPMI-1640 medium (Gibco, USA) containing 10% fetal bovine serum (Gibco) and 1% penicillin/streptomycin (Gibco). To maintain the resistant phenotype of SGC7901/Tax and BGC823/Tax cells, 5 nM Tax was supplemented to RPMI-1640 medium. All cells were maintained in an atmosphere of 5% CO2 at 37°C.

2.3 Cell transfection

Cell transfection was achieved in SGC7901/Tax and BGC823/Tax cells by performing Lipofectamine 2000 (Invitrogen, USA). The small-hairpin RNA targeting circ_002136 (si-circ_002136) and its negative control (si-NC), miR-16-5p mimics/inhibitors and its negative control miR-NC were provided by GenePharma (Shanghai, China). To construct stable circ_002136 low-expressing cell lines, lentivirus-mediated short-hairpin RNA against circ_002136 (sh-circ_002136) and its negative control sh-NC were transfected into SGC7901/Tax and BGC823/Tax cells, and 2 mg/mL puromycin was administrated to select stable expression colonies. pcDNA-HMGA1, an overexpression plasmid for HMGA1, was provided by GenePharma, and the empty pcDNA vector was set as negative control (pcDNA). Referring to the manufacturer’s protocols, cells were seeded on six-well plates, 24 h before transfection. After 48 h transfection at 37°C and 5% CO2, the cells were harvested for the next experiments.

2.4 Ribonuclease R (RNase R) treatment

To check the loop structure of circ_002136, 2 μg of RNA was extracted from GC cells treated with RNase R (Epicenter Technologies). For the experimental group, 1 μg of RNA was mixed with 2 μL of RNase R reaction buffer and 5 U/g of RNase R. For the Mock group, an equal volume of RNase-free water was substituted for RNase R. The prepared reaction system was maintained for additional 15 min at 37°C. Then, TRIzol reagent was immediately added for RNA extraction, followed by the quantitative real-time PCR (qRT-PCR) analysis.

2.5 Actinomycin D assay

SGC7901 and BGC823 cells were inoculated on six-well plates (5 × 105 cells/well). To inhibit cell transcription and degrade linear mRNA, cells were then exposed to actinomycin D (2 μg/mL, Sigma) for 0, 4, 8, 12, and 24 h. After actinomycin D treatment, RNA was collected from the cells and the abundance of circ_002136 was presented using qRT-PCR.

2.6 circ_002136 subcellular localization prediction

The nuclear and cytoplasmic fractions of SGC7901/Tax and BGC823/Tax cells were departed using the Cytoplasmic & Nuclear RNA Purification Kit (PARIS Kit; Invitrogen). Nucleoplasmic distribution and expression levels of circ_002136 in Tax-resistant GC cells were detected by qRT-PCR. U6 and GAPDH were set as controls for nuclear and cytoplasmic transcripts.

2.7 Cellular drug sensitivity assay

Cell viability and cellular Tax sensitivity were assayed by Cell Counting Kit-8 (CCK-8). The transfected cells in each group were resuspended and inoculated into 96-well plates (1 × 104 cells/well) and cultured separately in RPMI-1640 medium for 24 h. Cells were then exposed to several doses of Tax for 72 h. Hereafter, 10 μL of CCK-8 reagent was replenished to each well and maintained for another 2 h at 37°C. Finally, the optical density (OD) values were quantified using an enzyme marker (BioTek Instruments) at 450 nm. The half-maximal inhibitory concentration (IC50) values of Tax were determined based on the relationship between the percentage of viable cells and the concentration of Tax.

2.8 Wound-healing assays

The proliferative wound-healing assay was carried out to evidence the migratory properties of SGC7901/Tax and BGC823/Tax cells. Briefly, si-NC- or si-circ_002136-transfected cells were seeded into six-well plates for stable growth, followed by scratching when the cells reached 90–95% confluence. In monolayers of cells, pipette tips (200 μL, labeled 0 h) were introduced to create streaks followed by rinsing cells with phosphate buffered saline (PBS) and infusing fresh medium. After continuing incubation for 24 h, the rate of wound area closure was analyzed by light microscopy (Nikon, Tokyo, Japan, magnification ×40) and ImageJ (NIH).

2.9 Transwell assay

The abilities of cells invasion were assayed by the Transwell analysis. For the invasion analysis, trypsin (HyClone)-digested 2 × 104 GC cells were first resuspended in 200 μL of serum-free medium and then seeded in Matrigel (BD Biosciences)-coated upper chamber of the Transwell. Five hundred microliters of suitable medium was infused into the bottom chamber. Twenty-four hours later, cells were fixed with paraformaldehyde for 15 min, stained with 0.1% crystalline violet for 10 min, and washed twice with PBS. Five random fields were selected for observation and counting under a microscope (Olympus).

2.10 Cell apoptosis analysis

Flow cytometry was used for apoptosis analysis. SGC7901/Tax and BGC823/Tax cells were exposed to specific concentration of si-NC or si-circ_002136 followed by digesting in trypsin for 24 h. Then, cells were collected (1 × 105 cells) and resuspended in a volume of 500 μl of binding buffer. The target cells were then mixed and stained with 5 μL Annexin V/PE and 7-AAD, respectively, for 15 min at room temperature without light, according to the Annexin V PE/7-AAD Apoptosis Detection Kit (KeyGEN Biotech, China). FACScan® (BD Biosciences) was carried out to analyze apoptotic cell ratios.

2.11 Dual luciferase reporter gene assay

CircBank (http://www.circbank.cn/) and circinteractome (https://circinteractome.nia.nih.gov/) databases were conducted to predict the targeting relationship between circ_002136 and miR-16-5p, and the target gene of miR-16-5p was demonstrated by TargetScan (http://www.targetscan.org/). The circ_002136 and HMGA1 sequence fragments containing the miR-16-5p complementary sites were amplified and implanted into the reporter vector (pmirGLO; Promega, USA) to produce wild-type luciferase reporter vectors (named as WT-circ_002136 and WT-HMGA1), and the corresponding mutants were constructed (named as MUT-circ_ 002136 and MUT-HMGA1). The above luciferase reporter gene vectors and miR-16-5p mimics or miR-NC were cotransfected into SGC7901/Tax and BGC823/Tax cells to test the miR-16-5p-binding ability. Luciferase activity was obtained and displayed by a dual luciferase reporter gene assay system (Promega), following 48 h transfection.

2.12 RNA pull-down assay

The 3′ ends of miR-16-5p and miR-NC were biotin-labeled as Biotin-miR-16-5p and Biotin-NC (Genepharm, China). The biotin-labeled RNA probes were mixed and maintained with streptavidin beads (Thermo Scientific) at 37°C for 2 h. SGC7901/Tax and BGC823/Tax cell lysates were incubated with the probe-coated magnetic beads overnight at 4°C and then eluted with biotin elution buffer. Finally, the biotin-coupled RNA complexes were pulled down and the bound RNA was quantified by qRT-PCR.

2.13 qRT-PCR

First, the total RNA was isolated from GC tissues and cells with the help of TRIzol (Beyotime, China) kit. Then, the RNA was reverse transcribed to cDNA in line with the instructions of the reverse transcription kit (PrimeScript™ RT kit, Takara). The cDNA served as template was gently mixed with BeyoFast™ SYBR Green qPCR Mix (Takara) and specific primers. The expression levels of target mRNA and miRNA were amplified and manipulated in accordance with ABI 7500 PCR System (Applied Biosystems). U6 was acted as a reference for miR-16-5p, and GAPDH was functioned as a reference for circ_002136 and HMGA1, respectively. Relative gene expression levels were calculated and normalized by the 2−∆∆Ct method. The primer sequences used were:

circ_002136, F: 5′-CTTTCCGAGACATTTGCTGG-3′,

R: 5′-CATGGAGATCACAATAAGGAACTC-3′;

miR-16-5p, F: 5′-GTCGTGGAGTCGGCAATT-3′,

R: 5′-AUUUGCCAGG UCGGA AUG-3′;

HMGA1, F: 5′-GAAGTGCCAACACCTAAGAGAGACC-3′,

R: 5′-GGTTTCCTTCCTGGAGTTGTGG-3′;

GAPDH, F: 5′-AATGGATTTGGACGCATTGGT-3′,

R: 5′-TTTGCACTGGTACGTGTGTTGAT-3′;

U6, F: 5′-CTGGTAGGGTGCTCGCTTCGGCAG-3′,

R: 5′-CAACTGGTGTCGTGGAGTCGGC-3′.

2.14 Western blot analysis

Total proteins were separated from cells of each group in the presence of RIPA lysis buffer (Beyotime) containing protease inhibitors and phosphatase inhibitors. Protein concentrations were confirmed by operating the BCA Protein Assay Kit (Pierce, USA). Thirty micrograms of denatured protein samples were separated by 10% sodium dodecyl sulfate polyacrylamide gel electrophoresis and then transferred to polyvinylidene fluoride membranes. Membranes were blocked in 5% skimmed milk for 2 h and followed by incubation with primary antibody against HMAG1 (1:1,000; Cell Signaling Technologies, USA) at 4°C overnight. Then, all membranes were overlaid and probed with the secondary antibody for an additional 1 h at room temperature. Protein blot images were visualized using an ECL kit (Millipore, USA). GAPDH was treated as an internal reference.

2.15 Animal research

For in vivo tumorigenesis experiments, BALB/c nude mice (male, 4–6 weeks old) were obtained from Shanghai Animal Experiment Center (Shanghai, China) and randomly assigned to four groups: sh-NC + PBS, sh-circ_002136 + PBS, sh-NC + Tax, and sh-circ_002136 + Tax. circ_002136 (sh-circ_002136) of shRNA lentiviral vector and its negative control (sh-NC) were provided by GenePharma. Orthotopic transplantation models were constructed by subcutaneously injecting 4 × 106 SGC7901/Tax cells stably transfected with sh-circ_002136 or sh-NC into the right side of nude mice. After 7 days, the sh-NC + Tax and sh-circ_002136 + Tax groups were injected intraperitoneally with 30 mg/kg Tax every 3 days, while the sh-NC + PBS and sh-circ_002136 + PBS groups were injected with equal volume of PBS. Tumor size was recorded and volume was calculated according to the formula = 0.5 × length × width2. Nude mice were executed after 30 days, and the tumors were removed and weighed immediately. The expression of circ_002136 and miR-16-5p was analyzed by qRT-PCR. The surgically excised tumor tissues were paraffin-embedded for tissue sectioning (6 μm) and subjected to immunohistochemistry (IHC) [16]. Tissue sections were incubated with anti-HMGA1 (1:500) for 60 min. Biotinylated goat anti-rabbit serum IgG (Beyotime Institute of Biotechnology) was used as a secondary antibody. The antigen/antibody complexes were visualized with diaminobenzidine (Dako, Carpinteria, CA, USA) and re-stained with hematoxylin. Images were analyzed using an Institute of Medical Statistics imaging processing system.

2.16 Statistical analysis

The experiments used were performed three times independently and the data obtained are expressed as mean ± standard deviation. Statistical differences between the two or multiple groups were determined using Student’s t-test or one-way ANOVA. Statistical analysis was performed in SPSS 22.0 statistical software (Chicago, IL, USA) and graphs were plotted in GraphPad Prism 7.0 software. A P-value of less than 0.05 was considered as the criterion for statistical significance.

3 Results

3.1 hsa_circ_002136 expression is upregulated in Tax-resistant GC tissues and cells

The expression of circRNAs is closely related to the gene regulation of GC. Certainly, the properties of circ_002136 also need to be studied. A search in circBase and circBank revealed that hsa_circ_002136 (hsa_circ_0000005, hsa_circCDK11A_001) was originated from the linear CDK11A gene with the position of chr1: 1,586,822–1,650,894, which was formed by the transcript CDK11A-VT1 (cyclin-dependent kinase 11A transcript variant 1) closed into a loop with a length of 49,639 bp. Thereafter, to investigate the role of circ_002136 in regulating drug resistance progression in GC, we first determined the circ_002136 expression characteristics by qRT-PCR in 37 pairs of GC tissues. The obtained data showed that circ_002136 was significantly upregulated in GC tissues compared to paired non-tumor tissues (Figure 1a). Moreover, we also examined the expression levels of circ_002136 in Tax-sensitive (n = 20) and Tax-resistant (n = 17) GC tissues. The experimental results confirmed that circ_002136 expression was significantly enriched in Tax-resistant tissues compared to Tax-sensitive tissues (Figure 1b). In addition, the matched Tax-resistant GC cells (SGC7901/Tax and BGC823/Tax) showed higher expression of circ_002136 compared to parental SGC7901 and BGC823 cells (Figure 1c). Next, we analyzed the stability and localization of circ_002136 in Tax-resistant GC cells. The total RNA from GC cell lines was treated with or without RNase R. It was revealed that circ_002136 was resistant to nucleic acid exonuclease-mediated RNA degradation (expression was only slightly decreased compared to GAPDH mRNA), indicating that circ_002136 was more stable (Figure 1d). The function of circRNA is largely influenced by subcellular localization. Therefore, we analyzed cytoplasmic and nuclear RNA from GC cells by qRT-PCR to determine the subcellular localization of circ_002136. Figure 1e and f shows that circ_002136 had a ring-like structure and is mainly distributed in the cytoplasm. The above results suggest that circ_002136 may become a novel biomarker for GC.

Figure 1 circ_002136 was overexpressed in the GC tissues and cell lines. (a) circ_002136 expression was measured in adjacent normal tissues and tumor tissues by qRT-PCR. (b) The expression of circ_002136 was determined in patients responding or not responding to paclitaxel treatment. (c) Relative expression of circ_002136 was detected by qRT-PCR in SGC7901, SGC7901/Tax, BGC823, and BGC823/Tax cells. (d) The relative levels of circ_002136 and GAPDH mRNA were examined by qRT-PCR after treatment with RNase R in SGC7901/Tax and BGC823/Tax cells. (e and f) The qRT-PCR test was applied to determine the subcellular location of circ_00081001 in SGC7901/Tax and BGC823/Tax cells. *P < 0.05, **P < 0.01, and ***P < 0.001.
Figure 1

circ_002136 was overexpressed in the GC tissues and cell lines. (a) circ_002136 expression was measured in adjacent normal tissues and tumor tissues by qRT-PCR. (b) The expression of circ_002136 was determined in patients responding or not responding to paclitaxel treatment. (c) Relative expression of circ_002136 was detected by qRT-PCR in SGC7901, SGC7901/Tax, BGC823, and BGC823/Tax cells. (d) The relative levels of circ_002136 and GAPDH mRNA were examined by qRT-PCR after treatment with RNase R in SGC7901/Tax and BGC823/Tax cells. (e and f) The qRT-PCR test was applied to determine the subcellular location of circ_00081001 in SGC7901/Tax and BGC823/Tax cells. *P < 0.05, **P < 0.01, and ***P < 0.001.

3.2 Silencing of hsa_circ_002136 increases Tax sensitivity of GC cells

Afterwards, to further investigate the effect of circ_002136 on Tax-sensitive GC cells and Tax-resistant GC cells, small-interfering RNA (si-RNA) against circ_002136 was constructed and determined the si-circ_002136 knockdown efficiency in SGC7901/Tax and BGC823/Tax cell lines. qRT-PCR data indicated that si-circ_002136 transfection resulted in significantly lower circ_002136 levels in SGC7901/Tax and BGC823/Tax cells, compared to the corresponding controls (Figure 2a). As shown in Figure 2b and c, compared to Tax-resistant GC cells exposed to si-NC, the decrease of IC50 values was presented in si-circ_002136-transfected SGC7901/Tax and BGC823/Tax cells, indicating that both cells increased sensitivity to Tax. As expected, the migration and invasion abilities of SGC7901/Tax and BGC823/Tax cells were also weakened by the intervention of si-circ_002136 (Figure 2d and e). Besides, the flow cytometry analysis also revealed that silencing of circ_002136 activated the apoptosis of Tax-resistant GC cells (Figure 2f). In conclusion, the above experimental results suggest that circ_002136 inhibition enhances Tax-induced GC cytotoxicity and hinders GC progression in vitro.

Figure 2 Downregulation of circ_002136 inhibited paclitaxel resistance, migration, invasion and induced apoptosis in GC. (a) circ_002136 expression in SGC7901/Tax and BGC823/Tax cells with the transfection of si-circ_002136 or si-NC. (b and c) Cell viability and IC50 of paclitaxel in cells with the transfection of si-circ_002136 or si-NC after exposure to various doses of paclitaxel for 72 h. (d and e) Cell migration and invasion in cells with the transfection of si-circ_002136 or si-NC. Scale bars = 200, 50 μm. (f) Cell apoptosis in cells with the transfection of si-circ_002136 or si-NC. **P < 0.01, ***P < 0.001.
Figure 2

Downregulation of circ_002136 inhibited paclitaxel resistance, migration, invasion and induced apoptosis in GC. (a) circ_002136 expression in SGC7901/Tax and BGC823/Tax cells with the transfection of si-circ_002136 or si-NC. (b and c) Cell viability and IC50 of paclitaxel in cells with the transfection of si-circ_002136 or si-NC after exposure to various doses of paclitaxel for 72 h. (d and e) Cell migration and invasion in cells with the transfection of si-circ_002136 or si-NC. Scale bars = 200, 50 μm. (f) Cell apoptosis in cells with the transfection of si-circ_002136 or si-NC. **P < 0.01, ***P < 0.001.

3.3 hsa_circ_002136 knockdown enhances the Tax sensitivity of Tax-resistant GC cells by upregulating miR-16-5p

The regulation mechanism of circRNA on miRNA activity and its abundant or tissue-specific expression patterns make circRNA a potential molecular marker for diagnosing disease. To explore the molecular mechanisms of circ_002136 in GC, we used circBank (http://www.circbank.cn/) and circinteractome (https://circinteractome.nia.nih.gov/) bioinformatics prediction software to find potential target miRNAs for circ_002136. Finally, miR-16-5p was identified as a direct target (Figure 3a). Figure 3a shows the binding sites of circ_002136 to miR-16-5p. To verify the direct interaction between the above two RNAs, we constructed luciferase reporter genes (wild-type circ_002136 and mutant circ_002136) and cotransfected them with miR-16-5p mimic or miR-NC into SGC7901/Tax and BGC823/Tax cells. The obtained results demonstrated that miR-16-5p mimics transfection effectively attenuated the luciferase activity of the circ_002136-WT reporter vector in SGC7901/Tax and BGC823/Tax cells with significant reductions of 52 and 60% but had no effect on the luciferase activity of circ_002136-MUT (Figure 3b and c). In addition to analyzing the luciferase activity, we performed RNA pull-down analysis on specific biotin-labeled miR-16-5p by using SGC7901/Tax and BGC823/Tax cell lysates. As shown in Figure 3d, the biotin-miR-16-5p was specifically enriched for circ_002136. Meanwhile, we determined miR-16-5p expression in 37 GC patient tissues using qRT-PCR. The miR-16-5p levels in GC tissues (both Tax-sensitive GC tissues and Tax-resistant GC tissues) compared to non-tumor tissues were lower (Figure 3e). Correlation analysis showed that miR-16-5p was negatively correlated with circ_002136 in GC tissues (Figure 3f). Furthermore, miR-16-5p expression was dwindled in SGC7901/Tax and BGC823/Tax cells compared to parental cells SGC7901 and BGC823 (Figure 3g). Finally, we transfected circ_002136 siRNA into GC cells to assess miR-16-5p expression. The results indicated that knockdown of circ_002136 apparently enhanced the level of miR-16-5p in SGC7901/Tax and BGC823/Tax cells (Figure 3h and i). Our experimental results suggest that circ_002136 may mediate GC cell Tax resistance via miR-16-5p. Next, to elucidate whether miR-16-5p plays a role in circ_002136-mediated Tax resistance in GC cells, we co-transfected si-circ_002136 and miR-16-5p into SGC7901/Tax or BGC823/Tax cells for rescue experiments. The present results of CCK-8 assay validated that miR-16-5p inhibitor partially attenuated the inhibitory effect of circ_002136 silencing on Tax resistance in SGC7901/Tax and BGC823/Tax cells (Figure 4a and b). Similarly, miR-16-5p inhibitor also partially reversed the hampering effect of knockdown of circ_002136 on the migration and invasion of SGC7901/Tax and BGC823/Tax cells, as well as the promotion of apoptosis in SGC7901/Tax and BGC823/Tax cells (Figure 4c–h). All data suggest that circ_002136 can directly target miR-16-5p and regulate Tax resistance in GC cells.

Figure 3 miR-16-5p is a binding target of circ_002136. (a) The complementary sequence between circ_002136 and miR-16-5p. (b and c) Luciferase activity was detected in cells with the co-transfection of circ_002136-WT or circ_002136-MUT and miR-16-5p mimic or miR-NC. (d) circ_002136 expression in cells with the transfection of biotin-miR-NC or biotin-miR-16-5p after RNA pull-down. (e) miR-16-5p expression in adjacent normal tissues and GC tissues. (f) circ_002136 and miR-16-5p expression association in GC tissues. (g) miR-16-5p expression in SGC7901, SGC7901/Tax, BGC823, and BGC823/Tax cells. (h and i) miR-16-5p expression in cells after circ_002136 downregulation. *P < 0.05, **P < 0.01, ***P < 0.001.
Figure 3

miR-16-5p is a binding target of circ_002136. (a) The complementary sequence between circ_002136 and miR-16-5p. (b and c) Luciferase activity was detected in cells with the co-transfection of circ_002136-WT or circ_002136-MUT and miR-16-5p mimic or miR-NC. (d) circ_002136 expression in cells with the transfection of biotin-miR-NC or biotin-miR-16-5p after RNA pull-down. (e) miR-16-5p expression in adjacent normal tissues and GC tissues. (f) circ_002136 and miR-16-5p expression association in GC tissues. (g) miR-16-5p expression in SGC7901, SGC7901/Tax, BGC823, and BGC823/Tax cells. (h and i) miR-16-5p expression in cells after circ_002136 downregulation. *P < 0.05, **P < 0.01, ***P < 0.001.

Figure 4 Inhibition of miR-16-5p reversed the effects of circ_002136 knockdown in GC. (a and b) Cell viability after paclitaxel treatment in SGC7901/Tax and BGC823/Tax cells. (c and d) Migration, (e and f) invasion, and (g and h) apoptosis in cells with the transfection of si-NC, si-circ_002136, si-circ_002136 + miR-NC inhibitor, or miR-16-5p inhibitor. *P < 0.05, **P < 0.01, ***P < 0.001.
Figure 4

Inhibition of miR-16-5p reversed the effects of circ_002136 knockdown in GC. (a and b) Cell viability after paclitaxel treatment in SGC7901/Tax and BGC823/Tax cells. (c and d) Migration, (e and f) invasion, and (g and h) apoptosis in cells with the transfection of si-NC, si-circ_002136, si-circ_002136 + miR-NC inhibitor, or miR-16-5p inhibitor. *P < 0.05, **P < 0.01, ***P < 0.001.

3.4 HMGA1 is a new target of miR-16-5p in Tax-resistant GC cells

circRNAs/miRNAs/mRNAs crosstalk has a potential role as a tumor suppressor in GC cell lines [17]. To further investigate the mechanism of ceRNA crosstalk in GC, the bioinformatics online software TargetScan (http://www.targetscan.org/vert_72/) was applied to predict the potential targets of miR-16-5p. As shown in Figure 5a, as predicted, the HMGA1 3′-UTR had binding sites to miR-16-5p. The luciferase fluorescence activity measurements showed that miR-16-5p mimic caused sharply diminished the luciferase activity signal in WT-HMGA1-transfected SGC7901/Tax and BGC823/Tax cells, whereas MUT-HMGA1 had no such effect (Figure 5b). In addition, HMGA1 protein appeared high abundance expression in both SGC7901/Tax and BGC823/Tax cells, with an expression trend opposite to miR-16-5p (Figure 5c). To further verify the effect of miR-16-5p on HMGA1 expression, we examined the levels of HMGA1 protein after stimulation with miR-16-5p mimics and inhibitors. As shown in Figure 5d and e, weakened miR-16-5p level resulted in elevated HMGA1 level in SGC7901/Tax and BGC823/Tax cells. In contrast, overexpression of miR-16-5p caused attenuated expression of HMGA1 protein. These results suggest that HMGA1 is a direct target of miR-16-5p.

Figure 5 The relationship of miR-16-5p and HMGA1. (a) The complementary sequence between miR-16-5p and HMGA1. (b) Luciferase activity was examined in cells with the co-transfection of HMGA1-WT or HMGA1-MUT and miR-16-5p mimic or miR-NC. (c) HMGA1 expression in SGC7901, SGC7901/Tax, BGC823, and BGC823/Tax cells. (d and e) HMGA1 protein expression level in cells with the transfection of miR-NC, miR-16-5p mimic, miR-NC inhibitor or miR-16-5p inhibitor. *P < 0.05, **P < 0.01, ***P < 0.001.
Figure 5

The relationship of miR-16-5p and HMGA1. (a) The complementary sequence between miR-16-5p and HMGA1. (b) Luciferase activity was examined in cells with the co-transfection of HMGA1-WT or HMGA1-MUT and miR-16-5p mimic or miR-NC. (c) HMGA1 expression in SGC7901, SGC7901/Tax, BGC823, and BGC823/Tax cells. (d and e) HMGA1 protein expression level in cells with the transfection of miR-NC, miR-16-5p mimic, miR-NC inhibitor or miR-16-5p inhibitor. *P < 0.05, **P < 0.01, ***P < 0.001.

3.5 Restored expression of miR-16-5p suppresses Tax resistance, cell migration, invasion, and apoptosis in Tax-resistant GC cells through downregulation of HMGA1

Previous studies demonstrated that HMGA1 was an oncogene associated with GC tumors, which was involved in tumor cell migration, invasion, and cisplatin resistance. To explore the role of HMGA1 on Tax resistance in GC, we transfected miR-NC, miR-16-5p mimic, miR-16-5p mimic + pcDNA, or pcDNA HMGA1 into SGC7901/Tax and BGC823/Tax cells. qRT-PCR and western blot analyses confirmed that HMGA1 mRNA and protein levels were downregulated in both SGC7901/Tax and BGC823/Tax cells after the administration of miR-16-5p mimic, but introduction of HMGA1 overexpression plasmid in these cells improved the HMGA1 level after miR-16-5p overexpression (Figure 6a and b). Cells were treated with specific amount of paclitaxel and then subjected to CCK-8 assays. The obtained experimental data indicated that increased HMGA1 level partially restored Tax sensitivity mediated by miR-16-5p overexpression in SGC7901/Tax and BGC823/Tax, increasing cellular Tax resistance, as evidenced by increased OD 450 values (Figure 6c). Subsequent wound-healing, Transwell, and flow cytometry analyses showed that pcDNA HMGA1 effectively weakened the inhibitory effect on SGC7901/Tax and BGC823/Tax cells’ migration (Figure 6d and e), invasion (Figure 6f and g), and promotion of apoptosis (Figure 6h and i) induced by miR-16-5p overexpression. These results confirmed that HMGA1 could indeed affect paclitaxel resistance in GC cells.

Figure 6 miR-16-5p affected paclitaxel resistance, migration, invasion, and apoptosis by regulating HMGA1. (a) HMGA1 mRNA and (b) protein levels in SGC7901/Tax and BGC823/Tax cells with the transfection of miR-NC, miR-16-5p mimic, miR-16-5p mimic + pcDNA, or pcDNA HMGA1. (c) Cell viability after paclitaxel treatment in SGC7901/Tax and BGC823/Tax cells. (d and e) Migration, (f and g) invasion, and (h and i) apoptosis in cells with the transfection of miR-NC, miR-16-5p mimic, miR-16-5p mimic + pcDNA, or pcDNA HMGA1. *P < 0.05, **P < 0.01, ***P < 0.001.
Figure 6

miR-16-5p affected paclitaxel resistance, migration, invasion, and apoptosis by regulating HMGA1. (a) HMGA1 mRNA and (b) protein levels in SGC7901/Tax and BGC823/Tax cells with the transfection of miR-NC, miR-16-5p mimic, miR-16-5p mimic + pcDNA, or pcDNA HMGA1. (c) Cell viability after paclitaxel treatment in SGC7901/Tax and BGC823/Tax cells. (d and e) Migration, (f and g) invasion, and (h and i) apoptosis in cells with the transfection of miR-NC, miR-16-5p mimic, miR-16-5p mimic + pcDNA, or pcDNA HMGA1. *P < 0.05, **P < 0.01, ***P < 0.001.

3.6 Knockdown of hsa_circ_002136 enhances Tax sensitivity of GC in vivo and inhibits tumor malignant progression

To confirm the effect of circ_002136 on the growth of Tax-resistant GC tumors in vivo, we observed tumor growth after subcutaneous inoculation of sh-circ_002136 stably transfected SGC7901/Tax cells via xenograft tumor model. As shown in Figure 7a and b, compared with the sh-NC group, the tumor size and tumor weight in the sh-NC + Tax group treated with Tax were downregulated, which suggested that Tax treatment could control GC tumor development in vivo. Interestingly, we found that downregulation of circ_002136 enhanced the anti-tumor effect of Tax (Figure 7a and b). Correspondingly, qRT-PCR results showed an obvious decrease in circ_002136 in the sh-circ_002136 groups compared with the sh-NC groups (Figure 7c). Western blot and immunohistochemical analyses also presented that knockdown of circ_002136 reduced HMGA1 expression in vivo (Figure 7d and e). It can be concluded that silencing of circ_002136 induced Tax sensitivity of GC in vivo via the miR-16-5p/HMGA1 axis.

Figure 7 circ_002136 inhibition restrained tumor growth and sensitizes gastric cells to paclitaxel in vivo. (a) Growth curve of the tumors. (b) Representative images (right) and mean weight (left) of the xenograft tumors. (c) circ_002136 and miR-16-5p expression levels were examined by qRT-PCR. (d and e) HMGA1 expression level in tumors was detected by western blot (d) and IHC (e). Scale bar = 50 μm. *P < 0.05, **P < 0.01, ***P < 0.001.
Figure 7

circ_002136 inhibition restrained tumor growth and sensitizes gastric cells to paclitaxel in vivo. (a) Growth curve of the tumors. (b) Representative images (right) and mean weight (left) of the xenograft tumors. (c) circ_002136 and miR-16-5p expression levels were examined by qRT-PCR. (d and e) HMGA1 expression level in tumors was detected by western blot (d) and IHC (e). Scale bar = 50 μm. *P < 0.05, **P < 0.01, ***P < 0.001.

4 Discussion

Chemotherapy can improve the endpoints of progression-free survival and overall remission rate of cancer patients and is an effective treatment for advanced cancer patients who cannot undergo surgery. As a highly effective microtubulin cytotoxin, Tax can “freeze” the mitotic spindle of rapidly dividing cancer cells and induce G2/M cell cycle arrest [18]. Therefore, Tax has significant anti-tumor activity and has gradually developed into a first-line chemotherapeutic agent for the treatment of GC. However, most GC patients have developed drug resistance when treated with Tax. And the resistance mechanism of Tax is still in the exploration stage. It is hypothesized that the mechanism of Tax resistance involves multiple biological processes, including alterations in drug targets, alterations in intercellular signaling, and changes in cell cycle check proteins [19,20]. The stably expressed circRNAs are not only involved in the malignant progression of tumors, but there is now a wealth of data suggesting that circRNAs are also associated with Tax resistance in tumors. Circ-PVT1 could confer paclitaxel resistance to GC cells through upregulation of miR-124-3p-mediated ZEB1 [14]. CircCELSR1 shared the same response element with miR-1252 and bound competitively with miR-1252 to regulate FOXR2 expression, which in turn reduced the sensitivity of ovarian cancer cells to Tax [10]. circ_0006528 was highly expressed in Tax-resistant breast cancer tissues and cells and might regulate Tax resistance by binding to miR-1299 [21]. Therefore, in this study, we identified a novel circRNA associated with Tax resistance, circ_002136, which was significantly enriched in both Tax-sensitive and Tax-resistant GC tissues but presented at higher levels in Tax-resistant tissues than in Tax-sensitive tissues, implying that circ_002136 could play a relatively important role in both Tax-resistant and Tax-sensitive GC. Accordingly, we downregulated circ_002136 in Tax-resistant GC cells (SGC7901/Tax and BGC823/Tax) in vivo and in vitro to deepen the understanding of the potential mechanisms for chemoresistance in GC.

miR-16-5p has been observed to be involved in the propagation of chemoresistance in tumor cells and to predict cancer progression. Previous studies have found that miR-16-5p served as a potential biomarker, indicating a strong risk factor for GC progression [22]. Furthermore, miR-16-5p overexpression improved TAMR sensitivity in breast cancer cells [23] and cisplatin treatment sensitivity in osteosarcoma cells [24] and participated in anti-adriamycin chemoresistance in cervical cancer through PDK4-mediated metabolic reprogramming [25]. Therefore, this study determined whether miR-16-5p was involved in the induction of paclitaxel-resistant phenotype in GC cells. Here, we found that circ_002136 had endogenous sponge-like effect on miR-16-5p in GC. First, bioinformatics online software and luciferase reporter gene assay proved the targeted binding effect between circ_002136 and miR-16-5p. Second, miR-16-5p was lower expressed in Tax-resistant GC cells and tissues. Finally, circ_002136 silencing-induced Tax sensitivity in GC cells could be overridden by miR-16-5p knockdown. These data imply that circ_002136 may mediate Tax resistance in GC via miR-16-5p, suggesting a potential function of circ_002136/miR-16-5p as a drug-associated gene in cancer therapy.

An interesting finding in our study was that high mobility group A1 (HMGA1) could be involved in the induction of Tax resistance in GC cells. HMGA1 competitively was bound to miR-16-5p in GC cells to reduce its expression. It has been reported that the dysregulation of HMGA1 was correlated with the cancer drug-resistant phenotype [26,27]. Recent studies have shown that HMGA1 bound specifically to miR-218 to mediate cisplatin resistance in GC cells [28]. In our results, miR-16-5p could target HMGA1 3′-UTR, and HMGA1 overexpression promoted the progression of Tax resistance in GC cells. Also, HMGA1 overexpression partially reversed the inhibitory effect of miR-16-5p mimic on cell progression. Finally, knockdown of circ_002136 in vivo induced an increase in miR-16-5p and restrained HMGA1 level and ultimately curbed the growth of Tax-resistant tumors. Taken together, these results represent that circ_002136 causes activation of the miR-16-5p/HMGA1 pathway and induce a Tax-resistant phenotype in GC cells. Therefore, targeting circ_002136 may be a new goal to overcome paclitaxel resistance in GC.

5 Conclusion

To conclude, this study revealed for the first time that circ_002136 could be activated in Tax-resistant GC tissues and cells, and higher circ_002136 levels were related to tumor malignant phenotypes. In addition, in vitro experiments showed that knockdown of circ_002136 increased Tax sensitivity in GC cells, and also in vivo tests confirmed that silencing of circ_002136 controlled the growth of Tax-resistant GC tumors. Mechanically, the targeted binding of circ_002136 to miR-16-5p could unlock the translational repression of HMGA1, a downstream target gene of miR-16-5p. In summary, we provided a promising circRNA-targeted therapy for GC patients, in which the circ_002136/miR-16-5p/HMGA1 axis might provide a new idea for cancer treatment.

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Acknowledgements

None.

  1. Funding information: No funding was received.

  2. Author contributions: ZK designed the experiments and drafted the article. HY and SC collected the clinical samples and processed statistical data. XZ, LC, and YZ performed the experiments and analyzed the data. JZ designed, supervised the study, and revised the article. All authors read and approved the final version of the article.

  3. Conflict of interest: The authors declare that they have no conflicts of interest to report regarding the present study.

  4. Data availability statement: The data used to support the findings of this study are available from the corresponding author upon request.

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Received: 2022-06-07
Revised: 2022-11-21
Accepted: 2022-11-29
Published Online: 2023-01-31

© 2023 the author(s), published by De Gruyter

This work is licensed under the Creative Commons Attribution 4.0 International License.

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  111. circRNA THBS1 silencing inhibits the malignant biological behavior of cervical cancer cells via the regulation of miR-543/HMGB2 axis
  112. hsa_circ_0000285 sponging miR-582-3p promotes neuroblastoma progression by regulating the Wnt/β-catenin signaling pathway
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  114. lncRNA UCA1 regulates miR-132/Lrrfip1 axis to promote vascular smooth muscle cell proliferation
  115. Twenty-four-color full spectrum flow cytometry panel for minimal residual disease detection in acute myeloid leukemia
  116. Hsa-miR-223-3p participates in the process of anthracycline-induced cardiomyocyte damage by regulating NFIA gene
  117. Anti-inflammatory effect of ApoE23 on Salmonella typhimurium-induced sepsis in mice
  118. Analysis of somatic mutations and key driving factors of cervical cancer progression
  119. Hsa_circ_0028007 regulates the progression of nasopharyngeal carcinoma through the miR-1179/SQLE axis
  120. Variations in sexual function after laparoendoscopic single-site hysterectomy in women with benign gynecologic diseases
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  124. Alkbh5 plays indispensable roles in maintaining self-renewal of hematopoietic stem cells
  125. Study to compare the effect of casirivimab and imdevimab, remdesivir, and favipiravir on progression and multi-organ function of hospitalized COVID-19 patients
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  128. Norepinephrine alleviates cyclosporin A-induced nephrotoxicity by enhancing the expression of SFRP1
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  130. The function of Foxp1 represses β-adrenergic receptor transcription in the occurrence and development of bladder cancer through STAT3 activity
  131. Risk model and validation of carbapenem-resistant Klebsiella pneumoniae infection in patients with cerebrovascular disease in the ICU
  132. Calycosin protects against chronic prostatitis in rats via inhibition of the p38MAPK/NF-κB pathway
  133. Pan-cancer analysis of the PDE4DIP gene with potential prognostic and immunotherapeutic values in multiple cancers including acute myeloid leukemia
  134. The safety and immunogenicity to inactivated COVID-19 vaccine in patients with hyperlipemia
  135. Circ-UBR4 regulates the proliferation, migration, inflammation, and apoptosis in ox-LDL-induced vascular smooth muscle cells via miR-515-5p/IGF2 axis
  136. Clinical characteristics of current COVID-19 rehabilitation outpatients in China
  137. Luteolin alleviates ulcerative colitis in rats via regulating immune response, oxidative stress, and metabolic profiling
  138. miR-199a-5p inhibits aortic valve calcification by targeting ATF6 and GRP78 in valve interstitial cells
  139. The application of iliac fascia space block combined with esketamine intravenous general anesthesia in PFNA surgery of the elderly: A prospective, single-center, controlled trial
  140. Elevated blood acetoacetate levels reduce major adverse cardiac and cerebrovascular events risk in acute myocardial infarction
  141. The effects of progesterone on the healing of obstetric anal sphincter damage in female rats
  142. Identification of cuproptosis-related genes for predicting the development of prostate cancer
  143. Lumican silencing ameliorates β-glycerophosphate-mediated vascular smooth muscle cell calcification by attenuating the inhibition of APOB on KIF2C activity
  144. Targeting PTBP1 blocks glutamine metabolism to improve the cisplatin sensitivity of hepatocarcinoma cells through modulating the mRNA stability of glutaminase
  145. A single center prospective study: Influences of different hip flexion angles on the measurement of lumbar spine bone mineral density by dual energy X-ray absorptiometry
  146. Clinical analysis of AN69ST membrane continuous venous hemofiltration in the treatment of severe sepsis
  147. Antibiotics therapy combined with probiotics administered intravaginally for the treatment of bacterial vaginosis: A systematic review and meta-analysis
  148. Construction of a ceRNA network to reveal a vascular invasion associated prognostic model in hepatocellular carcinoma
  149. A pan-cancer analysis of STAT3 expression and genetic alterations in human tumors
  150. A prognostic signature based on seven T-cell-related cell clustering genes in bladder urothelial carcinoma
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  152. The antihypertensive felodipine shows synergistic activity with immune checkpoint blockade and inhibits tumor growth via NFAT1 in LUSC
  153. Tanshinone IIA attenuates valvular interstitial cells’ calcification induced by oxidized low density lipoprotein via reducing endoplasmic reticulum stress
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  155. Establishment of two oxaliplatin-resistant gallbladder cancer cell lines and comprehensive analysis of dysregulated genes
  156. Trial protocol: Feasibility of neuromodulation with connectivity-guided intermittent theta-burst stimulation for improving cognition in multiple sclerosis
  157. LncRNA LINC00592 mediates the promoter methylation of WIF1 to promote the development of bladder cancer
  158. Factors associated with gastrointestinal dysmotility in critically ill patients
  159. Mechanisms by which spinal cord stimulation intervenes in atrial fibrillation: The involvement of the endothelin-1 and nerve growth factor/p75NTR pathways
  160. Analysis of two-gene signatures and related drugs in small-cell lung cancer by bioinformatics
  161. Silencing USP19 alleviates cigarette smoke extract-induced mitochondrial dysfunction in BEAS-2B cells by targeting FUNDC1
  162. Menstrual irregularities associated with COVID-19 vaccines among women in Saudi Arabia: A survey during 2022
  163. Ferroptosis involves in Schwann cell death in diabetic peripheral neuropathy
  164. The effect of AQP4 on tau protein aggregation in neurodegeneration and persistent neuroinflammation after cerebral microinfarcts
  165. Activation of UBEC2 by transcription factor MYBL2 affects DNA damage and promotes gastric cancer progression and cisplatin resistance
  166. Analysis of clinical characteristics in proximal and distal reflux monitoring among patients with gastroesophageal reflux disease
  167. Exosomal circ-0020887 and circ-0009590 as novel biomarkers for the diagnosis and prediction of short-term adverse cardiovascular outcomes in STEMI patients
  168. Upregulated microRNA-429 confers endometrial stromal cell dysfunction by targeting HIF1AN and regulating the HIF1A/VEGF pathway
  169. Bibliometrics and knowledge map analysis of ultrasound-guided regional anesthesia
  170. Knockdown of NUPR1 inhibits angiogenesis in lung cancer through IRE1/XBP1 and PERK/eIF2α/ATF4 signaling pathways
  171. D-dimer trends predict COVID-19 patient’s prognosis: A retrospective chart review study
  172. WTAP affects intracranial aneurysm progression by regulating m6A methylation modification
  173. Using of endoscopic polypectomy in patients with diagnosed malignant colorectal polyp – The cross-sectional clinical study
  174. Anti-S100A4 antibody administration alleviates bronchial epithelial–mesenchymal transition in asthmatic mice
  175. Prognostic evaluation of system immune-inflammatory index and prognostic nutritional index in double expressor diffuse large B-cell lymphoma
  176. Prevalence and antibiogram of bacteria causing urinary tract infection among patients with chronic kidney disease
  177. Reactive oxygen species within the vaginal space: An additional promoter of cervical intraepithelial neoplasia and uterine cervical cancer development?
  178. Identification of disulfidptosis-related genes and immune infiltration in lower-grade glioma
  179. A new technique for uterine-preserving pelvic organ prolapse surgery: Laparoscopic rectus abdominis hysteropexy for uterine prolapse by comparing with traditional techniques
  180. Self-isolation of an Italian long-term care facility during COVID-19 pandemic: A comparison study on care-related infectious episodes
  181. A comparative study on the overlapping effects of clinically applicable therapeutic interventions in patients with central nervous system damage
  182. Low intensity extracorporeal shockwave therapy for chronic pelvic pain syndrome: Long-term follow-up
  183. The diagnostic accuracy of touch imprint cytology for sentinel lymph node metastases of breast cancer: An up-to-date meta-analysis of 4,073 patients
  184. Mortality associated with Sjögren’s syndrome in the United States in the 1999–2020 period: A multiple cause-of-death study
  185. CircMMP11 as a prognostic biomarker mediates miR-361-3p/HMGB1 axis to accelerate malignant progression of hepatocellular carcinoma
  186. Analysis of the clinical characteristics and prognosis of adult de novo acute myeloid leukemia (none APL) with PTPN11 mutations
  187. KMT2A maintains stemness of gastric cancer cells through regulating Wnt/β-catenin signaling-activated transcriptional factor KLF11
  188. Evaluation of placental oxygenation by near-infrared spectroscopy in relation to ultrasound maturation grade in physiological term pregnancies
  189. The role of ultrasonographic findings for PIK3CA-mutated, hormone receptor-positive, human epidermal growth factor receptor-2-negative breast cancer
  190. Construction of immunogenic cell death-related molecular subtypes and prognostic signature in colorectal cancer
  191. Long-term prognostic value of high-sensitivity cardiac troponin-I in patients with idiopathic dilated cardiomyopathy
  192. Establishing a novel Fanconi anemia signaling pathway-associated prognostic model and tumor clustering for pediatric acute myeloid leukemia patients
  193. Integrative bioinformatics analysis reveals STAT2 as a novel biomarker of inflammation-related cardiac dysfunction in atrial fibrillation
  194. Adipose-derived stem cells repair radiation-induced chronic lung injury via inhibiting TGF-β1/Smad 3 signaling pathway
  195. Real-world practice of idiopathic pulmonary fibrosis: Results from a 2000–2016 cohort
  196. lncRNA LENGA sponges miR-378 to promote myocardial fibrosis in atrial fibrillation
  197. Diagnostic value of urinary Tamm-Horsfall protein and 24 h urine osmolality for recurrent calcium oxalate stones of the upper urinary tract: Cross-sectional study
  198. The value of color Doppler ultrasonography combined with serum tumor markers in differential diagnosis of gastric stromal tumor and gastric cancer
  199. The spike protein of SARS-CoV-2 induces inflammation and EMT of lung epithelial cells and fibroblasts through the upregulation of GADD45A
  200. Mycophenolate mofetil versus cyclophosphamide plus in patients with connective tissue disease-associated interstitial lung disease: Efficacy and safety analysis
  201. MiR-1278 targets CALD1 and suppresses the progression of gastric cancer via the MAPK pathway
  202. Metabolomic analysis of serum short-chain fatty acid concentrations in a mouse of MPTP-induced Parkinson’s disease after dietary supplementation with branched-chain amino acids
  203. Cimifugin inhibits adipogenesis and TNF-α-induced insulin resistance in 3T3-L1 cells
  204. Predictors of gastrointestinal complaints in patients on metformin therapy
  205. Prescribing patterns in patients with chronic obstructive pulmonary disease and atrial fibrillation
  206. A retrospective analysis of the effect of latent tuberculosis infection on clinical pregnancy outcomes of in vitro fertilization–fresh embryo transferred in infertile women
  207. Appropriateness and clinical outcomes of short sustained low-efficiency dialysis: A national experience
  208. miR-29 regulates metabolism by inhibiting JNK-1 expression in non-obese patients with type 2 diabetes mellitus and NAFLD
  209. Clinical features and management of lymphoepithelial cyst
  210. Serum VEGF, high-sensitivity CRP, and cystatin-C assist in the diagnosis of type 2 diabetic retinopathy complicated with hyperuricemia
  211. ENPP1 ameliorates vascular calcification via inhibiting the osteogenic transformation of VSMCs and generating PPi
  212. Significance of monitoring the levels of thyroid hormone antibodies and glucose and lipid metabolism antibodies in patients suffer from type 2 diabetes
  213. The causal relationship between immune cells and different kidney diseases: A Mendelian randomization study
  214. Interleukin 33, soluble suppression of tumorigenicity 2, interleukin 27, and galectin 3 as predictors for outcome in patients admitted to intensive care units
  215. Identification of diagnostic immune-related gene biomarkers for predicting heart failure after acute myocardial infarction
  216. Long-term administration of probiotics prevents gastrointestinal mucosal barrier dysfunction in septic mice partly by upregulating the 5-HT degradation pathway
  217. miR-192 inhibits the activation of hepatic stellate cells by targeting Rictor
  218. Diagnostic and prognostic value of MR-pro ADM, procalcitonin, and copeptin in sepsis
  219. Review Articles
  220. Prenatal diagnosis of fetal defects and its implications on the delivery mode
  221. Electromagnetic fields exposure on fetal and childhood abnormalities: Systematic review and meta-analysis
  222. Characteristics of antibiotic resistance mechanisms and genes of Klebsiella pneumoniae
  223. Saddle pulmonary embolism in the setting of COVID-19 infection: A systematic review of case reports and case series
  224. Vitamin C and epigenetics: A short physiological overview
  225. Ebselen: A promising therapy protecting cardiomyocytes from excess iron in iron-overloaded thalassemia patients
  226. Aspirin versus LMWH for VTE prophylaxis after orthopedic surgery
  227. Mechanism of rhubarb in the treatment of hyperlipidemia: A recent review
  228. Surgical management and outcomes of traumatic global brachial plexus injury: A concise review and our center approach
  229. The progress of autoimmune hepatitis research and future challenges
  230. METTL16 in human diseases: What should we do next?
  231. New insights into the prevention of ureteral stents encrustation
  232. VISTA as a prospective immune checkpoint in gynecological malignant tumors: A review of the literature
  233. Case Reports
  234. Mycobacterium xenopi infection of the kidney and lymph nodes: A case report
  235. Genetic mutation of SLC6A20 (c.1072T > C) in a family with nephrolithiasis: A case report
  236. Chronic hepatitis B complicated with secondary hemochromatosis was cured clinically: A case report
  237. Liver abscess complicated with multiple organ invasive infection caused by hematogenous disseminated hypervirulent Klebsiella pneumoniae: A case report
  238. Urokinase-based lock solutions for catheter salvage: A case of an upcoming kidney transplant recipient
  239. Two case reports of maturity-onset diabetes of the young type 3 caused by the hepatocyte nuclear factor 1α gene mutation
  240. Immune checkpoint inhibitor-related pancreatitis: What is known and what is not
  241. Does total hip arthroplasty result in intercostal nerve injury? A case report and literature review
  242. Clinicopathological characteristics and diagnosis of hepatic sinusoidal obstruction syndrome caused by Tusanqi – Case report and literature review
  243. Synchronous triple primary gastrointestinal malignant tumors treated with laparoscopic surgery: A case report
  244. CT-guided percutaneous microwave ablation combined with bone cement injection for the treatment of transverse metastases: A case report
  245. Malignant hyperthermia: Report on a successful rescue of a case with the highest temperature of 44.2°C
  246. Anesthetic management of fetal pulmonary valvuloplasty: A case report
  247. Rapid Communication
  248. Impact of COVID-19 lockdown on glycemic levels during pregnancy: A retrospective analysis
  249. Erratum
  250. Erratum to “Inhibition of miR-21 improves pulmonary vascular responses in bronchopulmonary dysplasia by targeting the DDAH1/ADMA/NO pathway”
  251. Erratum to: “Fer exacerbates renal fibrosis and can be targeted by miR-29c-3p”
  252. Retraction
  253. Retraction of “Study to compare the effect of casirivimab and imdevimab, remdesivir, and favipiravir on progression and multi-organ function of hospitalized COVID-19 patients”
  254. Retraction of “circ_0062491 alleviates periodontitis via the miR-142-5p/IGF1 axis”
  255. Retraction of “miR-223-3p alleviates TGF-β-induced epithelial-mesenchymal transition and extracellular matrix deposition by targeting SP3 in endometrial epithelial cells”
  256. Retraction of “SLCO4A1-AS1 mediates pancreatic cancer development via miR-4673/KIF21B axis”
  257. Retraction of “circRNA_0001679/miR-338-3p/DUSP16 axis aggravates acute lung injury”
  258. Retraction of “lncRNA ACTA2-AS1 inhibits malignant phenotypes of gastric cancer cells”
  259. Special issue Linking Pathobiological Mechanisms to Clinical Application for cardiovascular diseases
  260. Effect of cardiac rehabilitation therapy on depressed patients with cardiac insufficiency after cardiac surgery
  261. Special issue The evolving saga of RNAs from bench to bedside - Part I
  262. FBLIM1 mRNA is a novel prognostic biomarker and is associated with immune infiltrates in glioma
  263. Special Issue Computational Intelligence Methodologies Meets Recurrent Cancers - Part III
  264. Development of a machine learning-based signature utilizing inflammatory response genes for predicting prognosis and immune microenvironment in ovarian cancer
https://doi.org/10.1515/med-2022-0625
Keywords for this article
gastric cancer; circ_002136; miR-16-5p; HMGA1; paclitaxel
Creative Commons
BY 4.0

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  132. Calycosin protects against chronic prostatitis in rats via inhibition of the p38MAPK/NF-κB pathway
  133. Pan-cancer analysis of the PDE4DIP gene with potential prognostic and immunotherapeutic values in multiple cancers including acute myeloid leukemia
  134. The safety and immunogenicity to inactivated COVID-19 vaccine in patients with hyperlipemia
  135. Circ-UBR4 regulates the proliferation, migration, inflammation, and apoptosis in ox-LDL-induced vascular smooth muscle cells via miR-515-5p/IGF2 axis
  136. Clinical characteristics of current COVID-19 rehabilitation outpatients in China
  137. Luteolin alleviates ulcerative colitis in rats via regulating immune response, oxidative stress, and metabolic profiling
  138. miR-199a-5p inhibits aortic valve calcification by targeting ATF6 and GRP78 in valve interstitial cells
  139. The application of iliac fascia space block combined with esketamine intravenous general anesthesia in PFNA surgery of the elderly: A prospective, single-center, controlled trial
  140. Elevated blood acetoacetate levels reduce major adverse cardiac and cerebrovascular events risk in acute myocardial infarction
  141. The effects of progesterone on the healing of obstetric anal sphincter damage in female rats
  142. Identification of cuproptosis-related genes for predicting the development of prostate cancer
  143. Lumican silencing ameliorates β-glycerophosphate-mediated vascular smooth muscle cell calcification by attenuating the inhibition of APOB on KIF2C activity
  144. Targeting PTBP1 blocks glutamine metabolism to improve the cisplatin sensitivity of hepatocarcinoma cells through modulating the mRNA stability of glutaminase
  145. A single center prospective study: Influences of different hip flexion angles on the measurement of lumbar spine bone mineral density by dual energy X-ray absorptiometry
  146. Clinical analysis of AN69ST membrane continuous venous hemofiltration in the treatment of severe sepsis
  147. Antibiotics therapy combined with probiotics administered intravaginally for the treatment of bacterial vaginosis: A systematic review and meta-analysis
  148. Construction of a ceRNA network to reveal a vascular invasion associated prognostic model in hepatocellular carcinoma
  149. A pan-cancer analysis of STAT3 expression and genetic alterations in human tumors
  150. A prognostic signature based on seven T-cell-related cell clustering genes in bladder urothelial carcinoma
  151. Pepsin concentration in oral lavage fluid of rabbit reflux model constructed by dilating the lower esophageal sphincter
  152. The antihypertensive felodipine shows synergistic activity with immune checkpoint blockade and inhibits tumor growth via NFAT1 in LUSC
  153. Tanshinone IIA attenuates valvular interstitial cells’ calcification induced by oxidized low density lipoprotein via reducing endoplasmic reticulum stress
  154. AS-IV enhances the antitumor effects of propofol in NSCLC cells by inhibiting autophagy
  155. Establishment of two oxaliplatin-resistant gallbladder cancer cell lines and comprehensive analysis of dysregulated genes
  156. Trial protocol: Feasibility of neuromodulation with connectivity-guided intermittent theta-burst stimulation for improving cognition in multiple sclerosis
  157. LncRNA LINC00592 mediates the promoter methylation of WIF1 to promote the development of bladder cancer
  158. Factors associated with gastrointestinal dysmotility in critically ill patients
  159. Mechanisms by which spinal cord stimulation intervenes in atrial fibrillation: The involvement of the endothelin-1 and nerve growth factor/p75NTR pathways
  160. Analysis of two-gene signatures and related drugs in small-cell lung cancer by bioinformatics
  161. Silencing USP19 alleviates cigarette smoke extract-induced mitochondrial dysfunction in BEAS-2B cells by targeting FUNDC1
  162. Menstrual irregularities associated with COVID-19 vaccines among women in Saudi Arabia: A survey during 2022
  163. Ferroptosis involves in Schwann cell death in diabetic peripheral neuropathy
  164. The effect of AQP4 on tau protein aggregation in neurodegeneration and persistent neuroinflammation after cerebral microinfarcts
  165. Activation of UBEC2 by transcription factor MYBL2 affects DNA damage and promotes gastric cancer progression and cisplatin resistance
  166. Analysis of clinical characteristics in proximal and distal reflux monitoring among patients with gastroesophageal reflux disease
  167. Exosomal circ-0020887 and circ-0009590 as novel biomarkers for the diagnosis and prediction of short-term adverse cardiovascular outcomes in STEMI patients
  168. Upregulated microRNA-429 confers endometrial stromal cell dysfunction by targeting HIF1AN and regulating the HIF1A/VEGF pathway
  169. Bibliometrics and knowledge map analysis of ultrasound-guided regional anesthesia
  170. Knockdown of NUPR1 inhibits angiogenesis in lung cancer through IRE1/XBP1 and PERK/eIF2α/ATF4 signaling pathways
  171. D-dimer trends predict COVID-19 patient’s prognosis: A retrospective chart review study
  172. WTAP affects intracranial aneurysm progression by regulating m6A methylation modification
  173. Using of endoscopic polypectomy in patients with diagnosed malignant colorectal polyp – The cross-sectional clinical study
  174. Anti-S100A4 antibody administration alleviates bronchial epithelial–mesenchymal transition in asthmatic mice
  175. Prognostic evaluation of system immune-inflammatory index and prognostic nutritional index in double expressor diffuse large B-cell lymphoma
  176. Prevalence and antibiogram of bacteria causing urinary tract infection among patients with chronic kidney disease
  177. Reactive oxygen species within the vaginal space: An additional promoter of cervical intraepithelial neoplasia and uterine cervical cancer development?
  178. Identification of disulfidptosis-related genes and immune infiltration in lower-grade glioma
  179. A new technique for uterine-preserving pelvic organ prolapse surgery: Laparoscopic rectus abdominis hysteropexy for uterine prolapse by comparing with traditional techniques
  180. Self-isolation of an Italian long-term care facility during COVID-19 pandemic: A comparison study on care-related infectious episodes
  181. A comparative study on the overlapping effects of clinically applicable therapeutic interventions in patients with central nervous system damage
  182. Low intensity extracorporeal shockwave therapy for chronic pelvic pain syndrome: Long-term follow-up
  183. The diagnostic accuracy of touch imprint cytology for sentinel lymph node metastases of breast cancer: An up-to-date meta-analysis of 4,073 patients
  184. Mortality associated with Sjögren’s syndrome in the United States in the 1999–2020 period: A multiple cause-of-death study
  185. CircMMP11 as a prognostic biomarker mediates miR-361-3p/HMGB1 axis to accelerate malignant progression of hepatocellular carcinoma
  186. Analysis of the clinical characteristics and prognosis of adult de novo acute myeloid leukemia (none APL) with PTPN11 mutations
  187. KMT2A maintains stemness of gastric cancer cells through regulating Wnt/β-catenin signaling-activated transcriptional factor KLF11
  188. Evaluation of placental oxygenation by near-infrared spectroscopy in relation to ultrasound maturation grade in physiological term pregnancies
  189. The role of ultrasonographic findings for PIK3CA-mutated, hormone receptor-positive, human epidermal growth factor receptor-2-negative breast cancer
  190. Construction of immunogenic cell death-related molecular subtypes and prognostic signature in colorectal cancer
  191. Long-term prognostic value of high-sensitivity cardiac troponin-I in patients with idiopathic dilated cardiomyopathy
  192. Establishing a novel Fanconi anemia signaling pathway-associated prognostic model and tumor clustering for pediatric acute myeloid leukemia patients
  193. Integrative bioinformatics analysis reveals STAT2 as a novel biomarker of inflammation-related cardiac dysfunction in atrial fibrillation
  194. Adipose-derived stem cells repair radiation-induced chronic lung injury via inhibiting TGF-β1/Smad 3 signaling pathway
  195. Real-world practice of idiopathic pulmonary fibrosis: Results from a 2000–2016 cohort
  196. lncRNA LENGA sponges miR-378 to promote myocardial fibrosis in atrial fibrillation
  197. Diagnostic value of urinary Tamm-Horsfall protein and 24 h urine osmolality for recurrent calcium oxalate stones of the upper urinary tract: Cross-sectional study
  198. The value of color Doppler ultrasonography combined with serum tumor markers in differential diagnosis of gastric stromal tumor and gastric cancer
  199. The spike protein of SARS-CoV-2 induces inflammation and EMT of lung epithelial cells and fibroblasts through the upregulation of GADD45A
  200. Mycophenolate mofetil versus cyclophosphamide plus in patients with connective tissue disease-associated interstitial lung disease: Efficacy and safety analysis
  201. MiR-1278 targets CALD1 and suppresses the progression of gastric cancer via the MAPK pathway
  202. Metabolomic analysis of serum short-chain fatty acid concentrations in a mouse of MPTP-induced Parkinson’s disease after dietary supplementation with branched-chain amino acids
  203. Cimifugin inhibits adipogenesis and TNF-α-induced insulin resistance in 3T3-L1 cells
  204. Predictors of gastrointestinal complaints in patients on metformin therapy
  205. Prescribing patterns in patients with chronic obstructive pulmonary disease and atrial fibrillation
  206. A retrospective analysis of the effect of latent tuberculosis infection on clinical pregnancy outcomes of in vitro fertilization–fresh embryo transferred in infertile women
  207. Appropriateness and clinical outcomes of short sustained low-efficiency dialysis: A national experience
  208. miR-29 regulates metabolism by inhibiting JNK-1 expression in non-obese patients with type 2 diabetes mellitus and NAFLD
  209. Clinical features and management of lymphoepithelial cyst
  210. Serum VEGF, high-sensitivity CRP, and cystatin-C assist in the diagnosis of type 2 diabetic retinopathy complicated with hyperuricemia
  211. ENPP1 ameliorates vascular calcification via inhibiting the osteogenic transformation of VSMCs and generating PPi
  212. Significance of monitoring the levels of thyroid hormone antibodies and glucose and lipid metabolism antibodies in patients suffer from type 2 diabetes
  213. The causal relationship between immune cells and different kidney diseases: A Mendelian randomization study
  214. Interleukin 33, soluble suppression of tumorigenicity 2, interleukin 27, and galectin 3 as predictors for outcome in patients admitted to intensive care units
  215. Identification of diagnostic immune-related gene biomarkers for predicting heart failure after acute myocardial infarction
  216. Long-term administration of probiotics prevents gastrointestinal mucosal barrier dysfunction in septic mice partly by upregulating the 5-HT degradation pathway
  217. miR-192 inhibits the activation of hepatic stellate cells by targeting Rictor
  218. Diagnostic and prognostic value of MR-pro ADM, procalcitonin, and copeptin in sepsis
  219. Review Articles
  220. Prenatal diagnosis of fetal defects and its implications on the delivery mode
  221. Electromagnetic fields exposure on fetal and childhood abnormalities: Systematic review and meta-analysis
  222. Characteristics of antibiotic resistance mechanisms and genes of Klebsiella pneumoniae
  223. Saddle pulmonary embolism in the setting of COVID-19 infection: A systematic review of case reports and case series
  224. Vitamin C and epigenetics: A short physiological overview
  225. Ebselen: A promising therapy protecting cardiomyocytes from excess iron in iron-overloaded thalassemia patients
  226. Aspirin versus LMWH for VTE prophylaxis after orthopedic surgery
  227. Mechanism of rhubarb in the treatment of hyperlipidemia: A recent review
  228. Surgical management and outcomes of traumatic global brachial plexus injury: A concise review and our center approach
  229. The progress of autoimmune hepatitis research and future challenges
  230. METTL16 in human diseases: What should we do next?
  231. New insights into the prevention of ureteral stents encrustation
  232. VISTA as a prospective immune checkpoint in gynecological malignant tumors: A review of the literature
  233. Case Reports
  234. Mycobacterium xenopi infection of the kidney and lymph nodes: A case report
  235. Genetic mutation of SLC6A20 (c.1072T > C) in a family with nephrolithiasis: A case report
  236. Chronic hepatitis B complicated with secondary hemochromatosis was cured clinically: A case report
  237. Liver abscess complicated with multiple organ invasive infection caused by hematogenous disseminated hypervirulent Klebsiella pneumoniae: A case report
  238. Urokinase-based lock solutions for catheter salvage: A case of an upcoming kidney transplant recipient
  239. Two case reports of maturity-onset diabetes of the young type 3 caused by the hepatocyte nuclear factor 1α gene mutation
  240. Immune checkpoint inhibitor-related pancreatitis: What is known and what is not
  241. Does total hip arthroplasty result in intercostal nerve injury? A case report and literature review
  242. Clinicopathological characteristics and diagnosis of hepatic sinusoidal obstruction syndrome caused by Tusanqi – Case report and literature review
  243. Synchronous triple primary gastrointestinal malignant tumors treated with laparoscopic surgery: A case report
  244. CT-guided percutaneous microwave ablation combined with bone cement injection for the treatment of transverse metastases: A case report
  245. Malignant hyperthermia: Report on a successful rescue of a case with the highest temperature of 44.2°C
  246. Anesthetic management of fetal pulmonary valvuloplasty: A case report
  247. Rapid Communication
  248. Impact of COVID-19 lockdown on glycemic levels during pregnancy: A retrospective analysis
  249. Erratum
  250. Erratum to “Inhibition of miR-21 improves pulmonary vascular responses in bronchopulmonary dysplasia by targeting the DDAH1/ADMA/NO pathway”
  251. Erratum to: “Fer exacerbates renal fibrosis and can be targeted by miR-29c-3p”
  252. Retraction
  253. Retraction of “Study to compare the effect of casirivimab and imdevimab, remdesivir, and favipiravir on progression and multi-organ function of hospitalized COVID-19 patients”
  254. Retraction of “circ_0062491 alleviates periodontitis via the miR-142-5p/IGF1 axis”
  255. Retraction of “miR-223-3p alleviates TGF-β-induced epithelial-mesenchymal transition and extracellular matrix deposition by targeting SP3 in endometrial epithelial cells”
  256. Retraction of “SLCO4A1-AS1 mediates pancreatic cancer development via miR-4673/KIF21B axis”
  257. Retraction of “circRNA_0001679/miR-338-3p/DUSP16 axis aggravates acute lung injury”
  258. Retraction of “lncRNA ACTA2-AS1 inhibits malignant phenotypes of gastric cancer cells”
  259. Special issue Linking Pathobiological Mechanisms to Clinical Application for cardiovascular diseases
  260. Effect of cardiac rehabilitation therapy on depressed patients with cardiac insufficiency after cardiac surgery
  261. Special issue The evolving saga of RNAs from bench to bedside - Part I
  262. FBLIM1 mRNA is a novel prognostic biomarker and is associated with immune infiltrates in glioma
  263. Special Issue Computational Intelligence Methodologies Meets Recurrent Cancers - Part III
  264. Development of a machine learning-based signature utilizing inflammatory response genes for predicting prognosis and immune microenvironment in ovarian cancer
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