Home hsa_circ_0000285 sponging miR-582-3p promotes neuroblastoma progression by regulating the Wnt/β-catenin signaling pathway
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hsa_circ_0000285 sponging miR-582-3p promotes neuroblastoma progression by regulating the Wnt/β-catenin signaling pathway

  • Jun Du , Yingquan Zhuo , Xu Sun , Meilan Nie , Jiafei Yang , Xi Luo and Huajian Gu EMAIL logo
Published/Copyright: July 14, 2023
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Open Medicine
From the journal Open Medicine Volume 18 Issue 1

Abstract

Circular RNA has been reported to play a key role in neuroblastoma (NB); however, the role of circ_0000285 in NB remains unclear. The aim of this study was to elucidate the role of circ_0000285 in NB. We studied the expression patterns of miR-582-3p and circ_0000285 in NB tissues and cells using real-time quantitative polymerase chain reaction. The expression of proteins associated with apoptosis (Bax and Bcl-2) and the proteins associated with Wnt/β-catenin (Wnt, p-Gsk-3β, Gsk-3β, β-catenin, and C-myc) were quantified by western blotting. In vivo animal models were prepared for the functional verification of circ_0000285 on tumor growth. The potential binding of circ_0000285 to miR-582-3p was ascertained using dual-luciferase reporter and RNA-binding protein immunoprecipitation experiments. Noticeable upregulation of circ_0000285 expression was observed in NB tumor samples and cell lines. In vivo and in vitro experiments indicated that the absence of circ_0000285 repressed NB cell proliferation and migration, provoked apoptosis, and impaired the activity of Wnt/β-catenin signaling. miR-582-3p is targeted by circ_0000285 and is poorly expressed in NB cells. The additional repression of miR-582-3p in NB cells after circ_0000285 silencing largely recovered circ_0000285 silencing-suppressed NB cell proliferation and migration and enhanced apoptosis. The absence of miR-582-3p restored Wnt/β-catenin signaling activity impaired by the knockdown of circ_0000285. circ_0000285 functions as an miR-582-3p sponge to strengthen Wnt/β-catenin signaling activity, thus exacerbating NB development.

Graphical abstract

Keywords: circ_0000285; neuroblastoma; miR-582-3p; Wnt/β-catenin

1 Introduction

Neuroblastoma (NB), formed by sympathetic nerve cells, is a heterogeneous solid tumor that can occur in any part of the sympathetic nervous system [1,2]. According to a recent report, NB makes up 7–8% of all childhood cancer cases and about 15% of deaths due to childhood cancer [3]. Despite multimodal treatment, most patients with recurrent high-risk NB die from the disease, with a 5-year survival rate of <50% [3,4]. Functional characterization of oncogenes or tumor suppressor genes in NB is needed to provide important insights into the unknown mechanisms of NB development and offer additional therapeutic strategies.

The definition of circular RNA (circRNA) as an oncogenic factor or cancer suppressor based on its function in cancer biology has generated widespread interest [5]. circRNA originates from precursor mRNA via a “back-splicing” mechanism, which is characterized by continuous loop-closed structures. With the wide application of RNA-sequencing technology, numerous circRNAs with tissue- or developmental-stage-specific expression have been identified in diverse cancers [6]. Accumulating evidence indicates that circRNA deregulation is linked to carcinogenesis by mediating various cellular biological functions, such as proliferation, survival, and energy metabolism [7,8]. Moreover, circRNA deregulation is associated with the activation or inactivation of several signaling pathways closely related to cancer development, such as PI3K/AKT and Wnt/β-catenin signaling [9,10]. Yang et al. revealed that circ_0133622 contributes to NB progression by enhancing NB cell growth, survival, migration, and invasion [11]. Given that the vital functionality of circRNAs in biology is newly recognized, there is still a large gap in our understanding of the effects and molecular mechanisms of circRNA action in different cancers. Herein, we focused on circ_0000285, which is derived from the HIPK3 mRNA. Studies have shown that it can be used as a driver of oncogenic development in several cancers, including cervical cancer and osteosarcoma [12,13]. To our knowledge, the function and mechanism of circ_0000285 in NB have rarely been reported.

It is canonical that circRNAs may exert effects by functioning as miRNA sponges. The potential binding of circ_0000285 to downstream miRNAs can be predicted by public bioinformatics tools, such as circInteractome and starBase [14,15]. Here, we obtained results from bioinformatic analysis that miR-582-3p could be targeted by circ_0000285. Previous research has shown that miR-582-3p has conflicting effects on a variety of cancers [16,17]. However, its role in NB remains unclear. The interplay between circ_0000285 and miR-582-3p in cancer development has not been clarified.

The purpose of the present study was to explore the function of circ_0000285 in NB progression using loss-of-function assays. In addition, we addressed the effects of circ_0000285 deregulation on the activation of canonical Wnt/β-catenin signaling and validated the interactions between circ_0000285 and miR-582-3p, thereby proposing a novel mechanism illustrating the role of circ_0000285 in NB.

2 Materials and methods

2.1 Clinical samples

Patients with NB were first diagnosed via biopsy or surgical pathology and underwent surgery at the Affiliated Hospital of Guizhou Medical University. Tumor samples (n = 23) and non-cancerous normal tissues (n = 23) from patients who provided written informed consent and did not receive chemotherapy or radiotherapy were used in our study. Patients with severe systemic diseases were excluded from the study.

2.2 Cell culture

Several NB cell lines, including SK-N-BE (Catalog No: BNCC337645), SK-N-SH (Catalog No: BNCC359892), SK-N-AS (Catalog No: BNCC342030), and IMR-32 (Catalog No: BNCC359788), and non-cancerous HEK293 (Catalog No: BNCC100449) cells were purchased from BeNa (China). SK-N-BE cells were maintained in F-12K complete medium (Catalog No: BNCC338550; BeNa) containing 10% fetal bovine serum (FBS), and all other cell lines were maintained in Dulbecco’s modification of eagle’s medium complete medium (Catalog No: BNCC363314; BeNa) containing 10% FBS and 5% CO2 at 37°C.

2.3 Real-time quantitative polymerase chain reaction (RT-qPCR)

A commercial TRIzol reagent (Catalog No: 15596018; Invitrogen, USA) was used to extract the total RNA. For the RNase R assay, the total RNA was treated with 2 U/μg RNase R at 37°C for 20 min. Next, RNA samples were subjected to reverse transcription using the High-Capacity cDNA Reverse Transcription Kit (Catalog No: 4368814; Applied Biosystems, USA) and quantified for RT-qPCR analysis using UltraSYBR Mixture (Catalog No: CW2601M; Cwbio, China). The Quant Studio6 PCR system (Life Technologies, USA) was used for RT-qPCR. For RT-qPCR of miRNAs, cDNA synthesis and quantification were conducted using an miRNA Real-Time PCR Assay Kit (Catalog No: CW2142; Cwbio). All experimental procedures were performed in accordance with the manufacturer’s protocol. In this study, relative expression was identified using the 2−△△Ct method, with GAPDH (for circ_0000285) and U6 (for miR-582-3p) as the housekeeping genes for circRNA and miRNA, respectively. Primer sequences are shown in Table 1.

Table 1

Real-time PCR primer synthesis list

Gene Sequences
circ_0000285 Forward 5′-TACCTCTGCAGGCAGGAACT-3′
Reverse 5′-TCACATGAATTTAGGTGGGACTT-3′
miR-582-3p Forward 5′-GCACCATTGAAGAGGACAGAC-3′
Reverse 5′-TATTGAAGGGGGTTCTGGTG-3′
U6 Forward 5′-CTCGCTTCGGCAGCACA-3′
Reverse 5′-AACGCTTCACGAATTTGCGT-3′
GAPDH Forward 5′-AGAAAAACCTGCCAAATATGATGAC-3′
Reverse 5′-TGGGTGTCGCTGTTGAAGTC-3′

2.4 Subcellular location

For location analysis of circ_0000285, a commercial PARIS Kit (Catalog No: AM1921; Thermo Fisher Scientific, USA) was used to separate RNA samples from the cytoplasmic and nuclear fractions of NB cells. The abundance of circ_0000285 in the separated fractions was determined using RT-qPCR. GAPDH was used as the internal control for the cytoplasm, and U6 was used as the internal control for the nucleus.

2.5 Cell transfection

Small-interfering RNA targeting circ_0000285 (si-circ), circ_0000285 overexpression vector (OE-circ), and their negative controls (si-NC and OE-NC) were obtained from Geneseed (China). miR-582-3p mimic (miR-582-3p), mimic NC (miR-NC), miR-582-3p inhibitor (inhibitor), and inhibitor-NC were purchased from Ribobio (China). Cells were transfected with siRNA (40 nM), miRNA mimic (40 nM), overexpression vectors (100 ng), or miRNA inhibitor (60 nM) using Lipofectamine 3000 (Catalog No: L3000015; Invitrogen). Cells collected after 24 h transfection were analyzed by RT-qPCR or western blotting to verify the efficacy of transfection.

2.6 Cell counting kit-8 (CCK-8) assay

Cells containing different transfections were seeded on plates of 96 wells (5 × 103 cells/well). Cells were then cultured at 37°C, and 10 μL/well CCK-8 reagent (Catalog No: C0038; Beyotime, China) was used to treat cells at 0, 24, 48, or 72 h post-seeding, for another 2 h. A cell viability curve was generated according to the 450 nM absorbance that was detected using a microplate reader (Bio-Rad, USA).

2.7 Wound-healing assay

Cells containing various transfections were seeded in 24-well plates (2 × 104 cells/well) and cultured overnight until they reached 90% confluence. Sterile pipette tips were used to scratch a wound on the cell surface, and the wound distance was quickly captured using a light microscope (Leica, Germany). After 24 h of cell culture in culture medium without serum, the distance of the wounds was captured again using a microscope. The distance was used to assess the cell migratory capacity.

2.8 Flow cytometry

Flow cytometry was performed to detect cell apoptosis using an Annexin V-FITC Apoptosis Detection Kit (Beyotime). Cells (1 × 106) were collected and resuspended in 100 μL 1× binding buffer. Annexin V-FITC and PI (1:1 in volume) were added to the cells for 20 min in the dark. The rate of apoptosis was determined using a flow cytometer (Beckman Coulter, USA). The sum of the upper and lower right quadrants represents the apoptosis rate.

2.9 Western blot

A commercial RIPA lysis reagent (Catalog No: CW2333; Cwbio) was used to extract total proteins. After quantification using the BCA Protein Assay Kit (Catalog No: CW0014; Cwbio), 20 μg of the protein sample was added to 10% sodium dodecyl sulfate-polyacrylamide gel electrophoresis to separate the protein bands. The separated proteins were transferred to a polyvinylidene fluoride membrane and blocked for 2 h in 5% milk at room temperature. Subsequently, the membrane was incubated overnight at 4°C with the primary antibody and the secondary antibody at room temperature for 2 h. Finally, the protein signals were scanned using an ECL kit (Abcam, USA). All antibodies were obtained from Abcam, including anti-Bax (Catalog No: ab32503; 1/2,000), anti-Bcl-2 (Catalog No: ab32124; 1/2,000), anti-Wnt (Catalog No: ab63934; 1/1,000), anti-Gsk-3β (Catalog No: ab131356; 1/1,000), anti-phosphorylated Gsk-3β (anti-p-Gsk-3β; Catalog No: ab75814; 1/10,000), anti-β-catenin (Catalog No: ab68183; 1/1,000), anti-c-Myc (Catalog No: ab168727; 1/1,000), anti-GAPDH (Catalog No: ab9485; 1/2,500), and HRP-labeled goat anti-rabbit IgG (Catalog No: ab205718; 1/5,000).

2.10 Animal study

Nude mice (Balb/c; 6 weeks old; n = 10) used for the experiment were acquired from Vital River (Beijing, China). shRNA targeting circ_0000285 (sh-circ_0000285), circ_0000285 overexpression (OE-circ), sh-NC, and OE-circ lentiviral vectors were purchased from OBiO Technology Shanghai Corp., Ltd. (Shanghai, China). sh-circ_0000285 sequences were synthesized and inserted into the pLV-CMV-puro-U6-lentiviral vector. SK-N-BE cells were then infected with lentivirus-packaged shRNA targeting circ_0000285 (sh-circ_0000285) or OE-circ for stable circ_0000285 knockdown or overexpresion using 2 μg/mL puromycin. Next, SK-N-BE cells (2 × 106 cells/100 μL) were hypodermically injected into nude mice (two groups; n = 5 per group) to induce tumor formation. During tumor development, the volume (length × width2 × 0.5) was measured weekly. After 5 weeks, all experimental mice were euthanized under anesthesia. Tumor tissues were collected and analyzed. The Animal Research Procedures Committee of the Affiliated Hospital of Guizhou Medical University authorized animal care and use.

2.11 Dual-luciferase reporter assay

The wild-type (WT, containing miR-582-3p binding sites) and mutant-type (MUT, containing scrambled miR-582-3p binding sites) sequence fragments of circ_0000285 were synthesized by GenePharma (China) and cloned into the pmirGLO vector to construct the WT and MUT reporter vectors of circ_0000285. The experimental cells were co-transfected with miR-582-3p (miR-NC as a control) and the WT or MUT vector circ_0000285 and incubated for 48 h. Luciferase activity in the cells was detected experimentally using a dual-luciferase reporter kit (Catalog No: RG027; Beyotime).

2.12 RNA binding-protein immunoprecipitation (RIP) assay

Following the guidelines of the Magna RIP RNA-Binding Protein Immunoprecipitation Kit (Catalog No: 17-700; Millipore, USA), RIP experiments were performed to determine whether circ_0000285 was involved in miR-582-3p-governed RNA-induced silencing complex (RISC). Simply put, magnetic beads prepared with anti-IgG or anti-Ago2 coatings were exposed to cell lysates to capture RNA complexes linked to Ago2. RNA complexes were eluted from the beads and extracted for RT-qPCR.

2.13 Statistical analysis

Experimental data were collected from three independent biological experiments and then processed using GraphPad Prism 7.0 (GraphPad, USA). Data are presented as the mean ± standard deviation. Spearman’s correlation coefficients were calculated to evaluate linear correlations between the two groups. Student’s t-test or analysis of variance was used to compare differences. P values <0.05 indicate a significant difference.

  1. Ethics approval: The study was approved by the research ethics committee of the Affiliated Hospital of Guizhou Medical University, Guizhou, China. The treatment of samples of clinical tissues is strictly in compliance with the Helsinki Declaration of Ethics. All patients who participate in the study have signed a written informed consent. This animal experiment was conducted in accordance with the ARRIVE guidelines. This animal experiment was authorized by the Animal Care and Use Committee of the Affiliated Hospital of Guizhou Medical University.

  2. Consent to participate: All patients have signed an informed written consent.

  3. Consent for publication: All participants gave their consent to publish.

3 Results

3.1 circ_0000285 showed a high expression level in NB tissues and cells

First, we elucidated the expression pattern of circ_0000285 in NB cells. As shown in Figure 1a, circ_0000285 expression was higher in NB tumor tissues than in normal samples. After dividing the circ_0000285 high and low expression groups based on the mean circ_0000285 expression, circ_0000285 with high expression suggested a higher International Neuroblastoma Staging System stage (P = 0.0430) and MYCN amplification (P = 0.0361, Table 2). Meanwhile, circ_0000285 expression was also increased in several NB cell lines, including SK-N-BE, SK-N-SH, SK-N-AS, and IMR-32, compared to that in HEK293 cells (Figure 1b). The following examinations selected cells of SK-N-BE and SK-N-SH with a relatively high circ_0000285 expression. In addition, we found that circ_0000285 was mostly expressed in the cytoplasmic fraction of NB cells but not in the nuclear fraction (Figure 1c). Next, total RNA was treated with RNase R, and RT-qPCR data showed that the linear parental gene HIPK3 was prominently digested by RNase R, whereas circ_0000285 was rarely digested by RNase R (Figure 1d), verifying the circular structure of circ_0000285. These results suggest that dysregulation of circ_0000285 may be associated with NB development.

Figure 1 circ_0000285 showed a high expression level in NB tissues and cells. (a) The relative circ_0000285 expression in the NB and normal samples. (b) The relative circ_0000285 expression in non-cancer control cells (HEK293) and NB cells (SK-N-BE, SK-N-AS, SK-N-SH, and IMR-32), **P < 0.01 vs HEK293. (c) Subcellular distribution of circ_0000285 in nucleus or cytoplasm of SK-N-BE and SK-N-SH cells was ensured by RT-qPCR. (d) The circular structure of circ_0000285 was checked using RNase R, **P < 0.01 vs control.
Figure 1

circ_0000285 showed a high expression level in NB tissues and cells. (a) The relative circ_0000285 expression in the NB and normal samples. (b) The relative circ_0000285 expression in non-cancer control cells (HEK293) and NB cells (SK-N-BE, SK-N-AS, SK-N-SH, and IMR-32), **P < 0.01 vs HEK293. (c) Subcellular distribution of circ_0000285 in nucleus or cytoplasm of SK-N-BE and SK-N-SH cells was ensured by RT-qPCR. (d) The circular structure of circ_0000285 was checked using RNase R, **P < 0.01 vs control.

Table 2

The correlation between circ_0000285 expression and characteristics

Characteristics All patients (n = 23) circ_0000285 expression P-value
High Low
Age (months) >0.9999
<10 13 6 7
≥10 10 4 6
Gender >0.9999
Boys 11 5 6
Girls 12 5 7
INSS stage 0.0430
1–2 8 1 7
3–4 13 7 6
4s 2 2 0
MYCN amplification 0.0361
Yes 12 8 4
No 11 2 9

INSS, International Neuroblastoma Staging System. P-value was analyzed by Fisher’s exact test.

3.2 circ_0000285 silencing decelerated NB cell growth and inactivated the Wnt/β-catenin signaling

To mediate circ_0000285 silencing and overexpression, si-circ and OE-circ were transfected into the SK-N-BE and SK-N-SH cells. We observed that circ_0000285 expression in experimental cells was considerably reduced after si-circ transfection, whereas circ_0000285 expression was enhanced after OE-circ transfection (Figure 2a). Next, the functions of circ_0000285 were investigated in detail. CCK-8 results showed that NB cells harboring circ_0000285 downregulation had impaired proliferative capacity, but NB cells with circ_0000285 transfection enhanced proliferative capacity (Figure 2b). Using a wound-healing assay, we observed that the migratory ability of SK-N-SH and SK-N-BE cells was strongly inhibited by circ_0000285 silencing, and the migratory ability of SK-N-SH and SK-N-BE cells was strongly promoted by circ_0000285 overexpression (Figure 2c). Western blot analysis revealed that enhanced Bax expression and impaired Bcl-2 expression caused by circ_0000285 silencing in SK-N-BE and SK-N-SH cells suggested that circ_0000285 knockdown induced cancer cell apoptosis, but circ_0000285 overexpression showed the opposite effect (Figure 2d). Flow cytometry further showed that the circ_0000285 knockdown induced apoptosis, and circ_0000285 overexpression suppressed apoptosis (Figure 2e). Moreover, the decrease of Wnt, β-catenin, and c-Myc levels and the increase of phosphorylated Gsk-3β level were observed in si-circ-transfected cells, but the increase of Wnt, β-catenin, and c-Myc levels and the decrease of phosphorylated Gsk-3β level were observed in OE-circ-transfected cells (Figure 3). In summary, circ_0000285 knockdown inhibited NB cell development, which might be associated with the inhibition of Wnt/β-catenin signaling.

Figure 2 circ_0000285 silencing restrained NB cell growth in vitro. (a) circ_0000285 expression in si-circ, OE-circ, OE-NC, or si-NC-transfected SK-N-BE and SK-N-SH cells. (b) Cell proliferation in SK-N-SH and SK-N-BE cells after circ_0000285 downregulation or upregulation was evaluated by CCK-8 assay. (c) Cell migration in SK-N-BE and SK-N-SH cells after circ_0000285 absence or presence was detected by wound-healing assay. (d) The protein levels of Bax and Bcl-2 in SK-N-BE and SK-N-SH cells after circ_0000285 absence or presence were ascertained by western blotting. (e) The apoptosis rate in SK-N-BE and SK-N-SH cells after circ_0000285 absence or presence was detected by flow cytometry. **P < 0.01 vs si-NC; ## P < 0.01 vs OE-NC.
Figure 2

circ_0000285 silencing restrained NB cell growth in vitro. (a) circ_0000285 expression in si-circ, OE-circ, OE-NC, or si-NC-transfected SK-N-BE and SK-N-SH cells. (b) Cell proliferation in SK-N-SH and SK-N-BE cells after circ_0000285 downregulation or upregulation was evaluated by CCK-8 assay. (c) Cell migration in SK-N-BE and SK-N-SH cells after circ_0000285 absence or presence was detected by wound-healing assay. (d) The protein levels of Bax and Bcl-2 in SK-N-BE and SK-N-SH cells after circ_0000285 absence or presence were ascertained by western blotting. (e) The apoptosis rate in SK-N-BE and SK-N-SH cells after circ_0000285 absence or presence was detected by flow cytometry. **P < 0.01 vs si-NC; ## P < 0.01 vs OE-NC.

Figure 3 circ_0000285 silencing impaired the activity of Wnt/β-catenin signaling. The levels of wnt, Gsk-3β, β-catenin p-Gsk-3β, and C-myc proteins were measured by Western Blotting. **P < 0.01 vs si-NC; ## P < 0.01 vs OE-NC.
Figure 3

circ_0000285 silencing impaired the activity of Wnt/β-catenin signaling. The levels of wnt, Gsk-3β, β-catenin p-Gsk-3β, and C-myc proteins were measured by Western Blotting. **P < 0.01 vs si-NC; ## P < 0.01 vs OE-NC.

3.3 circ_0000285 depletion decelerated tumor growth in animal models

To induce tumorigenesis, SK-N-BE cells were infected with lentivirus particles of sh-circ or OE-circ to mediate stable circ_0000285 downregulation. As a result, we observed that tumor growth was dramatically decelerated in sh-circ-administered animals relative to sh-NC, whereas tumor growth was significantly enhanced in oe-circ-administered animals relative to OE-NC (Figure 4a–c). In tumor tissues removed from animals, sh-circ induced the decrease of circ_0000285 expression, and OE-circ induced the increase of circ_0000285 expression (Figure 4d). In summary, circ_0000285 depletion largely restrained NB tumorigenesis in vivo.

Figure 4 circ_0000285 silencing repressed tumor development in animal models. (a) The tumor images were taken. The volume (b) and weight of the tumor (c) in the tissue of the tumor in animal models were measured to evaluate the NB tumor growth in vivo. (d) The circ_0000285 expression in the tissues of the tumor in animal models was measured by RT-qPCR. **P < 0.01 vs sh-NC; ## P < 0.01 vs OE-NC.
Figure 4

circ_0000285 silencing repressed tumor development in animal models. (a) The tumor images were taken. The volume (b) and weight of the tumor (c) in the tissue of the tumor in animal models were measured to evaluate the NB tumor growth in vivo. (d) The circ_0000285 expression in the tissues of the tumor in animal models was measured by RT-qPCR. **P < 0.01 vs sh-NC; ## P < 0.01 vs OE-NC.

3.4 circ_0000285 targeted miR-582-3p whose expression was declined in NB

In a canonical manner, we examined the downstream miRNAs targeted by circ_0000285 and clarified their functional mechanisms. Data from starBase showed that miR-582-3p is a hypothetical circ_0000285 target (Figure 5a). The binding sites between circ_0000285 and miR-582-3p, which were determined computationally, were then experimentally verified because deceased luciferase activity was found in the experimental cells containing the miR-582-3p and circ_0000285 wt constructs (Figure 5b). We then observed that a high abundance of circ_0000285 and miR-582-3p was enriched in anti-Ago2-mediated RIP, implying that circ_0000285 is involved in miR-582-3p-related RISC (Figure 5c). This evidence strongly validated the binding of circ_0000285 to miR-582-3p. Furthermore, miR-582-3p expression was significantly reduced in NB tumor tissues (Figure 5d) and cell lines (Figure 5e) relative to the matched non-cancerous samples. The expression of miR-582-3p and circ_0000285 were negatively correlated in NB tumor samples (Figure 5f). Taken together, miR-582-3p, a target of circ_0000285, showed an opposite expression pattern to that of circ_0000285 in NB.

Figure 5 circ_0000285 targeted miR-582-3p. (a) The computational binding sites between miR-582-3p and circ_0000285 were acquired from Starbase (https://starbase.sysu.edu.cn/). (b) The putative binding sites between miR-582-3p and circ_0000285 were further verified by dual-luciferase reporter assay, **P < 0.01 vs miR-NC. (c) The binding of circ_0000285 to miR-582-3p was verified by RIP assay, **P < 0.01 vs Anti-IgG. (d) In NB and normal samples, relative miR-582-3p expression was found. (e) The relative miR-582-3p expression in non-cancer cells (HEK293) and NB cells (SK-N-BE and SK-N-SH), **P < 0.01 vs HEK293. (f) The correlation analysis of Spearman examined the association between the expression of miR-582-3p and the expression of circ_0000285 in NB samples.
Figure 5

circ_0000285 targeted miR-582-3p. (a) The computational binding sites between miR-582-3p and circ_0000285 were acquired from Starbase (https://starbase.sysu.edu.cn/). (b) The putative binding sites between miR-582-3p and circ_0000285 were further verified by dual-luciferase reporter assay, **P < 0.01 vs miR-NC. (c) The binding of circ_0000285 to miR-582-3p was verified by RIP assay, **P < 0.01 vs Anti-IgG. (d) In NB and normal samples, relative miR-582-3p expression was found. (e) The relative miR-582-3p expression in non-cancer cells (HEK293) and NB cells (SK-N-BE and SK-N-SH), **P < 0.01 vs HEK293. (f) The correlation analysis of Spearman examined the association between the expression of miR-582-3p and the expression of circ_0000285 in NB samples.

3.5 circ_0000285 facilitated NB progression through Wnt/β-catenin pathway by targeting miR-582-3p

To further explore the interactions between circ_0000285 and miR-582-3p, we transfected miR-582-3p inhibitors into si-circ-transfected NB cells and monitored functional changes. MiR-582-3p expression was significantly enhanced in si-circ cells, but was weak in inhibitor-transfected cells. MiR-582-3p expression was partially decreased by si-circ + inhibitor transfection relative to si-circ transfection in NB cells (Figure 6a). The functional study determined that cell proliferation of SK-N-BE and SK-N-SH was markedly aggravated by miR-582-3p inhibitor, and cell proliferative capacity suppressed by circ_0000285 silencing was considerably restored by additional miR-582-3p depletion (Figure 6b). Similarly, relative to the suppressive cell migration ability of NB cells after si-circ transfection, cell migration was substantially recovered in NB cells after si-circ + inhibitor transfection (Figure 6c). In addition, the circ_0000285 silencing-strengthened Bax expression was notably weakened by miR-582-3p depletion, while circ_0000285 silencing-reduced Bcl-2 expression was notably reinforced by miR-582-3p depletion (Figure 6d). After detecting the apoptosis rate by flow cytometry, the increase in the apoptosis rate caused by si-circ was reduced by the miR-582-3p inhibitor (Figure 6e). Moreover, the transfection of miR-582-3p inhibitor affected the expression of Wnt/β-catenin signaling proteins, indicating that additional inhibition of miR-582-3p enhanced the Wnt, β-catenin, and c-Myc levels that were decreased by circ_0000285 absence, and diminished the level of phosphorylated Gsk-3β that was heightened by circ_0000285 absence (Figure 7). These data indicate that circ_0000285 modulates miR-582-3p expression to affect Wnt/β-catenin signaling activity, thus regulating NB cell functions.

Figure 6 circ_0000285 knockdown inhibited NB cell functions via promoting miR-582-3p expression. (a–e) Following assays were investigated using SK-N-SH and SK-N-BE cells with si-circ, si-NC, inhibitor, inhibitor-NC or si-circ + inhibitor transfection. (a) The expression of miR-582-3p in these cells was ensured by RT-qPCR. (b) Cell proliferative ability in these cells was checked by CCK-8 assay. (c) Cell migration in these cells was checked by wound-healing assay. (d) In these cells, the expression of Bax and Bcl-2 both proteins was analyzed via Western blotting method. (e) Cell apoptosis in these cells was identified by flow cytometry. *P < 0.05, **P < 0.01 vs si-NC; # P < 0.01, ## P < 0.01 vs inhibitor-NC; & P < 0.05, && P < 0.01 vs si-circ + inhibitor.
Figure 6

circ_0000285 knockdown inhibited NB cell functions via promoting miR-582-3p expression. (a–e) Following assays were investigated using SK-N-SH and SK-N-BE cells with si-circ, si-NC, inhibitor, inhibitor-NC or si-circ + inhibitor transfection. (a) The expression of miR-582-3p in these cells was ensured by RT-qPCR. (b) Cell proliferative ability in these cells was checked by CCK-8 assay. (c) Cell migration in these cells was checked by wound-healing assay. (d) In these cells, the expression of Bax and Bcl-2 both proteins was analyzed via Western blotting method. (e) Cell apoptosis in these cells was identified by flow cytometry. *P < 0.05, **P < 0.01 vs si-NC; # P < 0.01, ## P < 0.01 vs inhibitor-NC; & P < 0.05, && P < 0.01 vs si-circ + inhibitor.

Figure 7 circ_0000285 knockdown inhibited NB cell functions through Wnt/β-catenin pathway. The protein levels of wnt, p-Gsk-3β, Gsk-3β, β-catenin and C-myc were determined by western blot. *P < 0.05, **P < 0.01 vs si-NC; ## P < 0.01 vs inhibitor-NC; & P < 0.05, && P < 0.01 vs si-circ + inhibitor.
Figure 7

circ_0000285 knockdown inhibited NB cell functions through Wnt/β-catenin pathway. The protein levels of wnt, p-Gsk-3β, Gsk-3β, β-catenin and C-myc were determined by western blot. *P < 0.05, **P < 0.01 vs si-NC; ## P < 0.01 vs inhibitor-NC; & P < 0.05, && P < 0.01 vs si-circ + inhibitor.

4 Discussion

In addition to their abundant and stable expression, circRNAs have been found in exosomes, urine, saliva, and other body fluids in clinical practice, and circRNAs have attracted much attention as promising biomarkers and therapeutic targets for cancers. Therefore, the role of circRNAs in various cancers should be systematically investigated. Here, we characterized the function of circ_0000285, the expression of which was aberrantly upregulated in NB. Silencing of circ_0000285 repressed NB cell growth and tumorigenesis and depressed Wnt/β-catenin signaling activity, which was partially attributed to the regulation of circ_0000285 on miR-582-3p. These findings, for the first time, verify the cancer-promoting effects of circ_0000285 in NB.

Recently, several circRNAs have been functionally identified in NB. For instance, circKIF2A is expressed in NB tissues and cells at higher levels, and circKIF2A knockdown attenuates NB cell growth, migration, invasion, and glycolysis energy metabolism to block NB progression [18]. Similarly, circCUX1 was also highly expressed in NB and predicted poor prognosis, and circCUX1 repression restrained aerobic glycolysis and cell aggressiveness in NB cells [19]. Furthermore, the role of circ_0000285 in several cancers has been elucidated. Zhang et al. reported that circ_0000285 was strongly expressed in osteosarcoma cell lines, and ectopic circ_0000285 expression aggravated the proliferative and migratory potencies of osteosarcoma cells [12,20]. A high abundance of circ_0000285 was also identified in cervical cancer, and circ_0000285 downregulation attested to the cancer cell cycle and provoked cell apoptosis and autophagy to repress cervical cancer development [13]. Consistent with these findings, we exhibited elevated circ_0000285 expression in NB tissue samples and cells for the first time. In in vitro analysis, we found that circ_0000285 depletion repressed NB cell proliferation and migration while provoking apoptosis. For in vivo analysis, we found that the absence of circ_0000285 blocked NB tumorigenesis in nude mice. These results confirm the carcinogenic effects of circ_0000285 on NB development.

Based on the starBase prediction, we found that miR-582-3p is a target miRNA of circ_0000285. Due to the limited research on the miR-582-3p function in NB, we chose miR-582-3p for analysis. A dual role of miR-582-3p has been reported in various cancers. miR-582-3p is poorly expressed in metastatic prostate cancer (PCa) tissues, and miR-582-3p enrichment represses PCa cell migratory and invasive abilities [16]. In addition, miR-582-3p expression in gastric cancer is low, and its accumulation of miR-582-3p considerably restricted the invasion, migration, and proliferation capabilities of gastric cancer cells [17]. miR-582-3p, on the other hand, is highly expressed in lung cancer and cervical adenocarcinoma, and forced miR-582-3p expression contributes to cancer cell migration, invasion, and survival [21,22]. Our results identified the downregulation of miR-582-3p in NB specimens and cell lines and discovered that miR-582-3p deficiency aggravated NB cell proliferative/migratory capacities but repressed apoptosis. Importantly, miR-582-3p deficiency, at least in part, reversed the functional effects of circ_0000285 knockdown and restored the malignant functions of NB cells.

Accumulating research has established that the activation of the Wnt/β-catenin pathway is related to aggressive cancer stem cell renewal, cell proliferation, differentiation, and tumorigenesis, and targeted Wnt/β-catenin pathway inhibition has been proposed as a new strategy against numerous malignant cancers [23,24,25]. Studies have shown that the activation of Wnt/β-catenin signaling is inhibited by the binding of Wnt ligands to frizzled/lipoprotein receptor-related protein coreceptors, which triggers Ser9 phosphorylation of Gsk-3β, leading to Gsk-3β inactivation and subsequent β-catenin accumulation and nuclear translocation [26,27,28]. After reviewing the literature, we found that miR-582-3p regulates the Wnt/β-catenin signaling pathway to participate in the progression of lung cancer and hepatocellular carcinoma [29,30]. However, whether miR-582-3p regulates the Wnt/β-catenin signaling pathway to regulate NB progression remains unknown. Therefore, we selected the Wnt/β-catenin signaling pathway. In our study, we discovered that decreased expression of Wnt, β-catenin, and c-Myc and enhanced expression of phosphorylated Gsk-3β were observed in NB cells after circ_0000285 knockdown, suggesting that circ_0000285 knockdown inactivated the Wnt/β-catenin signaling pathway. Moreover, circ_0000285 knockdown-weakened the Wnt/β-catenin signaling pathway was promoted by additional miR-582-3p deficiency, indicating that circ_0000285 knockdown enhanced miR-582-3p expression, thus blocking NB progression, which might be implicated in the inactivation of the Wnt/β-catenin signaling pathway.

Although the current study partly addressed the functional role and mechanism of circ_0000285 in NB, more detailed functions of circ_0000285 should be explored in future studies. In addition, the downstream functional genes of the circ_0000285/miR-582-3p pathway were not characterized in our current study and need to be explored to further understand the regulatory networks of circ_0000285. The correlation between circ_0000285 expression and clinicopathological characteristics of patients with NB is not well documented and requires further investigation.

5 Conclusion

Our study identified high expression of circ_0000285 in NB. circ_0000285 could function as a miR-582-3p sponge to activate Wnt/β-catenin signaling and thus facilitate the malignant progression of NB. circ_0000285, an oncogenic factor, may be a potential therapeutic target for NB.

# The authors contribute equally to this work.

tel: +86 183 2715 2797, fax: +86 183 2715 2797

Acknowledgements

None.

  1. Funding information: Not applicable.

  2. Author contributions: MLN and JD carried out experiments and data analyses. YQZ and XS designed the study. JFY and XL acquired the data. HJG performed data analysis and interpretation. All authors have read and approved the manuscript.

  3. Conflict of interest: The authors state that there is no conflict of interest.

  4. Data availability statement: The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Received: 2022-03-22
Revised: 2023-04-26
Accepted: 2023-05-06
Published Online: 2023-07-14

© 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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  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
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  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
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  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-2023-0726
Keywords for this article
circ_0000285; neuroblastoma; miR-582-3p; Wnt/β-catenin
Creative Commons
BY 4.0

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  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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