Startseite SELENBP1 inhibits progression of colorectal cancer by suppressing epithelial–mesenchymal transition
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SELENBP1 inhibits progression of colorectal cancer by suppressing epithelial–mesenchymal transition

  • Xiaotian Zhang , Runqi Hong , Lanxin Bei , Zhiqing Hu , Ximin Yang , Tao Song EMAIL logo , Liang Chen , He Meng , Gengming Niu und Chongwei Ke
Veröffentlicht/Copyright: 1. September 2022
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Open Medicine
Aus der Zeitschrift Open Medicine Band 17 Heft 1

Abstract

Selenium-binding protein 1 (SELENBP1) is frequently dysregulated in various malignancies including colorectal cancer (CRC); however, its roles in progression of CRCs and the underlying mechanism remain to be elucidated. In this study, we compared the expression of SELENBP1 between CRCs and colorectal normal tissues (NTs), as well as between primary and metastatic CRCs; we determined the association between SELENBP1 expression and CRC patient prognoses; we conducted both in vitro and in vivo experiments to explore the functional roles of SELENBP1 in CRC progression; and we characterized the potential underlying mechanisms associated with SELENBP1 activities. We found that the expression of SELENBP1 was significantly and consistently decreased in CRCs than that in adjacent NTs, while significantly and frequently decreased in metastatic than primary CRCs. High expression of SELENBP1 was an independent predictor of favorable prognoses in CRC patients. Overexpression of SELENBP1 suppressed, while silencing of SELENBP1 promoted cell proliferation, migration and invasion, and in vivo tumorigenesis of CRC. Mechanically, SELENBP1 may suppress CRC progression by inhibiting the epithelial–mesenchymal transition.

Keywords: selenium-binding protein 1; colorectal cancer; progression; tumorigenesis; epithelial–mesenchymal transition

1 Introduction

Colorectal cancer (CRC) is one of the most prevalent and fatal malignancies worldwide [1]. Radical surgery alone or in combination with adjuvant therapies has been effective in CRC patients at earlier stages; however, many of these patients experience recurrence within the next several years, while approximately 20% of CRC patients already have metastatic diseases at the time of diagnosis [2]. Although some contributing events have been identified for the progression of CRCs [3,4,5], our understanding of this process is still limited. Characterizing the underlying mechanisms of CRC progression and identifying novel biomarkers are therefore urgently needed.

Selenium-binding protein 1 (SELENBP1), one of the proteins that directly bind to selenium, is encoded by a gene located at 1q21.3 near the epidermal differentiation complex (EDC), which is closely related to terminal differentiation of the human epidermis [6]. Previous evidence showed that SELENBP1 participated in a variety of physiological processes, such as cell differentiation and maturation [7,8], protein transport and degradation [9,10], and H2S biosynthesis and adipogenesis [11], while mutations in SELENBP1 caused dysregulated methanethiol oxidation and extraoral halitosis [12]. As a binding partner for selenium, SELENBP1 may mediate the connection between selenium deficiency and carcinogenesis [13]. Actually, suppression of SELENBP1 has been associated with carcinogenesis and disease progression in CRC [7,14] and many other malignancies [15,16,17,18,19,20,21,22]; however, the underlying mechanism is not fully elucidated. Besides, the emerging open access datasets in recent years necessitate further validation of these pilot studies.

In the current study, we utilized data from the Human Protein Atlas (HPA), the Gene Expression Omnibus (GEO), and The Cancer Genome Atlas (TCGA) to determine SELENBP1 expression under physiological conditions and compare the expression of SELENBP1 between CRCs and colorectal normal tissues (NTs), as well as between primary and metastatic CRCs. We also used TCGA Colon Adenocarcinoma (COAD) and Rectum Adenocarcinoma (READ) datasets (combined into the TCGA cohort), and a tissue microarray cohort [the tissue microarray (TMA) cohort] to validate the association between SELENBP1 expression and CRC patient prognoses. Furthermore, we conducted both in vitro and in vivo experiments to explore the functional roles of SELENBP1 in CRC progression. Finally, we characterized the potential underlying mechanisms associated with SELENBP1 activities.

2 Materials and methods

2.1 Access to public datasets

HPA is an open access program that integrates various omics data to map all the human proteins in cells, tissues, and organs (www.proteinatlas.org) [23]. We used HPA to predict SELENBP1 expression under both physiological and pathological conditions. We then searched CRC datasets that compared gene transcription between normal colorectal mucosae and CRCs, or between primary and metastatic CRCs in the GEO database [24], as described in our previously report [25]. Eleven datasets were retrieved to compare SELENBP1 expression between NTs and CRCs, including GSE3629 [26], GSE28000 [27], GSE31279 [28], GSE37182 [29], GSE44861 [30], GSE87221 [31], GSE90627 [32], GSE106582 (unpublished data), GSE6988 [33], GSE21510 [34], and GSE62322 [35]. We also downloaded the TCGA COAD and READ datasets from UCSC Xena (https://xenabrowser.net/heatmap/) and combined them into one CRC dataset[*]. These 12 datasets included 767 NTs and 1224 CRCs. In addition, 15 datasets containing both primary and metastatic CRCs were retrieved from GEO (GSE6988 [33], GSE18105 [36], GSE21510 [34], GSE27854 [37], GSE28722 [38], GSE29623 [39], GSE38832 [40], GSE40967 [41], GSE41568 [42], GSE51244 (unpublished data), GSE62322 [35], GSE71222 [43], GSE81582 [44], GSE81986 [45], and GSE68648 [46]), which included 1,534 primary and 667 metastatic CRCs.

2.2 Gene set enrichment analysis (GSEA)

To explore the potential mechanisms of SELENBP1 in CRC progression, a GSEA was employed using the combined TCGA COAD and READ datasets [47,48]. Gene sets with a false discovery rate q-value of <0.25 and a nominal p value of <0.05 were regarded as significantly enriched.

2.3 CRC TMA and immunohistochemical (IHC) staining

This study was approved by the Institutional Ethics Committee at Shanghai Fifth People’s Hospital and adhered to the principles listed in the Declaration of Helsinki. Informed consent was obtained from all patients. Collection of clinical samples and preparation of TMA were performed as described previously [25]. Detailed clinical variables of the TMA cohort, such as patient age and sex, are listed in Table 1. IHC staining and review of slides were performed as described in our previous report [49], using an immunoreactive score (IRS) system [50]. An anti-SELENBP1 rabbit polyclonal antibody was purchased from Sigma-Aldrich (HPA005741; St. Louis, MO, USA) and used at a dilution of 1:50.

Table 1

Clinical significance of SELENBP1 expression in colon cancers (n = 100)

Clinicopathological features Cases (N) SELENBP1 expression
Low High P-value
Sex
 Male 59 35 24
 Female 41 28 13 0.405
Age
 <67 43 26 17
 ≥67 57 37 20 0.680
Histological grade
 G2 70 41 29
 G3 30 22 8 0.182
Tumor size (cm)
 <7 70 38 32
 ≥7 30 25 5 0.007
Lymph node metastasis (n)
 <3 84 50 34
 ≥3 16 13 3 0.157
pStage
 I/II 51 32 19
 III/IV 49 31 18 1.000
Gross typing
 Protruded 20 15 5
 Ulcerative 47 24 23
 Infiltrative 25 16 9
 Colloid 8 8 0 0.030
Location
 Transverse colon 7 5 2
 Left colon 42 26 16
 Right colon 51 32 19 0.904

2.4 Cell culture

A colon epithelial cell line fetal human cells (FHC) and four human CRC cell lines COLO205, COLO320DM, HCT116, and HT15 were obtained from the Cell Bank of Chinese Academy of Sciences (Shanghai, China). Cells were cultured in Dulbecco′s Modified Eagle′s Medium (DMEM) supplemented with 10% fetal bovine serum (FBS), 100 µg/mL of penicillin, and 100 mg/mL of streptomycin at 37°C with 5% CO2 in a humidified incubator (Thermo, Waltham, MA, USA) [25].

2.5 Cell viability assays

A Cell Counting Kit-8 (CCK-8) assay was conducted as described in our previously study [25]. Briefly, stably transfected HCT15 and HCT116 cells (5 × 103 cells per well) were seeded in 96-well plates and cultivated overnight. Then, cells were serum-starved for another 24 h and 10% CCK-8 reagent (v/v in serum-free DMEM) was added to each well of the 96-well plates at 24, 48, 72, or 96 h. The absorbance at 450 nm was measured 1 h after addition of the reagent.

2.6 Cell proliferation assays

An EdU incorporation assay was performed using an EdU kit (C0071; Beyotime, Nantong, China) according to the manufacturer’s recommendation. Briefly, stably transfected HCT15 and HCT116 cells (1 × 105 cells/mL) were seeded in 6-well plates and cultivated for 24–48 h, and then 10 μM/L EDU was added to cells. After 2 h, cells were fixed with 4% paraformaldehyde, permeabilized by 0.3% Triton X-100, and stained with the Click Additive Solution in the kit. Cell nuclei were stained with Hoechst 33342 for 10 min. The number of EdU-positive cells was counted under a microscope in five random fields. All assays were independently performed in triplicate.

2.7 Transwell migration and invasion assays

These assays were conducted as described in our previous report [51]. Briefly, cells (4 × 105 cells/mL) were seeded in serum-free DMEM in the top chamber of a Transwell® insert coated without (migration assay) or with (invasion assay) Matrigel. The medium containing 20% FBS in the lower chamber served as a chemoattractant. After incubation for 24 h at 37°C, the cells on the top side of the membrane were removed with a cotton swab and those on the bottom side were fixed with methanol for 20 min and then stained with crystal violet (0.1% in PBS) for 15 min. Five randomly selected fields per well were photographed, and the numbers of migrated cells were enumerated.

2.8 Protein extraction and western blotting (WB)

Proteins were extracted and plotted as previously described [51]. Primary and secondary antibodies used are listed in Table S1. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) (1:2,000 dilutions, rabbit anti-human; Beyotime Biotechnology, Shanghai, China) served as a loading control.

2.9 Ectopic expression or silencing of SELENBP1

Lentiviral plasmids expressing SELENBP1 (using GV367 vector), short hairpin RNA oligos of SELENBP1 (using GV248 vector), or respective controls were constructed by Shanghai Genechem Co., Ltd (Shanghai, China). The target sequences were CACTTATATGTATGGGACT (shSELENBP1) and TTCTCCGAACGTGTCACGT (scramble control). Transfection and construction of stable transfectants were performed as previously reported [25].

2.10 Animal experiments

Female athymic BALB/c nude mice of 6–8 weeks old were purchased from Charles River Laboratories (Beijing, China) and maintained in the Animal Experimental Facility of Normal University of Eastern China in a pathogen-free environment. HCT-15 cells (2 × 106/mouse) stably expressing SELENBP1 or the vector were seeded subcutaneously into flanks of mice (n = 5 per group) and tumor growth was closely monitored twice a week (tumor volume = length × width2 × 3.14/6). One month after inoculation, tumors were isolated and weighed (g), and growth curves were drawn. Tumor samples were prepared for further use. All experiment procedures were conducted according to the Animal Care and Use guideline and were approved by the Animal Care Committee at the Normal University of Eastern China.

2.11 Immunofluorescence (IF) staining

The TMA was stained with antibodies against SELENBP1, E-cadherin, and N-cadherin by Wuhan Servicebio Technology Co., Ltd (Wuhan, China) according to their standard protocols as previously described [52] and signals were quantified by the same company using procedures recommended by Stephan et al. [53].

2.12 Statistical analyses

Analyses were performed using GraphPad Prism7 (GraphPad, San Diego, CA, USA), Microsoft Excel 2010 (Microsoft, Redmond, WA, USA), and SPSS statistical software for Windows, version 22 (SPSS, Chicago, IL, USA). Independent sample t-test or one-way analysis of variance was performed for comparisons of continuous variables. Nonparametric tests were performed if data did not follow a normal distribution. Pearson’s χ 2 test and Fisher’s exact test were used for categorical comparisons. IRSs of SELENBP1 staining in CRCs and paired NTs were compared using the Wilcoxon rank-sum test. Survival analyses were conducted using the Kaplan–Meier method and log-rank test. Univariate and multivariate survival analyses were conducted with a Cox proportional hazards regression model. Statistical significance was defined as a value of p < 0.05. All statistical tests were two-sided.

  1. Compliance with ethical standards: The study protocol was approved by the Institutional Ethics Committee at the Fifth People’s Hospital of Shanghai, Fudan University (Ethical Approval Form no. 2017-097) and adhered to the principles of the Declaration of Helsinki. Written informed consent was obtained from each patient prior to tissue collection for experimentation.

3 Results

3.1 SELENBP1 expression was suppressed during CRC metastasis

The HPA database was used to examine SELENBP1 expression profiles under physiological conditions. As shown in Figure S1, the mRNA and protein expressions of SELENBP1 were most abundant in the colon, rectum, and thyroid, followed by liver, lung, and appendix, suggesting its functional relevance in these organs. To further elucidate the roles of SELENBP1 in CRC progression, 12 and 15 public datasets were used to examine the differences of SELENBP1 mRNA expressions between CRCs and colorectal NTs, and between primary and metastatic CRCs, respectively. The mRNA expression of SELENBP1 was dramatically decreased in CRCs compared to that in NTs (all, p < 0.01; Figure 1a–l). In addition, SELENBP1 expression was significantly lower in metastatic than in primary CRCs in seven out of 15 datasets (Figure 2a–o). Meanwhile, no significant difference in SELENBP1 expression was observed between NTs and polyps (Figure 2o). To validate these observations, we first examined the protein content of SELENBP1 in 18 paired CRC samples. As shown in Figure 3a and b, SELENBP1 expression was significantly decreased in most CRCs compared to their matched NTs. Then, IHC staining of SELENBP1 in colorectal NTs and CRCs in the HPA database indicated that SELENBP1 was distributed diffusively in the nuclei and cytoplasm and on the membrane, and its expression was significantly lower in tumor cells than in glandular cells (p < 0.0001; Figure 3c and d). These observations were further confirmed by IHC staining of SELENBP1 in 100 CRCs and 80 NTs, which showed that the intensity of SELENBP1 expression was much less in tumors than in adjacent NTs (p < 0.0001; Figure 3e and f). Taken together, these results suggest that suppression of SELENBP1 is common during carcinogenesis and frequent during the metastasis of CRCs.

Figure 1 SELENBP1 expression is consistently downregulated in CRCs. The expression of SELENBP1 was compared between colorectal NTs and CRCs in 12 datasets from the TCGA and GEO databases (a–l). ** p < 0.01; **** p < 0.0001 vs the control group.
Figure 1

SELENBP1 expression is consistently downregulated in CRCs. The expression of SELENBP1 was compared between colorectal NTs and CRCs in 12 datasets from the TCGA and GEO databases (a–l). ** p < 0.01; **** p < 0.0001 vs the control group.

Figure 2 SELENBP1 expression is frequently downregulated in metastatic CRCs. The expression of SELENBP1 was compared between primary and metastatic CRCs in 15 datasets (a–o), and among different stages of colorectal tumors in one dataset (o). Abbreviation: NS, nonsignificant. * p < 0.05; ** p < 0.01; **** p < 0.0001 vs the control group.
Figure 2

SELENBP1 expression is frequently downregulated in metastatic CRCs. The expression of SELENBP1 was compared between primary and metastatic CRCs in 15 datasets (a–o), and among different stages of colorectal tumors in one dataset (o). Abbreviation: NS, nonsignificant. * p < 0.05; ** p < 0.01; **** p < 0.0001 vs the control group.

Figure 3 Suppressed expression of SELENBP1 in CRCs is associated with poor patient survival. The expression of SELENBP1 protein was detected by WB in 18 pairs of NTs and CRCs (a) and quantified by gray-scale analysis (b). Immunohistochemistry data of SELENBP1 were downloaded from the HPA database and compared between glandular tissues and CRCs using an IRS method (c and d). A TMA consisting of 100 CRCs and 80 NTs was stained with an anti-SELENBP1 antibody (d, 40×) and the IRS was evaluated (f). Kaplan–Meier plots were drawn for OS of patients in the TMA cohort (g) and TCGA cohort (h). Patients were stratified into low and high SELENBP1 expression groups according to SELENBP1 mRNA expression in the TCGA cohort and IRS of SELENBP1 in the TMA cohort (<median vs ≥median). Values of p were obtained using the log-rank test. Censored data are indicated by the + symbol. *** p < 0.001; **** p < 0.0001 vs the control group.
Figure 3

Suppressed expression of SELENBP1 in CRCs is associated with poor patient survival. The expression of SELENBP1 protein was detected by WB in 18 pairs of NTs and CRCs (a) and quantified by gray-scale analysis (b). Immunohistochemistry data of SELENBP1 were downloaded from the HPA database and compared between glandular tissues and CRCs using an IRS method (c and d). A TMA consisting of 100 CRCs and 80 NTs was stained with an anti-SELENBP1 antibody (d, 40×) and the IRS was evaluated (f). Kaplan–Meier plots were drawn for OS of patients in the TMA cohort (g) and TCGA cohort (h). Patients were stratified into low and high SELENBP1 expression groups according to SELENBP1 mRNA expression in the TCGA cohort and IRS of SELENBP1 in the TMA cohort (<median vs ≥median). Values of p were obtained using the log-rank test. Censored data are indicated by the + symbol. *** p < 0.001; **** p < 0.0001 vs the control group.

3.2 Suppression of SELENBP1 in CRCs correlated with an unfavorable prognosis

To test whether SELENBP1 suppression in CRCs contributed to increased tumor invasiveness, we analyzed the relationships between SELENBP1 expression and clinicopathological variables. As shown in Table 1, SELENBP1 expression was significantly associated with tumor size and gross typing.

Next, we determined the relationship between SELENBP1 expression and patient outcomes in the tissue microarray cohort. Kaplan–Meier survival analysis revealed that patients with high SELENBP1 expression had a better overall survival (OS) than those with low expression (Figure 3g). Using multivariate analysis with a Cox proportional hazards model, high SELENBP1 expression was significantly associated with a better OS, after adjustment for age, tumor size, lymph node metastasis number, and TNM stage (Table 2). Similarly, a Kaplan–Meier survival analysis using the combined TCGA COAD and READ dataset also revealed that high SELENBP1 expression was correlated with a better OS in patients (Figure 3h). Along with those already reported in the literature [7,14], these findings clearly indicate that SELENBP1 is a prognostic marker in CRCs and its abundance in tumors could predict favorable prognoses.

Table 2

Univariate and multivariate Cox proportional hazard models for overall survival in CRC patients (n = 100)

Clinicopathological features Univariate analysis Multivariate analysis
HR [95% CIs] P-value HR [95% CIs] P-value
Sex
 Male 1 [Reference]
 Female 0.78[0.44–1.38] 0.389
Age
 <67 1 [Reference] 1 [Reference]
 ≥67 1.90[1.05–3.44] 0.033 2.90[1.52–5.53] 0.001
Histological grade
 G2 1 [Reference]
 G3 1.40[0.78–2.50] 0.260
Tumor size (cm)
 <7 1 [Reference] 1 [Reference]
 ≥7 1.79[1.01–3.16] 0.045 1.64[0.90–3.01] 0.110
Lymph node metastasis (n)
 <3 1 [Reference] 0.000
 ≥3 4.69[2.50–8.77] 4.30[1.99–9.31] 0.000
pStage
 I/II 1 [Reference] 1 [Reference] 0.068
 III/IV 1.82[1.04–3.19] 0.035 1.92[0.95–3.87]
Gross typing
 Protruded 1 [Reference]
 Ulcerative 0.80[0.39–1.65] 0.547
 Infiltrative 0.83[0.37–1.85] 0.650
 Colloid 1.23[0.43–3.54] 0.704
Tumor location
 Left colon 1 [Reference] 0.821
 Right colon 0.94[0.53–1.66]
 Transverse colon 1.13[0.39–3.28] 0.822
SELENBP1 expression
 Low 1 [Reference] 1 [Reference]
 High 0.42[0.23–0.76] 0.004 0.34[0.17–0.68] 0.002

CI, confidence interval; HR, hazard ratio.

3.3 SELENBP1 inhibited CRC cell proliferation, migration, and invasion

To investigate the in vitro activities of SELENBP1 in CRC, we first compared its expression in a fetal colon cell line FHC and four CRC cell lines. As shown in Figure 4a, the expression of SELENBP1 was decreased in CRC cell lines compared to that in FHC. We then induced or knocked down the expression of SELENBP1 in HCT-15 and HCT-116 cells using lentiviruses (Figure 4b) and carried out CCK-8, Edu, Transwell® migration, and invasion assays. The results showed that overexpression of SELENBP1 inhibited while knocking down of SELENBP1 promoted cell viability (Figure 4c), proliferation (Figure 4d), migration (Figure 4e), and invasion (Figure 4f) in both cell lines. Taken together, these observations indicate that SELENBP1 has tumor-suppressive roles in vitro.

Figure 4 SELENBP1 inhibits cell proliferation, migration, and invasion of cultured CRC cells. The expression of SELENBP1 protein was determined in a fetal colon cell line FHC and several CRC cell lines (a). SELENBP1 was inducibly overexpressed and silenced in HCT-15 and HCT-116 cells (b). The in vitro effects of SELENBP1 on cell proliferation, migration, and invasion were evaluated by CCK-8 (c), Edu (d), Transwell migration (e), and invasion (f) assays, respectively. Experiments were repeated independently at least three times, and data are expressed as mean ± SEM (n = 3). *p < 0.05; ** p < 0.01; *** p < 0.001; **** p < 0.0001 vs the control group; #### p < 0.0001 vs the control group (for shSELENBP1 vs scramble in the CCK-8 assays only).
Figure 4

SELENBP1 inhibits cell proliferation, migration, and invasion of cultured CRC cells. The expression of SELENBP1 protein was determined in a fetal colon cell line FHC and several CRC cell lines (a). SELENBP1 was inducibly overexpressed and silenced in HCT-15 and HCT-116 cells (b). The in vitro effects of SELENBP1 on cell proliferation, migration, and invasion were evaluated by CCK-8 (c), Edu (d), Transwell migration (e), and invasion (f) assays, respectively. Experiments were repeated independently at least three times, and data are expressed as mean ± SEM (n = 3). *p < 0.05; ** p < 0.01; *** p < 0.001; **** p < 0.0001 vs the control group; #### p < 0.0001 vs the control group (for shSELENBP1 vs scramble in the CCK-8 assays only).

3.4 SELENBP1 may inhibit CRC progression by modulating epithelial–mesenchymal transition (EMT)

To characterize the potential mechanism of SELENBP1 in inhibiting tumor progression, we first used the combined TCGA COAD and READ dataset to conduct a GSEA [54] and found that high SELENBP1 expression was negatively correlated with the hallmark EMT gene set (Figure S2a). Subsequent gene–gene correlation analyses using the same dataset further confirmed that the expression of SELENBP1 was positively correlated with that of CDH1 but negatively correlated with that of CDH2 and several other EMT markers and transcription factors both in NTs (Figure S2b) and CRCs (Figure S2c). To further confirm these observations, we investigated the relationship between SELENBP1 and E-cadherin or N-cadherin in NTs and CRCs by staining the tissue microarray with IF. As shown in Figure 5, SELENBP1 was located in colon mucosae and its expression correlated with that of E-cadherin in both NTs (A) and CRCs (B). By contrast, no consistent trend was observed between SELENBP1 and N-cadherin, as the expression of N-cad was diffusive in these samples. In addition, overexpression of SELENBP1 increased the expression of E-cadherin but decreased that of N-cadherin, SNAIL, Vimentin, and Zeb-1 in CRC cell lines, which was reversed in cells with SELENBP1 silencing (Figure 5c). Taken together, these results indicate that SELENBP1 played an active role in antagonizing CRC progression via modulating EMT.

Figure 5 SELENBP1 inhibits EMT in CRC cells. A multicolor IF staining method was used to evaluate the expression and localization of SELENBP1 (red), E-cadherin (green), and N-cadherin (pink) in NTs (a) and CRCs (b), using the TMA cohort (scale bar = 50 μm). Percent of positive cells were calculated and correlation analyses were conducted based on the expression of these proteins (scatter plots on the right). Total proteins were extracted from HCT-15 and HCT-116 cells stably infected with SELENBP1, shSELENBP1, or relative control lentiviruses and were used to evaluate the expression of EMT markers and transcription factors by WB with GAPDH as a loading control (c). Experiments were repeated independently at least three times, and data are expressed as mean ± SEM (n = 3). *p < 0.05; **p < 0.01; ***p < 0.001; ****p < 0.0001 vs the control group.
Figure 5

SELENBP1 inhibits EMT in CRC cells. A multicolor IF staining method was used to evaluate the expression and localization of SELENBP1 (red), E-cadherin (green), and N-cadherin (pink) in NTs (a) and CRCs (b), using the TMA cohort (scale bar = 50 μm). Percent of positive cells were calculated and correlation analyses were conducted based on the expression of these proteins (scatter plots on the right). Total proteins were extracted from HCT-15 and HCT-116 cells stably infected with SELENBP1, shSELENBP1, or relative control lentiviruses and were used to evaluate the expression of EMT markers and transcription factors by WB with GAPDH as a loading control (c). Experiments were repeated independently at least three times, and data are expressed as mean ± SEM (n = 3). *p < 0.05; **p < 0.01; ***p < 0.001; ****p < 0.0001 vs the control group.

3.5 SELENBP1 inhibited in vivo tumorigenesis

To confirm whether SELENBP1 suppress CRC tumorigenesis in vivo, we inoculated HCT-15 cells that stably overexpressed SELENBP1 or the control subcutaneously into the flanks of nude mice (n = 5/group). As shown in Figure 6, SELENBP1 significantly inhibited tumor growth and tumor weight (a–c). Similar to the in vitro observations, SELENBP1 promoted E-cadherin but inhibited N-cadherin expression in vivo (Figure 6d).

Figure 6 SELENBP1 inhibits tumorigenesis of CRC cells. HCT-15 cells stably overexpressing SELENBP1 or vector were inoculated subcutaneously into the right flank of nude mice (n = 5 per group). Tumor growth was monitored twice a week (a). On Day 32 after inoculation, tumors were removed, photographed (b), and weighed (c). Formalin-fixed and paraffin-embedded tumor blocks were cut into 5 μm sections and stained with respective antibodies against SELENBP1, E-cadherin, and N-cadherin (d). * p < 0.05 vs the control group.
Figure 6

SELENBP1 inhibits tumorigenesis of CRC cells. HCT-15 cells stably overexpressing SELENBP1 or vector were inoculated subcutaneously into the right flank of nude mice (n = 5 per group). Tumor growth was monitored twice a week (a). On Day 32 after inoculation, tumors were removed, photographed (b), and weighed (c). Formalin-fixed and paraffin-embedded tumor blocks were cut into 5 μm sections and stained with respective antibodies against SELENBP1, E-cadherin, and N-cadherin (d). * p < 0.05 vs the control group.

4 Discussion

Although rapid progress has been made in recent years regarding the evolvement of CRCs, it is still incredibly challenging to interrupt this process. Identifying events that lead to progression of this malignancy could be beneficial, both clinically and scientifically. In the current study, we found that suppression of SELENBP1 might be such an event.

SELENBP1 was highly abundant in the colon and rectum under physiological conditions, but consistently suppressed in CRCs across different patient cohorts. A more remarkable suppression was observed in metastatic CRCs in some patient cohorts; in contrast, the expression of SELENBP1 was similar between NTs and polyps. Besides, suppression of SELENBP1 was correlated with increased tumor size and unfavorable patient prognosis, which validated the results from previous studies [7,14,55,56]. These observations, along with those from studies of other malignancies [15,16,17,22,57], suggest that suppression of SELENBP1 might be a common event during carcinogenesis across different malignancies, although the underlying mechanisms may vary.

Being a selenium-binding protein, SELENBP1 may duplicate some of the tumor-suppressive roles of selenium (Se), which is an essential trace mineral indispensable to human health [58]. In the form of selenocysteine, selenium constitutes the catalytic center of selenoproteins, such as glutathione peroxidases, iodothyronine deiodinases, and thioredoxin reductases. Many of these selenoproteins function as oxidoreductases that help maintain homeostasis of the internal environment by curbing the propagation of oxidative damages [59]. As such, selenium is regarded as an antioxidant, while inadequate selenium intake has been associated with increased cancer incidence and mortality [60]. Although initial clinical trials supported the use of dietary selenium replenishment in reducing both the incidence and mortality of cancer [61,62], later studies revealed that high selenium intake did not bring benefit, or even brought harmful effects [63,64,65]. The inconsistent efficacy of selenium as a candidate anticancer agent may in part be ascribed to its complex interactions with selenoproteins and selenium-binding proteins [9,13,17,55]. In the current study, we demonstrated that SELENBP1 has tumor-suppressive roles both in vitro and in vivo, in consistent with observations from other researchers [21,22,56]. Thus, the contribution of SELENBP1 should be considered in future selenium-oriented studies.

One intriguing observation was that SELENBP1 may inhibit EMT, which is one of the key processes mediating tumor metastasis [66]. The regulatory involvement of SELENBP1 in EMT has been reported in hepatobiliary tumors [22,67] but remains to be elucidated in CRC and other malignancies. Our investigation demonstrated that SELENBP1 induced the expression of E-cadherin and inhibited that of N-cadherin, which partly explains its suppressive roles during metastasis of CRC. The SELENBP1 gene located at chromosome 1q21.3 near the EDC, which contains genes that encode the S100A family members [6]. Amplification of 1q21.3, especially those fragments that encode the S100A family members, has been associated with tumor progression [68], while many of these family members are closely related to EMT and tumor metastasis [69–72]. Using the GEPIA database (http://gepia.cancer-pku.cn/), we found that the expression of SELENBP1 was negatively correlated with those of S100A1, S100A2, S100A3, S100A4, S100A7, S100A8, S100A9, S100A11, S100A12, and S100A13 in the TCGA COAD and READ datasets (data not shown). Thus, we surmise that SELENBP1 may interact with EDC genes to suppress EMT in CRCs.

Although this study presents some findings that are clinically and scientifically meaningful, there are some inherent limitations. First, we did not characterize the potential interaction of SELENBP1 with selenium and selenoproteins in CRC. Second, we did not observe a significant correlation between SELENBP1 expression and TNM staging in our patient cohort, maybe due to the sample size and patient heterogeneity. In addition, we only confirmed the in vivo tumor-suppressive activity of SELENBP1 using the subcutaneous xenograft model, since the cell lines we used failed to derive liver or lung metastasis. Finally, although we uncovered the inhibitory impact of SELENBP1 on EMT of CRCs, we did not further elaborate the underlying mechanism in the current study. These limitations should be addressed in future studies.

5 Conclusion

This study confirmed the active involvement of SELENBP1 in tumor progression of CRCs via modulating the EMT. SELENBP1 is therefore a candidate tumor suppressor, which should be further investigated in future studies.

Abbreviations

CRC

colorectal cancer

EMT

epithelial–mesenchymal transition

GEO

Gene Expression Omnibus

GSEA

gene set enrichment analysis

HPA

Human Protein Atlas

IHC

immunohistochemical

SELENBP1

selenium-binding protein 1

TCGA

The Cancer Genome Atlas

TCGA-COAD

The Cancer Genome Atlas Colorectal Adenocarcinoma

TMA

tissue microarray

# These authors contributed equally to this work.

tel: +86-21-24289021, fax: +86-21-64300477

Acknowledgments

We greatly appreciate the technological help from the Department of Pathology at our hospital for the IHC staining and data analysis. We also appreciate the valuable work done by Dr. Jun Hou at Zhongshan Hospital (Shanghai, China) for her interpretation of the IHC staining. The authors give special thanks to Shuyu Zheng from Shanghai Jiao Tong University, School of Medicine, for her help in proofreading the manuscript.

  1. Funding information: This work was supported by the Medical System of Shanghai Minhang District (grant numbers 2017MWDXK01 and 2020MWDXK02) and the Shanghai Minhang District Science and Technology Commission (grant numbers 2017MHZ02, 2019MHZ054, 2020MHZ080, and 2021MHZ038). The funding sources were not involved in the study design; in the collection, analysis, or interpretation of data; in the writing of the report; or in the decision to submit the manuscript for publication.

  2. Author contributions: Chongwei Ke, Gengming Niu, and Tao Song: study design; Xiaotian Zhang, Runqi Hong, Lanxin Bei, and Ximin Yang: conducted the experiments, Zhiqing Hu, Liang Chen, and He Meng: data analyses; Xiaotian Zhang and Gengming Niu: wrote the manuscript; Chongwei Ke and Gengming Niu: revised the manuscript. All authors read and approved the final article.

  3. Conflict of interest: The authors declare that they have no conflict of interest.

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

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Received: 2021-11-16
Revised: 2022-06-19
Accepted: 2022-07-11
Published Online: 2022-09-01

© 2022 Xiaotian Zhang et al., published by De Gruyter

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

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  73. A 16-gene signature associated with homologous recombination deficiency for prognosis prediction in patients with triple-negative breast cancer
  74. Lidocaine ameliorates chronic constriction injury-induced neuropathic pain through regulating M1/M2 microglia polarization
  75. MicroRNA 322-5p reduced neuronal inflammation via the TLR4/TRAF6/NF-κB axis in a rat epilepsy model
  76. miR-1273h-5p suppresses CXCL12 expression and inhibits gastric cancer cell invasion and metastasis
  77. Clinical characteristics of pneumonia patients of long course of illness infected with SARS-CoV-2
  78. circRNF20 aggravates the malignancy of retinoblastoma depending on the regulation of miR-132-3p/PAX6 axis
  79. Linezolid for resistant Gram-positive bacterial infections in children under 12 years: A meta-analysis
  80. Rack1 regulates pro-inflammatory cytokines by NF-κB in diabetic nephropathy
  81. Comprehensive analysis of molecular mechanism and a novel prognostic signature based on small nuclear RNA biomarkers in gastric cancer patients
  82. Smog and risk of maternal and fetal birth outcomes: A retrospective study in Baoding, China
  83. Let-7i-3p inhibits the cell cycle, proliferation, invasion, and migration of colorectal cancer cells via downregulating CCND1
  84. β2-Adrenergic receptor expression in subchondral bone of patients with varus knee osteoarthritis
  85. Possible impact of COVID-19 pandemic and lockdown on suicide behavior among patients in Southeast Serbia
  86. In vitro antimicrobial activity of ozonated oil in liposome eyedrop against multidrug-resistant bacteria
  87. Potential biomarkers for inflammatory response in acute lung injury
  88. A low serum uric acid concentration predicts a poor prognosis in adult patients with candidemia
  89. Antitumor activity of recombinant oncolytic vaccinia virus with human IL2
  90. ALKBH5 inhibits TNF-α-induced apoptosis of HUVECs through Bcl-2 pathway
  91. Risk prediction of cardiovascular disease using machine learning classifiers
  92. Value of ultrasonography parameters in diagnosing polycystic ovary syndrome
  93. Bioinformatics analysis reveals three key genes and four survival genes associated with youth-onset NSCLC
  94. Identification of autophagy-related biomarkers in patients with pulmonary arterial hypertension based on bioinformatics analysis
  95. Protective effects of glaucocalyxin A on the airway of asthmatic mice
  96. Overexpression of miR-100-5p inhibits papillary thyroid cancer progression via targeting FZD8
  97. Bioinformatics-based analysis of SUMOylation-related genes in hepatocellular carcinoma reveals a role of upregulated SAE1 in promoting cell proliferation
  98. Effectiveness and clinical benefits of new anti-diabetic drugs: A real life experience
  99. Identification of osteoporosis based on gene biomarkers using support vector machine
  100. Tanshinone IIA reverses oxaliplatin resistance in colorectal cancer through microRNA-30b-5p/AVEN axis
  101. miR-212-5p inhibits nasopharyngeal carcinoma progression by targeting METTL3
  102. Association of ST-T changes with all-cause mortality among patients with peripheral T-cell lymphomas
  103. LINC00665/miRNAs axis-mediated collagen type XI alpha 1 correlates with immune infiltration and malignant phenotypes in lung adenocarcinoma
  104. The perinatal factors that influence the excretion of fecal calprotectin in premature-born children
  105. Effect of femoral head necrosis cystic area on femoral head collapse and stress distribution in femoral head: A clinical and finite element study
  106. Does the use of 3D-printed cones give a chance to postpone the use of megaprostheses in patients with large bone defects in the knee joint?
  107. lncRNA HAGLR modulates myocardial ischemia–reperfusion injury in mice through regulating miR-133a-3p/MAPK1 axis
  108. Protective effect of ghrelin on intestinal I/R injury in rats
  109. In vivo knee kinematics of an innovative prosthesis design
  110. Relationship between the height of fibular head and the incidence and severity of knee osteoarthritis
  111. lncRNA WT1-AS attenuates hypoxia/ischemia-induced neuronal injury during cerebral ischemic stroke via miR-186-5p/XIAP axis
  112. Correlation of cardiac troponin T and APACHE III score with all-cause in-hospital mortality in critically ill patients with acute pulmonary embolism
  113. LncRNA LINC01857 reduces metastasis and angiogenesis in breast cancer cells via regulating miR-2052/CENPQ axis
  114. Endothelial cell-specific molecule 1 (ESM1) promoted by transcription factor SPI1 acts as an oncogene to modulate the malignant phenotype of endometrial cancer
  115. SELENBP1 inhibits progression of colorectal cancer by suppressing epithelial–mesenchymal transition
  116. Visfatin is negatively associated with coronary artery lesions in subjects with impaired fasting glucose
  117. Treatment and outcomes of mechanical complications of acute myocardial infarction during the Covid-19 era: A comparison with the pre-Covid-19 period. A systematic review and meta-analysis
  118. Neonatal stroke surveillance study protocol in the United Kingdom and Republic of Ireland
  119. Oncogenic role of TWF2 in human tumors: A pan-cancer analysis
  120. Mean corpuscular hemoglobin predicts the length of hospital stay independent of severity classification in patients with acute pancreatitis
  121. Association of gallstone and polymorphisms of UGT1A1*27 and UGT1A1*28 in patients with hepatitis B virus-related liver failure
  122. TGF-β1 upregulates Sar1a expression and induces procollagen-I secretion in hypertrophic scarring fibroblasts
  123. Antisense lncRNA PCNA-AS1 promotes esophageal squamous cell carcinoma progression through the miR-2467-3p/PCNA axis
  124. NK-cell dysfunction of acute myeloid leukemia in relation to the renin–angiotensin system and neurotransmitter genes
  125. The effect of dilution with glucose and prolonged injection time on dexamethasone-induced perineal irritation – A randomized controlled trial
  126. miR-146-5p restrains calcification of vascular smooth muscle cells by suppressing TRAF6
  127. Role of lncRNA MIAT/miR-361-3p/CCAR2 in prostate cancer cells
  128. lncRNA NORAD promotes lung cancer progression by competitively binding to miR-28-3p with E2F2
  129. Noninvasive diagnosis of AIH/PBC overlap syndrome based on prediction models
  130. lncRNA FAM230B is highly expressed in colorectal cancer and suppresses the maturation of miR-1182 to increase cell proliferation
  131. circ-LIMK1 regulates cisplatin resistance in lung adenocarcinoma by targeting miR-512-5p/HMGA1 axis
  132. LncRNA SNHG3 promoted cell proliferation, migration, and metastasis of esophageal squamous cell carcinoma via regulating miR-151a-3p/PFN2 axis
  133. Risk perception and affective state on work exhaustion in obstetrics during the COVID-19 pandemic
  134. lncRNA-AC130710/miR-129-5p/mGluR1 axis promote migration and invasion by activating PKCα-MAPK signal pathway in melanoma
  135. SNRPB promotes cell cycle progression in thyroid carcinoma via inhibiting p53
  136. Xylooligosaccharides and aerobic training regulate metabolism and behavior in rats with streptozotocin-induced type 1 diabetes
  137. Serpin family A member 1 is an oncogene in glioma and its translation is enhanced by NAD(P)H quinone dehydrogenase 1 through RNA-binding activity
  138. Silencing of CPSF7 inhibits the proliferation, migration, and invasion of lung adenocarcinoma cells by blocking the AKT/mTOR signaling pathway
  139. Ultrasound-guided lumbar plexus block versus transversus abdominis plane block for analgesia in children with hip dislocation: A double-blind, randomized trial
  140. Relationship of plasma MBP and 8-oxo-dG with brain damage in preterm
  141. Identification of a novel necroptosis-associated miRNA signature for predicting the prognosis in head and neck squamous cell carcinoma
  142. Delayed femoral vein ligation reduces operative time and blood loss during hip disarticulation in patients with extremity tumors
  143. The expression of ASAP3 and NOTCH3 and the clinicopathological characteristics of adult glioma patients
  144. Longitudinal analysis of factors related to Helicobacter pylori infection in Chinese adults
  145. HOXA10 enhances cell proliferation and suppresses apoptosis in esophageal cancer via activating p38/ERK signaling pathway
  146. Meta-analysis of early-life antibiotic use and allergic rhinitis
  147. Marital status and its correlation with age, race, and gender in prognosis of tonsil squamous cell carcinomas
  148. HPV16 E6E7 up-regulates KIF2A expression by activating JNK/c-Jun signal, is beneficial to migration and invasion of cervical cancer cells
  149. Amino acid profiles in the tissue and serum of patients with liver cancer
  150. Pain in critically ill COVID-19 patients: An Italian retrospective study
  151. Immunohistochemical distribution of Bcl-2 and p53 apoptotic markers in acetamiprid-induced nephrotoxicity
  152. Estradiol pretreatment in GnRH antagonist protocol for IVF/ICSI treatment
  153. Long non-coding RNAs LINC00689 inhibits the apoptosis of human nucleus pulposus cells via miR-3127-5p/ATG7 axis-mediated autophagy
  154. The relationship between oxygen therapy, drug therapy, and COVID-19 mortality
  155. Monitoring hypertensive disorders in pregnancy to prevent preeclampsia in pregnant women of advanced maternal age: Trial mimicking with retrospective data
  156. SETD1A promotes the proliferation and glycolysis of nasopharyngeal carcinoma cells by activating the PI3K/Akt pathway
  157. The role of Shunaoxin pills in the treatment of chronic cerebral hypoperfusion and its main pharmacodynamic components
  158. TET3 governs malignant behaviors and unfavorable prognosis of esophageal squamous cell carcinoma by activating the PI3K/AKT/GSK3β/β-catenin pathway
  159. Associations between morphokinetic parameters of temporary-arrest embryos and the clinical prognosis in FET cycles
  160. Long noncoding RNA WT1-AS regulates trophoblast proliferation, migration, and invasion via the microRNA-186-5p/CADM2 axis
  161. The incidence of bronchiectasis in chronic obstructive pulmonary disease
  162. Integrated bioinformatics analysis shows integrin alpha 3 is a prognostic biomarker for pancreatic cancer
  163. Inhibition of miR-21 improves pulmonary vascular responses in bronchopulmonary dysplasia by targeting the DDAH1/ADMA/NO pathway
  164. Comparison of hospitalized patients with severe pneumonia caused by COVID-19 and influenza A (H7N9 and H1N1): A retrospective study from a designated hospital
  165. lncRNA ZFAS1 promotes intervertebral disc degeneration by upregulating AAK1
  166. Pathological characteristics of liver injury induced by N,N-dimethylformamide: From humans to animal models
  167. lncRNA ELFN1-AS1 enhances the progression of colon cancer by targeting miR-4270 to upregulate AURKB
  168. DARS-AS1 modulates cell proliferation and migration of gastric cancer cells by regulating miR-330-3p/NAT10 axis
  169. Dezocine inhibits cell proliferation, migration, and invasion by targeting CRABP2 in ovarian cancer
  170. MGST1 alleviates the oxidative stress of trophoblast cells induced by hypoxia/reoxygenation and promotes cell proliferation, migration, and invasion by activating the PI3K/AKT/mTOR pathway
  171. Bifidobacterium lactis Probio-M8 ameliorated the symptoms of type 2 diabetes mellitus mice by changing ileum FXR-CYP7A1
  172. circRNA DENND1B inhibits tumorigenicity of clear cell renal cell carcinoma via miR-122-5p/TIMP2 axis
  173. EphA3 targeted by miR-3666 contributes to melanoma malignancy via activating ERK1/2 and p38 MAPK pathways
  174. Pacemakers and methylprednisolone pulse therapy in immune-related myocarditis concomitant with complete heart block
  175. miRNA-130a-3p targets sphingosine-1-phosphate receptor 1 to activate the microglial and astrocytes and to promote neural injury under the high glucose condition
  176. Review Articles
  177. Current management of cancer pain in Italy: Expert opinion paper
  178. Hearing loss and brain disorders: A review of multiple pathologies
  179. The rationale for using low-molecular weight heparin in the therapy of symptomatic COVID-19 patients
  180. Amyotrophic lateral sclerosis and delayed onset muscle soreness in light of the impaired blink and stretch reflexes – watch out for Piezo2
  181. Interleukin-35 in autoimmune dermatoses: Current concepts
  182. Recent discoveries in microbiota dysbiosis, cholangiocytic factors, and models for studying the pathogenesis of primary sclerosing cholangitis
  183. Advantages of ketamine in pediatric anesthesia
  184. Congenital adrenal hyperplasia. Role of dentist in early diagnosis
  185. Migraine management: Non-pharmacological points for patients and health care professionals
  186. Atherogenic index of plasma and coronary artery disease: A systematic review
  187. Physiological and modulatory role of thioredoxins in the cellular function
  188. Case Reports
  189. Intrauterine Bakri balloon tamponade plus cervical cerclage for the prevention and treatment of postpartum haemorrhage in late pregnancy complicated with acute aortic dissection: Case series
  190. A case of successful pembrolizumab monotherapy in a patient with advanced lung adenocarcinoma: Use of multiple biomarkers in combination for clinical practice
  191. Unusual neurological manifestations of bilateral medial medullary infarction: A case report
  192. Atypical symptoms of malignant hyperthermia: A rare causative mutation in the RYR1 gene
  193. A case report of dermatomyositis with the missed diagnosis of non-small cell lung cancer and concurrence of pulmonary tuberculosis
  194. A rare case of endometrial polyp complicated with uterine inversion: A case report and clinical management
  195. Spontaneous rupturing of splenic artery aneurysm: Another reason for fatal syncope and shock (Case report and literature review)
  196. Fungal infection mimicking COVID-19 infection – A case report
  197. Concurrent aspergillosis and cystic pulmonary metastases in a patient with tongue squamous cell carcinoma
  198. Paraganglioma-induced inverted takotsubo-like cardiomyopathy leading to cardiogenic shock successfully treated with extracorporeal membrane oxygenation
  199. Lineage switch from lymphoma to myeloid neoplasms: First case series from a single institution
  200. Trismus during tracheal extubation as a complication of general anaesthesia – A case report
  201. Simultaneous treatment of a pubovesical fistula and lymph node metastasis secondary to multimodal treatment for prostate cancer: Case report and review of the literature
  202. Two case reports of skin vasculitis following the COVID-19 immunization
  203. Ureteroiliac fistula after oncological surgery: Case report and review of the literature
  204. Synchronous triple primary malignant tumours in the bladder, prostate, and lung harbouring TP53 and MEK1 mutations accompanied with severe cardiovascular diseases: A case report
  205. Huge mucinous cystic neoplasms with adhesion to the left colon: A case report and literature review
  206. Commentary
  207. Commentary on “Clinicopathological features of programmed cell death-ligand 1 expression in patients with oral squamous cell carcinoma”
  208. Rapid Communication
  209. COVID-19 fear, post-traumatic stress, growth, and the role of resilience
  210. Erratum
  211. Erratum to “Tollip promotes hepatocellular carcinoma progression via PI3K/AKT pathway”
  212. Erratum to “Effect of femoral head necrosis cystic area on femoral head collapse and stress distribution in femoral head: A clinical and finite element study”
  213. Erratum to “lncRNA NORAD promotes lung cancer progression by competitively binding to miR-28-3p with E2F2”
  214. Retraction
  215. Expression and role of ABIN1 in sepsis: In vitro and in vivo studies
  216. Retraction to “miR-519d downregulates LEP expression to inhibit preeclampsia development”
  217. Special Issue Computational Intelligence Methodologies Meets Recurrent Cancers - Part II
  218. Usefulness of close surveillance for rectal cancer patients after neoadjuvant chemoradiotherapy
https://doi.org/10.1515/med-2022-0532
Schlagwörter für diesen Artikel
selenium-binding protein 1; colorectal cancer; progression; tumorigenesis; epithelial–mesenchymal transition
Creative Commons
BY 4.0

Artikel in diesem Heft

  1. Research Articles
  2. AMBRA1 attenuates the proliferation of uveal melanoma cells
  3. A ceRNA network mediated by LINC00475 in papillary thyroid carcinoma
  4. Differences in complications between hepatitis B-related cirrhosis and alcohol-related cirrhosis
  5. Effect of gestational diabetes mellitus on lipid profile: A systematic review and meta-analysis
  6. Long noncoding RNA NR2F1-AS1 stimulates the tumorigenic behavior of non-small cell lung cancer cells by sponging miR-363-3p to increase SOX4
  7. Promising novel biomarkers and candidate small-molecule drugs for lung adenocarcinoma: Evidence from bioinformatics analysis of high-throughput data
  8. Plasmapheresis: Is it a potential alternative treatment for chronic urticaria?
  9. The biomarkers of key miRNAs and gene targets associated with extranodal NK/T-cell lymphoma
  10. Gene signature to predict prognostic survival of hepatocellular carcinoma
  11. Effects of miRNA-199a-5p on cell proliferation and apoptosis of uterine leiomyoma by targeting MED12
  12. Does diabetes affect paraneoplastic thrombocytosis in colorectal cancer?
  13. Is there any effect on imprinted genes H19, PEG3, and SNRPN during AOA?
  14. Leptin and PCSK9 concentrations are associated with vascular endothelial cytokines in patients with stable coronary heart disease
  15. Pericentric inversion of chromosome 6 and male fertility problems
  16. Staple line reinforcement with nebulized cyanoacrylate glue in laparoscopic sleeve gastrectomy: A propensity score-matched study
  17. Retrospective analysis of crescent score in clinical prognosis of IgA nephropathy
  18. Expression of DNM3 is associated with good outcome in colorectal cancer
  19. Activation of SphK2 contributes to adipocyte-induced EOC cell proliferation
  20. CRRT influences PICCO measurements in febrile critically ill patients
  21. SLCO4A1-AS1 mediates pancreatic cancer development via miR-4673/KIF21B axis
  22. lncRNA ACTA2-AS1 inhibits malignant phenotypes of gastric cancer cells
  23. circ_AKT3 knockdown suppresses cisplatin resistance in gastric cancer
  24. Prognostic value of nicotinamide N-methyltransferase in human cancers: Evidence from a meta-analysis and database validation
  25. GPC2 deficiency inhibits cell growth and metastasis in colon adenocarcinoma
  26. A pan-cancer analysis of the oncogenic role of Holliday junction recognition protein in human tumors
  27. Radiation increases COL1A1, COL3A1, and COL1A2 expression in breast cancer
  28. Association between preventable risk factors and metabolic syndrome
  29. miR-29c-5p knockdown reduces inflammation and blood–brain barrier disruption by upregulating LRP6
  30. Cardiac contractility modulation ameliorates myocardial metabolic remodeling in a rabbit model of chronic heart failure through activation of AMPK and PPAR-α pathway
  31. Quercitrin protects human bronchial epithelial cells from oxidative damage
  32. Smurf2 suppresses the metastasis of hepatocellular carcinoma via ubiquitin degradation of Smad2
  33. circRNA_0001679/miR-338-3p/DUSP16 axis aggravates acute lung injury
  34. Sonoclot’s usefulness in prediction of cardiopulmonary arrest prognosis: A proof of concept study
  35. Four drug metabolism-related subgroups of pancreatic adenocarcinoma in prognosis, immune infiltration, and gene mutation
  36. Decreased expression of miR-195 mediated by hypermethylation promotes osteosarcoma
  37. LMO3 promotes proliferation and metastasis of papillary thyroid carcinoma cells by regulating LIMK1-mediated cofilin and the β-catenin pathway
  38. Cx43 upregulation in HUVECs under stretch via TGF-β1 and cytoskeletal network
  39. Evaluation of menstrual irregularities after COVID-19 vaccination: Results of the MECOVAC survey
  40. Histopathologic findings on removed stomach after sleeve gastrectomy. Do they influence the outcome?
  41. Analysis of the expression and prognostic value of MT1-MMP, β1-integrin and YAP1 in glioma
  42. Optimal diagnosis of the skin cancer using a hybrid deep neural network and grasshopper optimization algorithm
  43. miR-223-3p alleviates TGF-β-induced epithelial-mesenchymal transition and extracellular matrix deposition by targeting SP3 in endometrial epithelial cells
  44. Clinical value of SIRT1 as a prognostic biomarker in esophageal squamous cell carcinoma, a systematic meta-analysis
  45. circ_0020123 promotes cell proliferation and migration in lung adenocarcinoma via PDZD8
  46. miR-22-5p regulates the self-renewal of spermatogonial stem cells by targeting EZH2
  47. hsa-miR-340-5p inhibits epithelial–mesenchymal transition in endometriosis by targeting MAP3K2 and inactivating MAPK/ERK signaling
  48. circ_0085296 inhibits the biological functions of trophoblast cells to promote the progression of preeclampsia via the miR-942-5p/THBS2 network
  49. TCD hemodynamics findings in the subacute phase of anterior circulation stroke patients treated with mechanical thrombectomy
  50. Development of a risk-stratification scoring system for predicting risk of breast cancer based on non-alcoholic fatty liver disease, non-alcoholic fatty pancreas disease, and uric acid
  51. Tollip promotes hepatocellular carcinoma progression via PI3K/AKT pathway
  52. circ_0062491 alleviates periodontitis via the miR-142-5p/IGF1 axis
  53. Human amniotic fluid as a source of stem cells
  54. lncRNA NONRATT013819.2 promotes transforming growth factor-β1-induced myofibroblastic transition of hepatic stellate cells by miR24-3p/lox
  55. NORAD modulates miR-30c-5p-LDHA to protect lung endothelial cells damage
  56. Idiopathic pulmonary fibrosis telemedicine management during COVID-19 outbreak
  57. Risk factors for adverse drug reactions associated with clopidogrel therapy
  58. Serum zinc associated with immunity and inflammatory markers in Covid-19
  59. The relationship between night shift work and breast cancer incidence: A systematic review and meta-analysis of observational studies
  60. LncRNA expression in idiopathic achalasia: New insight and preliminary exploration into pathogenesis
  61. Notoginsenoside R1 alleviates spinal cord injury through the miR-301a/KLF7 axis to activate Wnt/β-catenin pathway
  62. Moscatilin suppresses the inflammation from macrophages and T cells
  63. Zoledronate promotes ECM degradation and apoptosis via Wnt/β-catenin
  64. Epithelial-mesenchymal transition-related genes in coronary artery disease
  65. The effect evaluation of traditional vaginal surgery and transvaginal mesh surgery for severe pelvic organ prolapse: 5 years follow-up
  66. Repeated partial splenic artery embolization for hypersplenism improves platelet count
  67. Low expression of miR-27b in serum exosomes of non-small cell lung cancer facilitates its progression by affecting EGFR
  68. Exosomal hsa_circ_0000519 modulates the NSCLC cell growth and metastasis via miR-1258/RHOV axis
  69. miR-455-5p enhances 5-fluorouracil sensitivity in colorectal cancer cells by targeting PIK3R1 and DEPDC1
  70. The effect of tranexamic acid on the reduction of intraoperative and postoperative blood loss and thromboembolic risk in patients with hip fracture
  71. Isocitrate dehydrogenase 1 mutation in cholangiocarcinoma impairs tumor progression by sensitizing cells to ferroptosis
  72. Artemisinin protects against cerebral ischemia and reperfusion injury via inhibiting the NF-κB pathway
  73. A 16-gene signature associated with homologous recombination deficiency for prognosis prediction in patients with triple-negative breast cancer
  74. Lidocaine ameliorates chronic constriction injury-induced neuropathic pain through regulating M1/M2 microglia polarization
  75. MicroRNA 322-5p reduced neuronal inflammation via the TLR4/TRAF6/NF-κB axis in a rat epilepsy model
  76. miR-1273h-5p suppresses CXCL12 expression and inhibits gastric cancer cell invasion and metastasis
  77. Clinical characteristics of pneumonia patients of long course of illness infected with SARS-CoV-2
  78. circRNF20 aggravates the malignancy of retinoblastoma depending on the regulation of miR-132-3p/PAX6 axis
  79. Linezolid for resistant Gram-positive bacterial infections in children under 12 years: A meta-analysis
  80. Rack1 regulates pro-inflammatory cytokines by NF-κB in diabetic nephropathy
  81. Comprehensive analysis of molecular mechanism and a novel prognostic signature based on small nuclear RNA biomarkers in gastric cancer patients
  82. Smog and risk of maternal and fetal birth outcomes: A retrospective study in Baoding, China
  83. Let-7i-3p inhibits the cell cycle, proliferation, invasion, and migration of colorectal cancer cells via downregulating CCND1
  84. β2-Adrenergic receptor expression in subchondral bone of patients with varus knee osteoarthritis
  85. Possible impact of COVID-19 pandemic and lockdown on suicide behavior among patients in Southeast Serbia
  86. In vitro antimicrobial activity of ozonated oil in liposome eyedrop against multidrug-resistant bacteria
  87. Potential biomarkers for inflammatory response in acute lung injury
  88. A low serum uric acid concentration predicts a poor prognosis in adult patients with candidemia
  89. Antitumor activity of recombinant oncolytic vaccinia virus with human IL2
  90. ALKBH5 inhibits TNF-α-induced apoptosis of HUVECs through Bcl-2 pathway
  91. Risk prediction of cardiovascular disease using machine learning classifiers
  92. Value of ultrasonography parameters in diagnosing polycystic ovary syndrome
  93. Bioinformatics analysis reveals three key genes and four survival genes associated with youth-onset NSCLC
  94. Identification of autophagy-related biomarkers in patients with pulmonary arterial hypertension based on bioinformatics analysis
  95. Protective effects of glaucocalyxin A on the airway of asthmatic mice
  96. Overexpression of miR-100-5p inhibits papillary thyroid cancer progression via targeting FZD8
  97. Bioinformatics-based analysis of SUMOylation-related genes in hepatocellular carcinoma reveals a role of upregulated SAE1 in promoting cell proliferation
  98. Effectiveness and clinical benefits of new anti-diabetic drugs: A real life experience
  99. Identification of osteoporosis based on gene biomarkers using support vector machine
  100. Tanshinone IIA reverses oxaliplatin resistance in colorectal cancer through microRNA-30b-5p/AVEN axis
  101. miR-212-5p inhibits nasopharyngeal carcinoma progression by targeting METTL3
  102. Association of ST-T changes with all-cause mortality among patients with peripheral T-cell lymphomas
  103. LINC00665/miRNAs axis-mediated collagen type XI alpha 1 correlates with immune infiltration and malignant phenotypes in lung adenocarcinoma
  104. The perinatal factors that influence the excretion of fecal calprotectin in premature-born children
  105. Effect of femoral head necrosis cystic area on femoral head collapse and stress distribution in femoral head: A clinical and finite element study
  106. Does the use of 3D-printed cones give a chance to postpone the use of megaprostheses in patients with large bone defects in the knee joint?
  107. lncRNA HAGLR modulates myocardial ischemia–reperfusion injury in mice through regulating miR-133a-3p/MAPK1 axis
  108. Protective effect of ghrelin on intestinal I/R injury in rats
  109. In vivo knee kinematics of an innovative prosthesis design
  110. Relationship between the height of fibular head and the incidence and severity of knee osteoarthritis
  111. lncRNA WT1-AS attenuates hypoxia/ischemia-induced neuronal injury during cerebral ischemic stroke via miR-186-5p/XIAP axis
  112. Correlation of cardiac troponin T and APACHE III score with all-cause in-hospital mortality in critically ill patients with acute pulmonary embolism
  113. LncRNA LINC01857 reduces metastasis and angiogenesis in breast cancer cells via regulating miR-2052/CENPQ axis
  114. Endothelial cell-specific molecule 1 (ESM1) promoted by transcription factor SPI1 acts as an oncogene to modulate the malignant phenotype of endometrial cancer
  115. SELENBP1 inhibits progression of colorectal cancer by suppressing epithelial–mesenchymal transition
  116. Visfatin is negatively associated with coronary artery lesions in subjects with impaired fasting glucose
  117. Treatment and outcomes of mechanical complications of acute myocardial infarction during the Covid-19 era: A comparison with the pre-Covid-19 period. A systematic review and meta-analysis
  118. Neonatal stroke surveillance study protocol in the United Kingdom and Republic of Ireland
  119. Oncogenic role of TWF2 in human tumors: A pan-cancer analysis
  120. Mean corpuscular hemoglobin predicts the length of hospital stay independent of severity classification in patients with acute pancreatitis
  121. Association of gallstone and polymorphisms of UGT1A1*27 and UGT1A1*28 in patients with hepatitis B virus-related liver failure
  122. TGF-β1 upregulates Sar1a expression and induces procollagen-I secretion in hypertrophic scarring fibroblasts
  123. Antisense lncRNA PCNA-AS1 promotes esophageal squamous cell carcinoma progression through the miR-2467-3p/PCNA axis
  124. NK-cell dysfunction of acute myeloid leukemia in relation to the renin–angiotensin system and neurotransmitter genes
  125. The effect of dilution with glucose and prolonged injection time on dexamethasone-induced perineal irritation – A randomized controlled trial
  126. miR-146-5p restrains calcification of vascular smooth muscle cells by suppressing TRAF6
  127. Role of lncRNA MIAT/miR-361-3p/CCAR2 in prostate cancer cells
  128. lncRNA NORAD promotes lung cancer progression by competitively binding to miR-28-3p with E2F2
  129. Noninvasive diagnosis of AIH/PBC overlap syndrome based on prediction models
  130. lncRNA FAM230B is highly expressed in colorectal cancer and suppresses the maturation of miR-1182 to increase cell proliferation
  131. circ-LIMK1 regulates cisplatin resistance in lung adenocarcinoma by targeting miR-512-5p/HMGA1 axis
  132. LncRNA SNHG3 promoted cell proliferation, migration, and metastasis of esophageal squamous cell carcinoma via regulating miR-151a-3p/PFN2 axis
  133. Risk perception and affective state on work exhaustion in obstetrics during the COVID-19 pandemic
  134. lncRNA-AC130710/miR-129-5p/mGluR1 axis promote migration and invasion by activating PKCα-MAPK signal pathway in melanoma
  135. SNRPB promotes cell cycle progression in thyroid carcinoma via inhibiting p53
  136. Xylooligosaccharides and aerobic training regulate metabolism and behavior in rats with streptozotocin-induced type 1 diabetes
  137. Serpin family A member 1 is an oncogene in glioma and its translation is enhanced by NAD(P)H quinone dehydrogenase 1 through RNA-binding activity
  138. Silencing of CPSF7 inhibits the proliferation, migration, and invasion of lung adenocarcinoma cells by blocking the AKT/mTOR signaling pathway
  139. Ultrasound-guided lumbar plexus block versus transversus abdominis plane block for analgesia in children with hip dislocation: A double-blind, randomized trial
  140. Relationship of plasma MBP and 8-oxo-dG with brain damage in preterm
  141. Identification of a novel necroptosis-associated miRNA signature for predicting the prognosis in head and neck squamous cell carcinoma
  142. Delayed femoral vein ligation reduces operative time and blood loss during hip disarticulation in patients with extremity tumors
  143. The expression of ASAP3 and NOTCH3 and the clinicopathological characteristics of adult glioma patients
  144. Longitudinal analysis of factors related to Helicobacter pylori infection in Chinese adults
  145. HOXA10 enhances cell proliferation and suppresses apoptosis in esophageal cancer via activating p38/ERK signaling pathway
  146. Meta-analysis of early-life antibiotic use and allergic rhinitis
  147. Marital status and its correlation with age, race, and gender in prognosis of tonsil squamous cell carcinomas
  148. HPV16 E6E7 up-regulates KIF2A expression by activating JNK/c-Jun signal, is beneficial to migration and invasion of cervical cancer cells
  149. Amino acid profiles in the tissue and serum of patients with liver cancer
  150. Pain in critically ill COVID-19 patients: An Italian retrospective study
  151. Immunohistochemical distribution of Bcl-2 and p53 apoptotic markers in acetamiprid-induced nephrotoxicity
  152. Estradiol pretreatment in GnRH antagonist protocol for IVF/ICSI treatment
  153. Long non-coding RNAs LINC00689 inhibits the apoptosis of human nucleus pulposus cells via miR-3127-5p/ATG7 axis-mediated autophagy
  154. The relationship between oxygen therapy, drug therapy, and COVID-19 mortality
  155. Monitoring hypertensive disorders in pregnancy to prevent preeclampsia in pregnant women of advanced maternal age: Trial mimicking with retrospective data
  156. SETD1A promotes the proliferation and glycolysis of nasopharyngeal carcinoma cells by activating the PI3K/Akt pathway
  157. The role of Shunaoxin pills in the treatment of chronic cerebral hypoperfusion and its main pharmacodynamic components
  158. TET3 governs malignant behaviors and unfavorable prognosis of esophageal squamous cell carcinoma by activating the PI3K/AKT/GSK3β/β-catenin pathway
  159. Associations between morphokinetic parameters of temporary-arrest embryos and the clinical prognosis in FET cycles
  160. Long noncoding RNA WT1-AS regulates trophoblast proliferation, migration, and invasion via the microRNA-186-5p/CADM2 axis
  161. The incidence of bronchiectasis in chronic obstructive pulmonary disease
  162. Integrated bioinformatics analysis shows integrin alpha 3 is a prognostic biomarker for pancreatic cancer
  163. Inhibition of miR-21 improves pulmonary vascular responses in bronchopulmonary dysplasia by targeting the DDAH1/ADMA/NO pathway
  164. Comparison of hospitalized patients with severe pneumonia caused by COVID-19 and influenza A (H7N9 and H1N1): A retrospective study from a designated hospital
  165. lncRNA ZFAS1 promotes intervertebral disc degeneration by upregulating AAK1
  166. Pathological characteristics of liver injury induced by N,N-dimethylformamide: From humans to animal models
  167. lncRNA ELFN1-AS1 enhances the progression of colon cancer by targeting miR-4270 to upregulate AURKB
  168. DARS-AS1 modulates cell proliferation and migration of gastric cancer cells by regulating miR-330-3p/NAT10 axis
  169. Dezocine inhibits cell proliferation, migration, and invasion by targeting CRABP2 in ovarian cancer
  170. MGST1 alleviates the oxidative stress of trophoblast cells induced by hypoxia/reoxygenation and promotes cell proliferation, migration, and invasion by activating the PI3K/AKT/mTOR pathway
  171. Bifidobacterium lactis Probio-M8 ameliorated the symptoms of type 2 diabetes mellitus mice by changing ileum FXR-CYP7A1
  172. circRNA DENND1B inhibits tumorigenicity of clear cell renal cell carcinoma via miR-122-5p/TIMP2 axis
  173. EphA3 targeted by miR-3666 contributes to melanoma malignancy via activating ERK1/2 and p38 MAPK pathways
  174. Pacemakers and methylprednisolone pulse therapy in immune-related myocarditis concomitant with complete heart block
  175. miRNA-130a-3p targets sphingosine-1-phosphate receptor 1 to activate the microglial and astrocytes and to promote neural injury under the high glucose condition
  176. Review Articles
  177. Current management of cancer pain in Italy: Expert opinion paper
  178. Hearing loss and brain disorders: A review of multiple pathologies
  179. The rationale for using low-molecular weight heparin in the therapy of symptomatic COVID-19 patients
  180. Amyotrophic lateral sclerosis and delayed onset muscle soreness in light of the impaired blink and stretch reflexes – watch out for Piezo2
  181. Interleukin-35 in autoimmune dermatoses: Current concepts
  182. Recent discoveries in microbiota dysbiosis, cholangiocytic factors, and models for studying the pathogenesis of primary sclerosing cholangitis
  183. Advantages of ketamine in pediatric anesthesia
  184. Congenital adrenal hyperplasia. Role of dentist in early diagnosis
  185. Migraine management: Non-pharmacological points for patients and health care professionals
  186. Atherogenic index of plasma and coronary artery disease: A systematic review
  187. Physiological and modulatory role of thioredoxins in the cellular function
  188. Case Reports
  189. Intrauterine Bakri balloon tamponade plus cervical cerclage for the prevention and treatment of postpartum haemorrhage in late pregnancy complicated with acute aortic dissection: Case series
  190. A case of successful pembrolizumab monotherapy in a patient with advanced lung adenocarcinoma: Use of multiple biomarkers in combination for clinical practice
  191. Unusual neurological manifestations of bilateral medial medullary infarction: A case report
  192. Atypical symptoms of malignant hyperthermia: A rare causative mutation in the RYR1 gene
  193. A case report of dermatomyositis with the missed diagnosis of non-small cell lung cancer and concurrence of pulmonary tuberculosis
  194. A rare case of endometrial polyp complicated with uterine inversion: A case report and clinical management
  195. Spontaneous rupturing of splenic artery aneurysm: Another reason for fatal syncope and shock (Case report and literature review)
  196. Fungal infection mimicking COVID-19 infection – A case report
  197. Concurrent aspergillosis and cystic pulmonary metastases in a patient with tongue squamous cell carcinoma
  198. Paraganglioma-induced inverted takotsubo-like cardiomyopathy leading to cardiogenic shock successfully treated with extracorporeal membrane oxygenation
  199. Lineage switch from lymphoma to myeloid neoplasms: First case series from a single institution
  200. Trismus during tracheal extubation as a complication of general anaesthesia – A case report
  201. Simultaneous treatment of a pubovesical fistula and lymph node metastasis secondary to multimodal treatment for prostate cancer: Case report and review of the literature
  202. Two case reports of skin vasculitis following the COVID-19 immunization
  203. Ureteroiliac fistula after oncological surgery: Case report and review of the literature
  204. Synchronous triple primary malignant tumours in the bladder, prostate, and lung harbouring TP53 and MEK1 mutations accompanied with severe cardiovascular diseases: A case report
  205. Huge mucinous cystic neoplasms with adhesion to the left colon: A case report and literature review
  206. Commentary
  207. Commentary on “Clinicopathological features of programmed cell death-ligand 1 expression in patients with oral squamous cell carcinoma”
  208. Rapid Communication
  209. COVID-19 fear, post-traumatic stress, growth, and the role of resilience
  210. Erratum
  211. Erratum to “Tollip promotes hepatocellular carcinoma progression via PI3K/AKT pathway”
  212. Erratum to “Effect of femoral head necrosis cystic area on femoral head collapse and stress distribution in femoral head: A clinical and finite element study”
  213. Erratum to “lncRNA NORAD promotes lung cancer progression by competitively binding to miR-28-3p with E2F2”
  214. Retraction
  215. Expression and role of ABIN1 in sepsis: In vitro and in vivo studies
  216. Retraction to “miR-519d downregulates LEP expression to inhibit preeclampsia development”
  217. Special Issue Computational Intelligence Methodologies Meets Recurrent Cancers - Part II
  218. Usefulness of close surveillance for rectal cancer patients after neoadjuvant chemoradiotherapy
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Heruntergeladen am 3.12.2025 von https://www.degruyterbrill.com/document/doi/10.1515/med-2022-0532/html?lang=de
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