The MRTF-A/miR-155/SOX1 pathway mediates gastric cancer migration and invasion.

BACKGROUND: Gastric cancer (GC) is the leading cause of death worldwide and is closely related to metastasis. MRTF-A is one of the most well-characterized genetic markers in cancer. However, the mechanism whereby MRTF-A mediate gastric cancer (GC) tumorigenesis is not fully clear. Increasing evidence has confirmed that miRNA dysregulation is involved in MRTF-A-mediated tumorigenesis, supporting their potential as therapeutic targets for cancer. Although miR-155 has been reported as an upregulated miRNA, the interplay between miR-155 and MRTF-A-mediated gastric cancer progression remain largely elusive. METHODS: Real-time PCR was performed to determine miR-155 expression after transfected with MRTF-A encoding plasmids and siRNA. Potential target genes were identified by Western blot and luciferase reporter assay. Chip assay was proved that MRTF-A binds in the promoter region of miR-155. Transwell assay and Scratch-healing migration assay was used to investigate the role of MRTF-A and SOX1 in gastric cancer cell migration and invasion. RESULTS: MRTF-A can interact with the miR-155 promoter to promote histone acetylation and RNA polymerase II recruitment via the Wnt-ß-catenin pathway. miR-155 promotes gastric cancer cell migration by suppressing SOX1 expressiom by targeting its 3'UTR in vitro and in vivo. MRTF-A inhibited the inhibitory effects of SOX1 on gastric cancer cell migration by promoting the express -ion of miR-155. CONCLUSION: Our data therefore provide important and novel insights into how the MRTF-A/miR-155/SOX1 pathway mediates migration and invasion in GC.

Silencing of TMEM158 Inhibits Tumorigenesis and Multidrug Resistance in Colorectal Cancer.

Transmembrane protein 158 (TMEM158) plays pivotal roles in many cancers, including colorectal cancer (CRC). It has been reported that it is a recently identified upregulated gene during Ras-induced senescence. However, the clinical significance and biological functions of TMEM158 in CRC remain largely unknown. In this study, we found that TMEM158 was highly expressed in CRC tissues and cell lines compared with the corresponding noncancerous samples and normal colon epithelial cells. In vitro studies showed that TMEM158 silencing inhibited proliferation, and migration and increased apoptosis of CRC cells, whereas overexpression of TMEM158 increased proliferation, migration, and apoptosis escape of CRC cells. Mechanically, the levels of drug resistance-associated molecules, including multidrug resistance 1 and multidrug resistance protein 1, as well as the expression of antiapoptotic Bcl-2 were significantly upregulated. In addition, TMEM158 knockdown significantly inhibited tumor growth in vivo. Collectively, these results demonstrated that TMEM158 is a significant regulator of tumorigenesis and drug resistance in CRC and provided evidence that TMEM158 may be a promising target for CRC therapy.

Prognostic roles of microRNA 143 and microRNA 145 in colorectal cancer: A meta-analysis.

BACKGROUND: A systematic analysis was conducted to clarify the relationship between miR-143/145 and the prognosis of colorectal cancer. MATERIALS AND METHODS: We searched four databases: PubMed, EMBASE, Web of Science, and the Cochrane Library. We extracted and estimated the hazard ratios for survival outcomes, which compared low and high expression levels of miR-143/145 in colorectal cancer patients in the available studies. Each individual hazard ratio was used to calculate the pooled hazard ratio. RESULTS: A total of 17 articles including 5128 patients were ultimately included. The results showed that there was no significant difference between low expression and high expression of miR-143 in the overall survival of colon cancer patients. However, low expression of miR-143 was significantly associated with high event-free survival (hazard ratio (HR) 0.6; 95% confidence interval (CI) 0.40, 0.88). Low expression of miR-145 was associated with poor prognosis of patients (HR 1.92; 95% CI 1.45, 2.54); those with low expression of miR-145 were at 1.92-fold higher risk for short-term overall survival than those with high expression of miR-145. MiR-145 was an unfavorable factor for the prognosis of colorectal cancer. There were no significant differences between low expression of miR-145 and high expression of miR-143 in event-free survival. CONCLUSION: miR-143 and miR-145 have promising prognostic value for colorectal cancer. Low expression of miR-143 can predict high event-free survival, and low expression of miR-145 can predict poor overall survival.

Prognostic and clinicopathological value of MUC1 expression in colorectal cancer: A meta-analysis.

BACKGROUND: Accumulating evidence supports the overexpression of mucin 1 (MUC1) in colorectal cancer (CRC), but the value of elevated MUC1 expression remains controversial. Here, we evaluated the prognostic and clinicopathological value of MUC1 expression in CRC. MATERIALS AND METHODS: The Web of Science, PubMed, Embase, Cochrane Library, and Wanfang databases, as well as the China Biology Medicine disc (CBMdisc) and China National Knowledge Infrastructure (CNKI) were searched for studies on MUC1 expression and prognosis of CRC through July 20, 2018. The pooled relative risks (RRs) and hazard ratios (HRs) with 95% confidence intervals (95% CIs) were calculated to evaluate the prognostic and clinicopathological value of MUC1 expression in CRC. The Revman version 5.3 package and STATA, version 12 were employed for pooled analysis and analysis of publication bias. RESULTS: This meta-analysis included 16 published studies. The combined analysis showed that CRC patients with high MUC1 expression had a worse clinical outcome in overall survival (OS) (HR = 1.51, 95% CI = 1.30-1.75, P <.00001). In addition, high MUC1 expression was associated with higher TNM stage (RR = 1.44, 95% CI = 1.17-1.77, P = .0007), greater depth of invasion (RR = 1.30, 95% CI = 1.10-1.53, P = .002), and lymph node metastasis (RR = 1.47, 95% CI = 1.20-1.80, P = .0002) of CRC. However, the elevated MUC1 expression was not related to disease-free survival/recurrence-free survival (DFS/RFS) (HR = 1.51, 95% CI = 0.78-2.89, P = .22), histological grade (RR = 1.15, 95% CI = 0.96-1.38, P = .12), gender (RR = 0.95; 95% CI = 0.83-1.08, P = .44), tumor size (RR = 1.11, 95% CI = 0.85-1.44, P = .44), tumor site (RR = 1.01, 95% CI = 0.88-1.16, P = .84), or mucinous component (RR = 0.83, 95% CI = 0.60-1.14, P = .24) in CRC. CONCLUSION: Our findings indicated that high MUC1 expression represents a marker of poor prognosis in CRC. Meanwhile, elevated MUC1 expression was associated with advanced TNM stage, greater depth of invasion, and lymph node metastasis.

Prognostic and Clinicopathological Significance of MUC Family Members in Colorectal Cancer: A Systematic Review and Meta-Analysis.

OBJECTIVE: To assess the association between MUC expression levels in colorectal cancer (CRC) tissues and prognosis and investigate the associations between MUC expression levels and CRC clinicopathological characteristics. METHODS: The PubMed, Embase, Cochrane Library, and Web of Science databases were searched from inception through September 13, 2019, to identify studies investigating the association between MUC expression levels in CRC tissues and prognosis. Pooled hazard ratios (HRs) or odds ratio (ORs) with 95% confidence intervals (CIs) were used to evaluate associations between MUC expression levels and prognosis or clinicopathological characteristics, respectively. The heterogeneity between studies was assessed by the I 2 values, whereas the likelihood of publication bias was assessed by Egger's linear regression and Begg's rank correlation test. RESULTS: Among 33 included studies (n = 6032 patients), there were no associations between combined MUC phenotype expression levels and overall survival (OS) or disease-free survival (DFS)/relapse-free survival (RFS) in patients with CRC. In subgroup analyses, the upregulated MUC1 expression (HR = 1.50; 95% CI, 1.29-1.74; P < 0.00001) was associated with poor OS. However, the upregulated MUC2 expression (HR = 0.64; 95% CI, 0.52-0.79; P < 0.00001) was associated with better OS. Furthermore, a high level of MUC1 expression (HR = 1.99; 95% CI, 0.99-3.99; P = 0.05) was associated with shorter DFS/RFS. However, patients with a low level of MUC2 tumors showed better DFS/RFS than patients with a high level of MUC2 tumors (HR = 0.71; 95% CI, 0.49-1.04; P = 0.08; P = 0.0.009, I 2 = 67%) and MUC5AC expression (HR = 0.56; 95% CI, 0.38-0.82; P = 0.003) was associated with longer DFS/RFS. In addition, a high level of MUC1 expression was associated with CRC in the rectum, deeper invasion, lymph node metastasis, distant metastasis, advanced tumor stage, and lymphatic invasion. A high level of MUC2 expression had a protective effect. High secretion of MUC5AC is associated with colon cancer compared with rectal cancer. CONCLUSION: The protein expression of MUC1 might be a poor biomarker in colorectal cancer and might play a role in tumor transformation and metastasis. However, the protein expression of MUC2 expression might have a protective effect. Furthermore, randomized controlled trials (RCTs) of large patients are needed to confirm the results.

Prognostic Value of MUC2 Expression in Colorectal Cancer: A Systematic Review and Meta-Analysis.

BACKGROUND: The reliability of MUC2 as a prognostic marker in colorectal cancer (CRC) is controversial. This study evaluated the association between MUC2 expression levels in CRC tissues and prognosis. METHODS: The PubMed, Web of Science, Embase, Cochrane Library, China Biology Medicine disc (CBMdisc), Wanfang Database, and China National Knowledge Infrastructure (CNKI) databases were searched to identify studies exploring the relationship between MUC2 expression in CRC tissues and overall survival (OS). Pooled hazard ratios (HRs) and risk ratios (RRs) with 95% confidence intervals (CIs) were used to evaluate the associations between MUC2 expression levels and prognosis and MUC2 expression levels and CRC clinicopathological characteristics, respectively. RESULTS: The meta-analysis included 11 studies (2619 patients). Low MUC2 expression level was significantly associated with poor OS (HR, 1.67; 95% CI, 1.43-1.94; P < 0.00001) and disease-free survival (DFS)/recurrence-free survival (RFS) (HR, 1.60; 95% CI, 1.21-2.12; P = 0.001) in patients with CRC. Low MUC2 expression level was associated with advanced TNM stage (RR, 1.42; 95% CI, 1.26-1.60; P < 0.00001), lymph node metastasis (RR, 1.41; 95% CI, 1.25-1.60; P < 0.00001), lymphatic invasion (RR,1.64; 95% CI, 1.26-2.12; P = 0.0002), rectal tumor site (RR, 1.26; 95% CI, 1.09-1.46; P = 0.001), and large tumor size (RR,1.32; 95% CI, 1.02-1.70; P = 0.03). There were no associations between low MUC2 expression level and gender, histological grade, depth of invasion, and distant metastasis. CONCLUSION: The low levels of MUC2 in CRC tissues are poor prognostic factor independent of stage or other well-recognized markers of later-stage disease. Large well-designed cohort studies are required to validate MUC2 as a biomarker for poor prognosis in CRC.

Levels of peripheral Th17 cells and serum Th17-related cytokines in patients with colorectal cancer: a meta-analysis.

Studies suggest that inflammation is involved in the colorectal cancer (CRC) pathology and symptoms. This study sought to quantitatively summarize the clinical cytokine data. Multiple reports have described the proportion of Th17 cells in peripheral blood and serum levels of Th17-related cytokines in patients with colorectal cancer (CRC). To clarify the status of Th17 cells and Th17-related cytokines in CRC patients, we did a meta-analysis of the results published previously to quantitatively assess the levels of peripheral Th17 cells and serum Th17-related cytokines in patients with CRC. We searched PubMed, Embase, web of Science, Cochrane Library and China National Knowledge Infrastructure (CNKI) systematically for studies reporting the proportion of Th17 cells and the serum levels of Th17-related cytokines (IL-17, IL-17A, IL-6, IL-22, IL-23) in CRC patients. Studies measuring the proportion of Th17 cells and the serum levels of Th17-related cytokines (IL-17, IL-17A, IL-6, IL-22, IL-23) in CRC and healthy control subjects were included. Mean (standard deviation) proportion of Th17 cells and cytokine concentrations for CRC and control subjects were extracted. We assessed pooled data by using a random-effects model. We identified 1276 studies, of which 24 studies were included in the final meta-analytical processes. The quality was reliable according to the Newcastle-Ottawa Quality Assessment Scale (Case Control Studies). Compared with control subjects, CRC patients had a higher proportion of Th17 cells [2.37%, (0.53, 2.21)]; an elevated levels of serum IL-17A 1.11 pg./ml, 95%CI (0.16-2.07); an elevated levels of serum IL-6 3.42 pg/ml, 95%CI (3.14-3.70); an elevated levels of serum IL-22 1.32 pg/ml, 95%CI (0.94-1.70); an elevated levels of serum IL-23 0.16pg/ml, 95%CI(1.94-5.39). After sensitivity analysis, an elevated level of serum IL-17 was showed. The data showed that the proportion of Th17 cells in PB and levels of serum IL-17, IL-17A, IL-6, IL-22, IL-23 increased among CRC patients compared to control subjects. This result demonstrated that Th17 cells and Th17-related cytokines may be involved in the pathogenic mechanisms of CRC.

A meta-analysis of microRNA-17 as a potential biomarker in diagnosis of colorectal cancer.

This meta-analysis was aimed to determine the diagnostic accuracy of circulating microRNA-17 for colorectal Cancer (CRC). Databases including PubMed, Embase, Web of Science, Cochrane Library and China National Knowledge Infrastructure (CNKI) were searched up to February 23, 2018 for eligible studies. Quality Assessment of Diagnostic Accuracy Studies (QUADAS) was employed to assess the quality of the included studies. Meta-analysis was performed in STATA 13.0. Ten studies with total 938 CRC patients and 638 control individuals were included in this meta-analysis. All of the included studies are of high quality. The summary estimates revealed that the pooled sensitivity is 0.75 (95% confidence interval (CI): 0.60-0.85) and the specificity is 68% (95% CI: 0.56-0.77), for the diagnosis of CRC. In addition, the area under the summary ROC curve (AUC) is 0.76. The current evidence suggests that circulating miR-17 has the potential diagnostic value for CRC. More prospective studies on the diagnostic value of circulating miR-17 for CRC are needed in the future. Together, microRNA-17 might be a novel potential biomarker in the diagnosis of colorectal cancer, and more studies are needed to highlight the theoretical strengths.

The family of apoptosis-stimulating proteins of p53 is dysregulated in colorectal cancer patients.

The apoptosis-stimulating protein of p53 (ASPP) family is a newly identified family protein including ASPP1, ASPP2 and inhibitor of ASPP (iASPP), by which the tumor protein 53 (TP53)-mediated apoptotic process is selectively regulated. Downregulation of ASPP1/ASPP2 and upregulation of iASPP were revealed to be associated with a poor prognosis and metastasis in several types of cancer. However, to the best of our knowledge, the expression of ASPP in colorectal cancer (CRC) has not previously been investigated. The present study analyzed ASPP expression in human CRC tissues with multiple clinical and pathological profiles. A total of 41 patients diagnosed with CRC were enrolled in the present study. The expression of ASPP was detected by immunohistochemistry, immunofluorescence and reverse transcription-quantitative polymerase chain reaction. In addition, the variation in ASPP expression was examined in a number of pathological groups. The associations among ASPP expression, and the expression of TP53, plasma carcinoembryonic antigen (CEA) levels and α-fetoprotein (AFP) levels were also investigated. ASPP1 and ASPP2 expression was significantly reduced, while iASPP expression was elevated in CRC samples compared with expression in adjacent non-cancerous tissues. Downregulation of ASPP1 was detected in the TP53-positive group compared with the TP53-negative group. The increase in iASPP expression was correlated with the grade of malignancy, but not with regional lymph node status or metastases. The expression of ASPP2 was negatively correlated with plasma CEA levels. The results of the present study, not only enrich CRC epidemic and pathological data, but also provide valuable indices for CRC clinical treatment and prognosis.