Shuai Meng

c-Met and CREB1 are involved in miR-433-mediated inhibition of the epithelial-mesenchymal transition in bladder cancer by regulating Akt/GSK-3β/Snail signaling.

Emerging evidence has suggested that microRNAs (miRNAs) have an important role in tumor development and progression by regulating diverse cellular pathways. Here we describe the function and regulation network of miR-433 in bladder cancer (BCa). miR-433 is frequently downregulated in BCa tissues compared with adjacent non-cancerous tissues. Epigenetic mechanisms may be involved in the regulation of miR-433 expression. Enforced expression of miR-433 significantly inhibits proliferation, colony formation, migration, and invasion in BCa cells. In addition, miR-433 inhibits the epithelial–mesenchymal transition (EMT) in BCa cells by regulating c-Met/Akt/GSK-3β/Snail signaling pathway. Both c-Met and CREB1 are downstream target genes of miR-433. CREB1 can also indirectly regulate c-Met/Akt/GSK-3β/Snail signaling via MITF. Furthermore, CREB1 expression is an independent prognostic factor for overall survival in patients with BCa. Finally, there appears to exist a reciprocal regulation between c-Met and miR-433/miR-409-3p. Taken together, this study reveals that miR-433-c-MET/CREB1-Akt/GSK-3β/Snail signaling is critical to EMT in BCa. Targeting the pathway described here may open up new prospects to restrict metastatic progression of BCa.

A meta-analysis including dose-response relationship between night shift work and the risk of colorectal cancer

A meta-analysis was conducted to quantitatively evaluate the correlation between night shift work and the risk of colorectal cancer. We searched for publications up to March 2015 using PubMed, Web of Science, Cochrane Library, EMBASE and the Chinese National Knowledge Infrastructure databases, and the references of the retrieved articles and relevant reviews were also checked. OR and 95% CI were used to assess the degree of the correlation between night shift work and risk of colorectal cancer via fixed- or random-effect models. A dose-response meta-analysis was performed as well. The pooled OR estimates of the included studies illustrated that night shift work was correlated with an increased risk of colorectal cancer (OR = 1.318, 95% CI 1.121–1.551). No evidence of publication bias was detected. In the dose-response analysis, the rate of colorectal cancer increased by 11% for every 5 years increased in night shift work (OR = 1.11, 95% CI 1.03–1.20). In conclusion, this meta-analysis indicated that night shift work was associated with an increased risk of colorectal cancer. Further researches should be conducted to confirm our findings and clarify the potential biological mechanisms.

miR-148a-3p represses proliferation and EMT by establishing regulatory circuits between ERBB3/AKT2/c-myc and DNMT1 in bladder cancer

miR-148a-3p downregulation has emerged as a critical factor in cancer progression yet, the underlying mechanisms of miR-148a-3p expression pattern and its function in bladder cancer remains to be elucidated. Here, we illustrate that miR-148a-3p is frequently downregulated in bladder cancer and that its expression may be regulated by DNA methylation. DNA methyltransferase 1 (DNMT1) and miR-148a-3p function in a positive feedback loop in bladder cancer. miR-148a-3p overexpression functions as a tumor suppressor in bladder cancer cells. miR-148a-3p inhibits bladder cancer cell proliferation and epithelial–mesenchymal transition (EMT) by regulating ERBB3/AKT2/c-myc and ERBB3/AKT2/Snail signaling. ERBB3, DNMT1 and AKT2 are downstream miR-148a-3p target genes. Furthermore, the miR-148a-3p/ERBB3/AKT2/c-myc signaling axis establishes a positive feedback loop in the regulation of bladder cancer. Taken together, our study demonstrates novel regulatory circuits involving miR-148a-3p/ERBB3/AKT2/c-myc and DNMT1 that controls bladder cancer progression, which may be useful in the development of more effective therapies against bladder cancer.

MicroRNA-608 inhibits proliferation of bladder cancer via AKT/FOXO3a signaling pathway

BackgroundCurrent evidence indicates that miR-608 is widely down-regulated in various malignant tumors including liver cancer, colon cancer, lung cancer and glioma, and acts as a tumor suppressor by inhibiting cell proliferation, invasion and migration or by promoting apoptosis. The specific biological function of miR-608 in bladder cancer is still unknown.MethodsqRT-PCR and Chromogenic in Situ Hybridization (CISH) was conducted to assess the expression of miR-608 in paired BCa tissues and adjacent non-tumor bladder urothelial tissues. Bisulfite sequencing PCR was used for DNA methylation analysis. CCK-8, colony formation and flow cytometry assays were performed, and a xenograft model was studied. Immunohistochemistry staining was performed with peroxidase and DAB. The target of miR-608 was validated with a dual-luciferase reporter assay, quantitative RT-PCR, and Western blotting.ResultsmiR-608 is frequently down-regulated in human BCa tissues. The methylation status of CpG islands is involved in the regulation of miR-608 expression. Overexpression of miR-608 inhibits the proliferation and tumorigenesis of BCa cells in vitro and in vivo. Additionally, up-regulation of miR-608 in BCa cells induces G1-phase arrest through AKT/FOXO3a signaling. In contrast, down-regulation of miR-608 promotes proliferation and cell cycle progression in BCa cells. Moreover, the expression of FLOT1 was directly inhibited by miR-608, the down-regulation of FLOT1 induced by siFLOT1 could be significantly reversed by miR-608 inhibitor. Similarly, the up-regulation of FLOT1 by FLOT1 overexpression plasmid (pFLOT1) could also reverse the suppressed cell proliferation caused by miR-608.ConclusionsmiR-608 is a potential tumor suppressor in BCa, and the restoration of miR-608 might be a promising therapeutic option for BCa.

Up-regulation of p16 by miR-877-3p inhibits proliferation of bladder cancer.

Despite the recent studies which have shown that microRNA (miRNA) negatively regulates gene expression by silencing the expression of target genes, here we reported the new evidence of microRNA-mediated gene activation by targeting specific promoter sites. We identified a miR-877-3p binding site on the promoter site of tumor suppressor gene p16 which alters frequently in bladder cancer. Enforced expression of miR-877-3p could increase the expression of p16, which inhibit the proliferation and tumorigenicity of bladder cancer through cell cycle G1-phase arrest. Further evidences confirmed that the correlation between p16 activation and miR-877-3p was due to the direct binding. These findings demonstrate the anti-tumor function of miR-877-3p in bladder cancer cells and reveal a new pattern of miRNA involved gene regulation.

Apigenin inhibits renal cell carcinoma cell proliferation

Apigenin, a natural flavonoid found in vegetables and fruits, has antitumor activity in several cancer types. The present study evaluated the effects and mechanism of action of apigenin in renal cell carcinoma (RCC) cells. We found that apigenin suppressed ACHN, 786-0, and Caki-1 RCC cell proliferation in a dose- and time-dependent manner. A comet assay suggested that apigenin caused DNA damage in ACHN cells, especially at higher doses, and induced G2/M phase cell cycle arrest through ATM signal modulation. Small interfering RNA (siRNA)-mediated p53 knockdown showed that apigenin-induced apoptosis was likely p53 dependent. Apigenin anti-proliferative effects were confirmed in an ACHN cell xenograft mouse model. Apigenin treatment reduced tumor growth and volume in vivo, and immunohistochemical staining revealed lower Ki-67 indices in tumors derived from apigenin-treated mice. These findings suggest that apigenin exposure induces DNA damage, G2/M phase cell cycle arrest, p53 accumulation and apoptosis, which collectively suppress ACHN RCC cell proliferation in vitro and in vivo. Given its antitumor effects and low in vivo toxicity, apigenin is a highly promising agent for treatment of RCC.

Tomato consumption and prostate cancer risk: a systematic review and meta-analysis

Previous studies have reported controversial results on the association between tomato consumption and prostate cancer risk. Hence, we performed a meta-analysis to comprehensively evaluate this relationship. A total of 24 published studies with 15,099 cases were included. Relative risks (RR) and 95% confidence intervals (CI) were pooled with a random-effects model. Tomato intake was associated with a reduced risk of prostate cancer (RR 0.86, 95% CI 0.75–0.98, P = 0.019; P < 0.001 for heterogeneity, I2 = 72.7%). When stratified by study design, the RRs for case-control and cohort studies were 0.76 (95% CI 0.61–0.94, P = 0.010) and 0.96 (95% CI 0.84–1.10, P = 0.579), respectively. In the subgroup analysis by geographical region, significant protective effects were observed in Asian (RR 0.43, 95% CI 0.22–0.85, P = 0.015) and Oceania populations (RR 0.81, 95% CI 0.67–0.99, P = 0.035), but not in other geographical populations. Begg’s test indicated a significant publication bias (P = 0.015). Overall, tomato intake may have a weak protective effect against prostate cancer. Because of the huge heterogeneity and null results in cohort studies, further prospective studies are needed to explore the potential relationship between tomato consumption and prostate cancer risk.

MiR-22 suppresses epithelial–mesenchymal transition in bladder cancer by inhibiting Snail and MAPK1/Slug/vimentin feedback loop

MicroRNAs (miRNAs) have been validated to play prominent roles in the occurrence and development of bladder cancer (BCa). MiR-22 was previously reported to act as a tumor suppressor or oncomiRNA in various types of cancer. However, its accurate expression, function, and mechanism in BCa remain unclear. Here, we find that miR-22 is frequently downregulated in BCa tissues compared with adjacent non-cancerous tissues. Overexpression of miR-22 significantly inhibits proliferation, migration, and invasion of BCa cells both in vitro and in vivo. Importantly, miR-22 is found to suppress cell proliferation/apoptosis by directly targeting MAPK1 (mitogen-activated protein kinase 1, ERK2) and inhibit cell motility by targeting both MAPK1 and Snail. Further statistical analysis shows that low-expression of MAPK1 or Snail is an independent prognostic factor for a better overall survival in patients with BCa (n = 401). Importantly, we describe an important regenerative feedback loop among vimentin, Slug and MAPK1 in BCa cells. MAPK1-induced Slug expression upregulates vimentin. Vimentin in turn activates MAPK1. By inhibiting Snail and MAPK1/Slug/vimentin feedback loop, miR-22 suppresses epithelial–mesenchymal transition (EMT) of BCa cells in vitro as well as in vivo. Taken together, this study reveals that miR-22 is critical to the proliferation, apoptosis and EMT progression in BCa cells. Targeting the pathway described here may be a novel approach for inhibiting proliferation and metastasis of BCa.

MET|[sol]|SMAD3|[sol]|SNAIL circuit mediated by miR-323a-3p is involved in regulating epithelial|[ndash]|mesenchymal transition progression in bladder cancer

Bladder cancer (BCa) is the one of the most common cancers with high incidence, occurrence and low 5-year survival rate. Emerging evidence indicates that DLK1-DIO3 genomic region especially the miRNA cluster in this region is involved in several pathologic processes and various cancers, and miR-323a-3p is a member of this miRNA cluster. In this study, we investigate the function and regulatory network of miR-323a-3p in BCa. miR-323a-3p is frequently downregulated in BCa tissues and three cell lines compared with adjacent non-tumorous tissues and bladder normal cell line (SV-HUC-1). Besides, downregulation of miR-323a-3p is significantly associated with poor overall survival rate of BCa. Methylation of DLK1-MEG3 intergenic DMR (IG-DMR) contributes to the reduction of miR-323a-3p. Overexpression of miR-323a-3p significantly inhibits the epithelial–mesenchymal transition (EMT) progression of BCa. Both upregulated MET and SMAD3 are direct targets of miR-323a-3p, and the knockdown of MET and SMAD3 also represses the EMT progression consistently with overexpression of miR-323a-3p. SNAIL is detected in the last targeted confocal protein of both MET and SMAD3 signaling that trigger EMT consequently. Hence, a miR-323a-3p/MET/SMAD3/SNAIL circuit is established to regulate the EMT progression of BCa. And a mutual regulatory mechanism between miR-323a-3p/miR-433/miR-409 and MET also participates in this circuit. In conclusion, our study demonstrates a novel regulatory mechanism of the miR-323a-3p/MET/SMAD3/SNAIL circuit that is involved in the EMT regulation of BCa, which may be a potential therapy target for BCa.

Hypertension and risk of prostate cancer: a systematic review and meta-analysis

The previously reported association between hypertension and prostate cancer risk was controversial. We performed this systematic review and meta-analysis of all available studies to summarize evidence on this association. Studies were identified by searching PubMed, Web of Science and Chinese National Knowledge Infrastructure (CNKI) databases through January 2016. Pooled relative risks (RRs) with their corresponding 95% confidence intervals (CIs) were calculated using a random-effects model. A total of 21 published studies were included in this meta-analysis. A significant increase in the risk of prostate cancer (RR 1.08, 95% CI 1.02–1.15, P = 0.014) was observed among individuals with hypertension. There was statistically significant heterogeneity among included studies (P < 0.001 for heterogeneity, I2 = 72.1%). No obvious evidence of significant publication bias was detected by either Begg’s test (P = 0.174) or Egger’s test (P = 0.277). In conclusion, this meta-analysis indicates that hypertension may be associated with an increased risk of prostate cancer. Considering the substantial heterogeneity and residual confounding among included studies, further large-scale, well-designed prospective cohorts, as well as mechanistic studies, are urgently needed to confirm our preliminary findings.