MiR-34a, a direct target of p53, has been shown to target several molecules associated with the cell cycle and cell survival pathways, and its dysregulation is implicated in cancer drug resistance or sensitivity in several human cancers. However, the correlation between miR-34a expression and chemoresistance has not been explored in HCC. In this study, we confirmed that miR-34a was significantly down-regulated in HCC tissues and HCC cell lines by qRT-PCR. HCC tissues with lower miR-34a expression displayed higher expression of Bcl-2 protein than those with high expression of miR-34a; therefore, an inverse correlation is evident between the miR-34a level and Bcl-2 expression. Moreover, patients with lower miR-34a expression had significantly poorer overall survival. Bioinformatics and luciferase reporter assays revealed that miR-34a binds the 3-UTR of the Bcl-2 mRNA and represses its translation. Western blotting analysis and qRT-PCR confirmed that Bcl-2 is inhibited by miR-34a overexpression. Functional analyses indicated that the restoration of miR-34a reduced cell viability, promoted cell apoptosis and potentiated sorafenib-induced apoptosis and toxicity in HCC cell lines by inhibiting Bcl-2 expression. This study is the first to demonstrate that miR-34a induces sensitivity to the anti-tumor effect of sorafenib in human HCC cells, suggesting a potential role of miR-34a in the treatment of HCC.

Our previous studies provided evidence that COMMD7 was associated with tumor progression in human solid cancer. Herein, we aimed to investigate its expression pattern, clinical significance, and biological function in pancreatic ductal adenocarcinoma (PDAC). We found that high COMMD7 expression was specifically detected in PDAC tissues and PDAC cell lines. In addition, COMMD7 overexpression positively correlated with histological differentiation and tumor node metastasis (TNM) stage. Patients with high COMMD7 expression had significantly poorer overall survival, and high COMMD7 expression was an independent predictor of poor prognosis. To further explore the regulatory mechanism of COMMD7, we used stable short hairpin RNA (shRNA)-mediated knockdown and divided the work into in vitro and in vivo experiments. In vitro, the anti-proliferation effects of COMMD7 inhibition were observed under long-time stress conditions, which correlated with cyclin D1 and Bcl-2 downregulation and Bax upregulation. We found that under short-time stress conditions, decreased COMMD7 expression also inhibited PDAC cell invasion in vitro which decreased the secretion of matrix metalloproteinase 2 (MMP-2). Moreover, extracellular signal-regulated kinase1/2 (ERK1/2) was identified as a direct target of COMMD7. The inhibition of ERK1/2 activity under short- or long-time stress conditions using specific inhibitors in COMMD7 inhibition cells all exhibited a strong tumorigenic role. In vivo, COMMD7 was sufficient to impair tumor growth. Our results suggest that COMMD7 plays an important role in the late progression of PDAC and is a potential novel target. © 2016 Wiley Periodicals, Inc.

Abstract. Metadherin (MTDH), which is an HIV-1 or TNF-α-inducible transcript, has a crucial role in several types of cancer by regulating multiple cellular signaling processes. However, to date, the role of MTDH in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) is still unclear. In the present study, we detected MTDH expression in normal liver, chronic hepatitis B and HBV-related HCC tissues. The data showed that MTDH expression levels were elevated in the hepatitis B tissues and especially in the HBV-related HCC tissues compared to normal liver tissues. There was a trend for gradually increased MTDH expression from normal liver tissue to hepatitis B and HBV-related HCC tissues. Furthermore, a statistical analysis revealed that MTDH expression significantly correlated with the American Joint Committee on Cancer (AJCC, 7th edition) stage (P=0.020), T classification (P= 0.007), N classification (P= 0.044), vascular invasion (P=0.006) and histological differentiation (P=0.020) in the HBV-related HCC patients. In addition, patients with high MTDH levels had shorter survival times compared to those with low MTDH expression (P=0.001). Taken together, these results suggest that MTDH could be a potential prognostic marker for overall survival and tumor progression and a chemotherapeutic target in HBV-related HCC patients.

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