Abstract
Objectives Long noncoding RNA (LncRNA) growth arrest-specific 5 (GAS5) has been characterized as a tumor suppressor in numerous kinds of human cancers. Its anticancer function in hepatocellular carcinoma (HCC) includes repression of cell proliferation and metastasis, leaving the internal mechanisms unclear. In this study, we intended to examine the anti-invasion effects of GAS5 on HCC and explore the downstream regulatory mechanisms. Methods Expression of GAS5 and microRNA-135b (miR-135b) was analyzed by qRT-PCR in paired HCC tissue samples. Their correlation with HCC patients' survival was determined. Transwell assays were done to evaluate in vitro invasion ability. Targeting of GAS5 and RECK by miR-135b was confirmed by qRT-PCR, western blot, and luciferase reporter assays. Results Decreased GAS5 and increased miR-135b in HCC inversely correlate with each other and both correlate with poor prognosis of HCC patients. Functionally, GAS5 suppresses while miR-135b promotes HCC cell invasion capacities in vitro. Mechanistically, GAS5 is a target of miR-135b. Furthermore, GAS5 positively regulates expression of RECK, also a target of miR-135b, which further inhibits MMP-2 expression and contributes to invasion repression. Conclusion GAS5 acted as a tumor suppressor in HCC invasion in a competing endogenous RNA manner. Our findings indicate that GAS5 is a promising therapeutic target for HCC treatment.
Highlights
According to the latest statistics, hepatocellular carcinoma (HCC) is the sixth common malignancy over the world, and the main cause of mortality for patients with cirrhosis [1, 2]
The results showed that growth arrest-specific 5 (GAS5) expression was significantly downregulated while miR-135b was upregulated in HCC tissues compared with paired nontumor tissues (Figure 1(a))
Consistent with the tissue expression patterns, we found that GAS5 was downregulated while miR-135b was upregulated in several HCC cell lines, in comparison with that in the human normal hepatocytes QSG-7701, respectively (Figures 1(e) and 1(f))
Summary
According to the latest statistics, hepatocellular carcinoma (HCC) is the sixth common malignancy over the world, and the main cause of mortality for patients with cirrhosis [1, 2]. Accounting for over 85% of all primary liver cancers, HCC is associated with poor prognosis and becomes incurable because of occurrence of intrahepatic and extrahepatic metastasis [3, 4]. Carcinogenesis of HCC is known to be a sequential multistep process consisting of various genetic and epigenetic alterations [5]. Current HCC therapy options include surgery, biotherapy, and chemotherapy. It is the dimness of HCC pathophysiological mechanisms that largely limits treatment effect of this disease. Keeping on investigating more on its pathological mechanism driving HCC progression is of great importance for drug development
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