Abstract
Hypoxia is a common feature of solid tumors and an important contributor to anti-tumor drug resistance. Hypoxia inducible factor-1 (HIF-1) is one of the key mediators of the hypoxia signaling pathway, and was recently proven to be required for sorafenib resistance in hepatocarcinoma (HCC). MicroRNAs have emerged as important posttranslational regulators in HCC. It was reported that miR-338-3p levels are associated with clinical aggressiveness of HCC. However, the roles of miR-338-3p in HCC disease and resistance to its therapeutic drugs are unknown. In this study, we found that miR-338-3p was frequently down-regulated in 14 HCC clinical samples and five cell lines. Overexpression of miR-338-3p inhibited HIF-1α 3′-UTR luciferase activity and HIF-1α protein levels in HepG2, SMMC-7721, and Huh7 cells. miR-338-3p significantly reduced cell viability and induced cell apoptosis of HCC cells. Additionally, HIF-1α overexpression rescued and HIF-1α knock-down abrogated the anti-HCC activity of miR-338-3p. Furthermore, miR-338-3p sensitized HCC cells to sorafenib in vitro and in a HCC subcutaneous nude mice tumor model by inhibiting HIF-1α. Collectively, miR-338-3p inhibits HCC tumor growth and sensitizes HCC cells to sorafenib by down-regulating HIF-1α. Our data indicate that miR-338-3p could be a potential candidate for HCC therapeutics.
Highlights
Hepatocarcinoma (HCC) is one of the most common human malignancies, causing more than 600,000 deaths worldwide each year
Using the DNA Intelligent Analysis -miRPath v2.0 program, we observed that Hypoxia-inducible factor (HIF)-1a contains conserved miR-338-3p recognition sites in its 39-UTR (Fig. 2A). [24, 25] To confirm that miR-338-3p regulates HIF-1a expression, we assessed HIF-1a protein levels in HepG2, SMMC7721, and Huh-7 cells expressing ectopic miR-338-3p, using western blot
The results showed that HIF-1a levels, under hypoxia, were consistently reduced by miR-338-3p overexpression in all three types of cell lines (Fig. 2B)
Summary
Hepatocarcinoma (HCC) is one of the most common human malignancies, causing more than 600,000 deaths worldwide each year. Half of cases and deaths were estimated to occur in China, the incidence is increasing in Asia, and in the USA, Europe, and Africa [1]. Treatment options for HCC include surgical resection, liver transplantation, radioimmunotherapy, and chemotherapy. The choice of treatment depends on the cancer stage, resource availability, and practitioner choices [2]. Chemotherapy is an important therapeutic strategy for patients who are in advanced stages of disease but are not candidates for surgery [3]. Novel targets and approaches are needed to successfully treat this deadly cancer
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