Abstract
Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and is one of the leading causes of cancer-related deaths worldwide. Regorafenib, a multi-kinase inhibitor, is used as a second-line treatment for advanced HCC. Here, we aimed to investigate the mechanism of the antitumor effect of regorafenib on HCC and evaluate altered microRNA (miRNA) expression. Cell proliferation was examined in six HCC cell lines (HuH-7, HepG2, HLF, PLC/PRF/5, Hep3B, and Li-7) using the Cell Counting Kit-8 assay. Xenografted mouse models were used to assess the effects of regorafenib in vivo. Cell cycle analysis, western blotting analysis, and miRNA expression analysis were performed to identify the antitumor inhibitory potential of regorafenib on HCC cells. Regorafenib suppressed proliferation in HuH-7 cell and induced G0/G1 cell cycle arrest and cyclin D1 downregulation in regorafenib-sensitive cells. During miRNA analysis, miRNA molecules associated with the antitumor effect of regorafenib were found. Regorafenib suppresses cell proliferation and tumor growth in HCC by decreasing cyclin D1 via alterations in intracellular and exosomal miRNAs in HCC.
Highlights
Hepatocellular carcinoma (HCC) is the most common primary malignant tumor of the liver [1] and is an important medical problem
The aim of this study was to confirm that regorafenib suppresses cell proliferation and tumor growth in HCC cells by inducing cell cycle arrest in vitro and in vivo, and to identify miRNA signatures associated with its antitumor effect
We analyzed other proteins involved in the G0 to G1 transition and found that CDK4 levels decreased after the addition of regorafenib. These results indicate that regorafenib suppresses the G0/G1 phase transition and suppresses cell growth in HuH-7 cells by reducing cyclin D1
Summary
Hepatocellular carcinoma (HCC) is the most common primary malignant tumor of the liver [1] and is an important medical problem. In 2012, 782,000 cases were diagnosed worldwide, with 746,000 deaths, and the worldwide age-adjusted incidence rate was 10 cases per 100,000 person-years [2,3]. It is the second most common neoplasm and is ranked as the third leading cause of cancer-related deaths [2,3]. Standard systemic chemotherapy in patients with advanced HCC relies on the multi-kinase inhibitors sorafenib and lenvatinib, with regorafenib as the second-line therapy [5,6,7]. Novel and effective therapeutic strategies are of prime importance for advanced HCC
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