Abstract
MicroRNAs are small RNAs involved in various biological processes and cancer metastasis. miR-196a was associated with aggressive behaviors in several cancers. The role of miR-196a in hepatocellular carcinoma (HCC) metastasis remains unknown. This study aimed to examine the role of miR-196a in HCC progression. Expression of miR-196a was measured in 83 human HCC samples. The HCC patients with high miR-196a expression had younger ages, lower albumin levels, higher frequency with alpha-fetoprotein (AFP) levels ≥20 ng/mL, more macrovascular invasion, and non-early stages. Kaplan–Meier analysis showed that high miR-196a expression was associated with lower recurrence-free survival. Knockdown of miR-196a decreased transwell invasiveness, sphere formation, transendothelial invasion, and Slug, Twist, Oct4, and Sox2 expression, suppressed angiogenesis, and reduced sizes of xenotransplants and number of pulmonary metastasis. Down-regulation of miR-196a decreased Runx2 and osteopontin (OPN) levels. Knockdown of Runx2 in vitro resulted in comparable phenotypes with miR-196a down-regulation. Restoration of Runx2 in miR-196a-knockdown HCC reverted tumor phenotypes. This study showed that high expression of miR-196a is associated with HCC progression in a subset of younger patients. miR-196a mediates HCC progression via upregulation of Runx2, OPN, epithelial–mesenchymal transition (EMT) regulators, and stemness genes. We proposed that miR-196a can be used as a prognostic marker and a potential therapeutic target.
Highlights
Hepatocellular carcinoma (HCC) is the most lethal and prevalent type of liver cancer; it is the sixth most common cancer worldwide, with 841,080 new cases every year
We investigated the role and clinical significance of miR-196a in HCC, and the interaction between miR-196a and epithelial–mesenchymal transition (EMT) regulators and stemness genes
A total of 83 patients with HCC and hepatitis B virus (HBV) infection received tumor resection were recruited in this study
Summary
Hepatocellular carcinoma (HCC) is the most lethal and prevalent type of liver cancer; it is the sixth most common cancer worldwide, with 841,080 new cases every year. HCC ranks third for mortality, and an estimated 781,631 cases die of HCC in the world annually [1]. Despite enormous efforts to improve clinical treatment, HCC remains a major carcinoma with high mortality. Large tumor size, portal invasion, and intrahepatic metastasis are known to shorten the disease-free survival in this carcinoma [2]. Recurrence remains high and is the major cause of mortality of HCC patients [2]. Elucidation of the molecular mechanisms, which induce highly invasive behavior of HCC, is the most important issue for developing strategies to prevent and treat HCC metastasis
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