MicroRNA-10a Is Involved in the Metastatic Process by Regulating Eph Tyrosine Kinase Receptor A4-Mediated Epithelial-Mesenchymal Transition and Adhesion in Hepatoma Cells

Abstract

MicroRNAs (miRNAs) have been reported to be associated with the development of cancers. However, the function of miRNAs in human hepatocellular carcinoma (HCC) remains largely undefined. Here we found that overexpression of miR-10a promoted the migration and invasion of QGY-7703 and HepG2 cells in vitro but suppressed metastasis in vivo. Cell adhesion assays showed that miR-10a suppressed HCC cell-matrix adhesion, which could explain the results of the in vivo animal experiments. The Eph tyrosine kinase receptor, EphA4, was identified as the direct and functional target gene of miR-10a. Knockdown of EphA4 phenocopied the effect of miR-10a and ectopic expression of EphA4 restored the effect of miR-10a on migration, invasion, and adhesion in HCC cells. We further demonstrated that miR-10a and EphA4 regulated the epithelial-mesenchymal transition process and the b1-integrin pathway to affect cell invasion and adhesion. Conclusion: Our findings highlight the importance of miR-10a in regulating the metastatic properties of HCC by directly targeting EphA4 and may provide new insights into the pathogenesis of HCC. (HEPATOLOGY 2013;57:667-677)

TGF-β-induced miR10a/b expression promotes human glioma cell migration by targeting PTEN

“…The homolog of miR10a, miR10b, has been suggested to enhance tumor cell migration and the invasion of metastatic breast cancer cells by repressing the translation of HoxD10 (16). In addition, miR10a is believed to regulate the metastatic properties of HCC by directly targeting EphA4 (13). miR-10b inhibits translation of the mRNA of HOXD10, a transcription factor known for its roles in cell motility, resulting in the increased expression of a pro-metastatic gene, RHOC.…”

“…The miR10a homolog miR10b is highly overexpressed in several tumor types and is reportedly involved in the progression of cancer (12). miR10a regulates the metastatic properties of hepatocellular cancer (HCC) by directly targeting EphA4 (13) and is involved in the metastatic behavior of pancreatic cancer (14). The homolog of miR10a, miR10b, has been suggested to enhance the migration and invasion of metastatic breast cancer cells by repressing the translation of HoxD10 (15)(16)(17).…”

miRNAs affect the development of hepatocellular carcinoma via dysregulation of their biogenesis and expression

“…For example, miR-612 has inhibitory effects on HCC migration, invasion and metastasis with one direct target, AKT2, through which EMT is inhibited [83]. The Eph tyrosine kinase receptor (EphA4) is one of target genes of miR-10a; by specifically targeting EphA4, miR-10a can act on invasion through EMT and on adhesion through the β1-integrin pathway in HCC cells [84]. ROCK2 (Rho-associated protein kinase 2, ROCK2) can promote EMT through a Rho-dependent actin cytoskeleton remodeling pathway to enhance the invasive and metastatic activity of HCC, and miR-124 can directly target ROCK2 and EZH2 genes to inhibit EMT, which leads to inhibition of the invasive and metastatic activity of HCC [85].…”

DNA Methylation-mediated Repression of miR-941 Enhances Lysine (K)-specific Demethylase 6B Expression in Hepatoma Cells

“…miRNAs can function as tumor suppressors or oncogenes by targeting oncogenes or tumor suppressor genes, respectively (2). There is increasing evidence indicating that miRNAs exist in many types of cancers (3)(4)(5), including hepatocellular carcinoma (HCC) (6,7). HCC is one of the most common malignant tumors with a poor prognosis and is the third leading cause of cancer-related death in the world (8).…”