Functional Characterization Of MiRNA-7and Autocrine Growth Hormone And Prolactin In Cancer Development

Focal adhesion kinase (FAK) is an important mediator of extracellular matrix integrin signaling, cell motility, cell proliferation and cell survival. Increased FAK expression is observed in a variety of solid human tumors and increased FAK expression and activity frequently correlate with metastatic disease and poor prognosis. Herein we identify miR-7as a direct regulator of FAK expression. miR-7expression is decreased in malignant versus normal breast tissue and its expression correlates inversely with metastasis in human breast cancer patients. Forced expression of miR-7produced increased E-CADHERIN and decreased FIBRONECTIN and VIMENTIN expression in breast cancer cells. The levels of miR-7expression was positively correlated with E-CADHERIN mRNA and negatively correlated with VIMENTIN mRNA levels in breast cancer samples. Forced expression of miR-7in aggressive breast cancer cell lines suppressed tumor cell monolayer proliferation, anchorage independent growth, three-dimensional growth in Matrigel, migration and invasion. Conversely, inhibition of miR-7in the HBL-100mammary epithelial cell line promoted cell proliferation and anchorage independent growth. Rescue of FAK expression reversed miR-7suppression of migration and invasion. miR-7also inhibited primary breast tumor development, local invasion and metastatic colonization of breast cancer xenografts. Thus, miR-7expression is decreased in metastatic breast cancer, correlates with the level of epithelial differentiation of the tumor and inhibits metastatic progression.Hepatocellular carcinoma (HCC) is a malignant tumor which have extreme high incidence and mortality rate in China. The molecular targeted therapy is a emerging strategy for treatment of HCC. We find that both growth hormone (hGH) and prolactin (hPRL) are upregulated in HCC tissues compared with corresponding normal tissues. hGH expression was significantly associated with tumor size and tumor grade. No significant association was observed between the expression of hPRL and any histopathological features. Both hGH and hPRL expression were associated with worse relapse-free and overall survival in HCC patients. Autocrine expression of hGH or hPRL in HCC cells increased STAT3activation, oncogenicity tumor growth while functional antagonism with hGH-G120R, a hGH and hPRL dual antagonist, significantly reduced these parameters. hGH and hPRL function as autocrine/paracrine growth factors in HCC.