Macrophages-induced long noncoding RNA H19 up-regulation triggers and activates the miR-193b/MAPK1 axis and promotes cell aggressiveness in hepatocellular carcinoma.

Abstract

Dysregulation of long noncoding RNA (lncRNA) H19 has been implicated in hepatocellular carcinoma (HCC), but the concrete regulatory mechanism is lack of research. We mined gene expression profiles of 457 HCC samples from TCGA and TJMUCH cohorts and further validated in 64 FFPE HCC tissues. LncRNA H19 overexpression in situ was significantly correlated with poor prognosis of HCC patients, which induced EMT, promoted stemness and accelerated invasion of HCC cells in vitro. Co-expression network analysis indicated lncRNA H19 negatively correlated with miR-193b and positively correlated with MAPK1 gene, which implicated that lncRNA H19 served as a sponge molecule to hijack miR-193b and protect MAPK1. Forced overexpression of H19 attenuated miR-193b-mediated inhibition on multiple driver oncogenes (EGFR, KRAS, PTEN and IGF1R) and MAPK1 gene, thus triggered EMT and stem cell transformation in HCC. LncRNA H19 positively correlated with CD68 + TAMs in situ. TAMs-induced lncRNA H19 promotes HCC aggressiveness via triggering and activating the miR-193b/MAPK1 axis, mediates the crosstalk between HCC and immunological microenvironment, and causes poor clinical outcomes. LncRNA H19 is a valuable predictive biomarker and potential therapeutic target in HCC.