Factor VII-Induced MicroRNA-135a Inhibits Autophagy and Is Associated with Poor Prognosis in Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) is one of the most common and aggressive malignancies worldwide. Treatment outcomes remain poor mainly due to lack of good diagnostic/prognostic markers and limited therapeutic strategies. We previously characterized aberrant activation of the TF/FVII/PAR2 pathway, which subsequently results in decreased autophagy, as a crucial event in malignant progression of HCC. Here, we identified miR-135a as a highly upregulated miRNA in HCC in response to TF/FVII/PAR2 activation. Analyzing 103 HCC patient specimens, we confirmed that miR-135a was frequently elevated in HCC tissues with higher FVII expression compared to adjacent non-cancerous counterparts. Increased miR-135a levels in HCC were also associated with tumor staging, recurrence, microvascular invasion, and decreased disease-free survival. We subsequently identified Atg14, a key component that regulates the formation of autophagosome as a direct target of miR-135a. Ectopic expression of miR-135a suppressed Atg14 levels and inhibited the autophagic processes. Our results indicate strong positive correlations between miR-135a levels and malignant behaviors in HCC patients and also suggest novel functions of miR-135a in regulation of autophagy, which could be useful as a potential target for prognostic and therapeutic uses.

Keywords

• hepatocellular carcinoma
• FVII
• miR-135a
• autophagy
• Atg14
• recurrence
• microvascular invasion
• survival