Regulatory MiR‐148a‐ACVR1/BMP circuit defines a cancer stem cell‐like aggressive subtype of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide and the third most common cancer in Asia. HCC has heterogeneous etiologic and molecular profiles and a varied response to therapeutics. The high recurrence rate and curtailed survival in this cancer are attributed to its resistance to therapy. The ultimate goal is to develop a more effective personalized therapeutic strategy for HCC, but the first step is to develop a system for classifying the disease on the basis of molecular biomarkers. To that end, we performed mRNA and microRNA (miRNA) expression profiling in 100 HCC tissues. Clustering analysis of informative genes identified two robust subtypes, which were validated by an independent dataset. The subtype characterized by a cancer stem cell-like signature was clinically aggressive and associated with poor survival. Integrated analysis of miRNA and mRNA expression in this subtype showed that miR-148a was expressed at a significantly lower level in these tumors than in the other subtype. MiR-148a has been shown to directly suppress the expression of activin A receptor type 1 (ACVR1), a key receptor in the signaling pathway of the bone morphogenetic proteins (BMPs), which regulate many stem cell markers as well as the clinically important cytokine interleukin-8 (IL-8). Increased expression of ACVR1 and its downstream genes EPCAM, CD24, CD90, and IL-8 was associated with shorter survival in a larger cohort of 227 HCC cases. Introduction of miR-148a resulted in suppressed tumor phenotypes both in vitro and in vivo.