Hepatocellular carcinoma (HCC) is one of the main causes of cancer-related mortality worldwide. It has a poor prognosis due to aggressive phenotype, and limited and insufficient treatment options. In HCCs, acquisition of epithelial mesenchymal transition (EMT) features may account for tumor aggressiveness and chemo-resistance. Many of G protein-coupled receptors (GPCRs) are overexpressed and mutated in tumor microenvironments, promoting tumor growth and metastasis. The heterotrimeric guanine nucleotide-binding proteins are responsible for pathophysiological processes by transducing signals from GPCRs to downstream effectors. With the accumulation of knowledge that overexpression of specific G proteins are present in tumors, there has been an increased interest in identifying the role of specific G protein subtypes in the regulation of tumor biology. Among them, Gα12 facilitates potent neoplastic transformation and change of cancer cell to a more aggressive phenotype. In recent studies, we found the overexpression of Gα12 in the patients with HCC and their poor survival rate [1, 2]. microRNAs (miRNAs) are small non-coding RNAs regulating gene expression and recently emerged as crucial players in hepatocarcinogenesis and HCC progression because of the ability to control multiple targets and modulate biological activities. In the previous study, we found that Gα12 overexpression causes dysregulation of a set of miRNAs necessary for the maintenance of epithelial phenotype [1]. One of the most interesting findings in our miRNome study was that Gα12 activation significantly repressed (5 years). Our findings provide a key information on (1) the crosstalk of GPCR-Gα12-RTK receptors or enforcement of GPCR-G protein signaling through a positive feedback loop, and (2) the impact of the identified molecular network on the progression of HCC to more aggressive phenotype, supporting the concept that intervention of the molecules in the network may be of help to slow invasion and improve targeted therapy. From a clinical perspective, the molecules identified in the present study may be utilized as prognostic biomarkers to predict recurrence of HCC.