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Introduction
Human hepatocellular carcinoma (HCC) is one of the most common types of cancer, causing almost 600,000 mortalities annually, worldwide (1). Chronic inflammatory liver disease including viral infection and exposure to chemical carcinogens are the common prologues of HCC. Surgical removal of the tumor and liver transplant are currently the most effective treatment options for HCC, although metastasis and recurrence are extremely common in patients who have undergone resection. Therefore, understanding the molecular mechanisms of HCC tumorigenesis is an essential step in identifying more effective treatments.
The Hippo signaling pathway is an evolutionary conserved cascade, and it was previously reported to play a critical role in liver regeneration and, more significantly, HCC tumorigenesis (2). The machinery of the Hippo signaling pathway consists of Mst1/2, WW45, Lats1/2 and Mob1, and the downstream effectors are Yes-associated protein 1 (YAP1), TAZ and transcriptional enhancer activation domain family members (TEADs) (1). When the upstream effectors are activated they recruit YAP1-TAZ complex, which is transferred into the nucleus to interact with TEADs, and drives target gene expression to promote cell proliferation and suppress apoptosis (3). The disruption of YAP1-TEAD interaction by YAP-like peptides leads to a significant decrease in the tumor growth rate (4,5). The overexpression of YAP1 in transgenic mice was observed to lead to liver outgrowth and HCC (6). YAP1 was reported to be upregulated in over 60% of HCC patients, and is an independent predictor for patient survival (7). These studies clearly suggest that YAP1 is an essential downstream effector of the Hippo signaling pathway and furthermore a promising drug target for the inhibition of HCC tumorigenesis.
microRNAs (miRNAs or miRs) are a class of 21–25 nucleotide long, small non-coding RNA molecules, which recognize specific complementary sequences predominantly identified in the 3′-untranslated region (UTR) of target mRNAs. miRNAs either repress translation or degrade target mRNAs (8,9). miRNAs have been implicated in various forms of cancer, including liver cancer, by altering the expression of oncogenes or tumor suppressor genes (10,11). One of the most extensively studied microRNAs targeting YAP1 is miR-375. It was initially identified as a negative regulator of YAP1 by targeting its 3′-UTR in HCC patient tissues and human HCC cell lines (12). It was later confirmed that miR-375 also exhibited the same functions in HCC...