MicroRNAs Regulating Hippo-YAP Signaling in Liver Cancer

Abstract

Liver cancer is one of the most common cancers worldwide, and its prevalence and mortality rate are increasing due to the lack of biomarkers and effective treatments. The Hippo signaling pathway has long been known to control liver size, and genetic depletion of Hippo kinases leads to liver cancer in mice through activation of the downstream effectors yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ). Both YAP and TAZ not only reprogram tumor cells but also alter the tumor microenvironment to exert carcinogenic effects. Therefore, understanding the mechanisms of YAP/TAZ-mediated liver tumorigenesis will help overcome liver cancer. For decades, small noncoding RNAs, microRNAs (miRNAs), have been reported to play critical roles in the pathogenesis of many cancers, including liver cancer. However, the interactions between miRNAs and Hippo-YAP/TAZ signaling in the liver are still largely unknown. Here, we review miRNAs that influence the proliferation, migration and apoptosis of tumor cells by modulating Hippo-YAP/TAZ signaling during hepatic tumorigenesis. Previous findings suggest that these miRNAs are potential biomarkers and therapeutic targets for the diagnosis, prognosis, and treatment of liver cancer.

Keywords: Hippo kinase; Yes-associated protein; cancer therapy; diagnosis; hepatocellular carcinoma; liver disease; microRNAs; prognosis.

Figure 1

MicroRNAs that regulate the core components of Hippo signaling pathway. Several microRNAs are involved in kinase cascade (MST1/2 and LATS1/2) and downstream effectors (YAP/TAZ) of the Hippo signaling pathway in liver cancer as either oncogenes or tumor suppressors. Abbreviations: NF2, Neurofibromin 2; MST1/2, Mammalian STE20-like 1/2; SAV, Salvador; LATS1/2, Large Tumor Suppressor 1/2; MOB, Mps one binder kinase activator; YAP/TAZ, Yes-associated protein and transcriptional coactivator with PDZ-binding motif; TEAD, TEA domain family member; VGLL4, Vestigial like family member 4; AREG, amphiregulin; CTGF, connective tissue growth factor; CYR61, Cysteine-rich angiogenic inducer 61.