Investigating the role of transforming growth factor-beta/transforming growth factor-beta receptor in the development of hepatocellular carcinoma through the Salvador-Warts-Hippo pathway.

Abstract

A key component of the Hippo signaling pathway (HSP) is a kinase cascade that connects the tumor suppressor Hippo to the oncoprotein Yki (YAP and TAZ). This oncoprotein functions as a transcriptional coactivator for target genes that play critical roles in cell proliferation and survival. The objective of this study is to evaluate the interaction between TGF-β proteins and key components of the Hippo signaling pathway in regulating hepatocellular carcinoma (HCC) cell behavior. One important achievement of this study was to reveal the significant inhibitory role of the HSP in the growth of HCC cells through TGF-β proteins. In the present study, we examined the expression of key proteins of the Hippo pathway in HCC cells treated with TGF-β proteins and their correlation with the Hippo signaling pathway (HSP) by immunofluorescent staining, immunoblotting method, and Real-time PCR. Both Yes‑associated protein (YAP) and large tumor suppressor 1 (LATS1) were correlated with HCC cells. In the HSP, LATS1 plays as an upstream inhibitory agent of YAP. Nucleus-cytoplasm translocation of YAP1 and overexpression of LATS1 occurred in HCC cells treated with TGF-β. The nucleocytoplasmic distribution of YAP1 and overexpression of LATS1 have anti-oncogenetic roles in the incidence and progression of HCC. TGF-β in 5 ng/mL treatment resulted in a 2.5-fold increase in LATS1 expression and significant YAP1 translocation from the nucleus to the cytoplasm. We concluded that the Hippo signaling pathway mediates TGF-β/TBR-induced effects on HCC progression.