Downregulation of CYR61 promotes hepatocellular carcinoma progression by ameliorating the protumor functions of TGF-β/YAP and impeding the activation of stromal hepatic stellate cells

ABSTRACT: Hepatic stellate cells (HSCs) in the tumor microenvironment play a pivotal role in the development of hepatocellular carcinoma (HCC), which is the major form of primary liver cancers and one of the most lethal cancer types worldwide. TGF-β and Hippo signaling are two critical pathways regulating HSC activation and HCC development through their downstream transcriptional regulators, i.e., Smad proteins and YAP/TEADs, respectively. However, how the two pathways coordinately exert their functions in HCC remains elusive. In this study, we performed integrated analyses of public liver cancer databases and clinical cancer tissues, leading to identification of CYR61 as one of the key candidate genes that may regulate liver cancer progression. TGF-β-activated Smad2/3 and YAP/TEAD4 can form a protein complex to induce CYR61 expression in both cancer cells and stellate cells. As a secreted matricellular protein, CYR61 exerts its tumor suppressor functions via acting on cancer cells directly or regulating the stromal stellate cells. On one hand, CYR61 ameliorates TGF-β- or YAP-mediated liver cancer cell proliferation, colony formation and invasion in vitro, and also tumor growth in nude mice. On the other, CYR61 also impedes cancer cell- or TGF-β-induced stellate cell activation, thereby mitigating the tumor-promoting functions of HSCs as assessed both in vitro and in vivo. In support of its tumor suppressor function, the expression of CYR61 is reduced in HCC tissues and cell lines when compared with their normal counterparts, which is associated with a shorter survival period in cancer patients. Together, these results add new evidence for the interplay between TGF-β and Hippo signaling in regulating gene transcription, and unveil a pivotal role of CYR61 in suppressing liver cancer progression by controlling the activation of hepatic stellate cells in the tumor microenvironment.

ORGANISM(S): Homo sapiens

PROVIDER: GSE222402 | GEO | 2023/01/11

REPOSITORIES: GEO