OncoTargets and Therapy (Oct 2020)
Targeting Yes1 Associated Transcriptional Regulator Inhibits Hepatocellular Carcinoma Progression and Improves Sensitivity to Sorafenib: An in vitro and in vivo Study
Abstract
Liwen Guo,* Jiaping Zheng,* Jun Luo, Zhewei Zhang, Guoliang Shao 1Department of Interventional Radiology, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, People’s Republic of China*These authors contributed equally to this workCorrespondence: Guoliang ShaoDepartment of Interventional Radiology, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, 1 East Banshan Road, Hangzhou 310022, People’s Republic of ChinaTel +86-0571-88122222Email [email protected]: The aim of this study was to investigate the role of Yes1 associated transcriptional regulator (YAP1) in the pathology of hepatocellular carcinoma (HCC) and its potential as a therapeutic target.Methods: YAP1 expression in HCC and adjacent tissues was determined via immunohistochemistry; in HCC and human normal liver cell lines, expression was examined via Western blotting. The effects of YAP1 knockdown and overexpression were detected following transfection of HCC cells with siRNA-YAP1 recombinants or pcDNA3.1-YAP1 plasmids. A tumor xenograft model was constructed by implanting YAP1-knockdown lentivirus-infected Hep-3B cells into nude mice, and the animals were treated with sorafenib.Results: In patients with HCC, YAP1 was upregulated in tumor tissue compared with adjacent tissue, and its high expression in the tumor was associated with increased Edmonson grade. In vitro, YAP1 expression was increased in Hep-3B, SK-HEP-1 and Huh7 cells, while it was similar in SMMC-7721 cells and LO2 cells. Meanwhile, YAP1 increased cell proliferation and invasion, promoted the progression of epithelial–mesenchymal transition, and inhibited cell apoptosis in HCC cells; furthermore, YAP1 knockdown combined with the administration of sorafenib decreased cell viability and increased cell apoptosis compared with YAP1 knockdown or treatment with sorafenib alone. In vivo, YAP1 knockdown inhibited tumor growth and metastasis, whereas it promoted apoptosis; meanwhile, YAP1 knockdown synergized with sorafenib to suppress tumor progression in HCC mice.Conclusion: YAP1 is upregulated in both HCC tumor tissues and cell lines. Moreover, it promotes cell proliferation and invasion and promoted the progression of epithelial–mesenchymal transition in vitro. Furthermore, targeting YAP1 inhibits HCC progression and improves sensitivity to sorafenib in vitro and in vivo.Keywords: Yes1 associated transcriptional regulator, hepatocellular carcinoma, sorafenib, proliferation, invasion, apoptosis
