PAK3 promotes the metastasis of hepatocellular carcinoma by regulating EMT process

Zhi Gao; Mengya Zhong; Zhijian Ye; Zhengxin Wu; Yubo Xiong; Jinsong Ma; Huiyu Chen; Yuekun Zhu; Yan Yang; Yongxiang Zhao; Zhiyong Zhang

doi:10.7150/jca.61918

PAK3 promotes the metastasis of hepatocellular carcinoma by regulating EMT process

J Cancer. 2022 Jan 1;13(1):153-161. doi: 10.7150/jca.61918. eCollection 2022.

Authors

Zhi Gao¹, Mengya Zhong^{2

3}, Zhijian Ye^{1

2}, Zhengxin Wu⁴, Yubo Xiong^{2

3}, Jinsong Ma^{2

3}, Huiyu Chen³, Yuekun Zhu^{5

6}, Yan Yang³, Yongxiang Zhao¹, Zhiyong Zhang^{1

7}

Affiliations

¹ National Center for International Research of Bio-targeting Theranostics, Guangxi Key Laboratory of Bio-targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Bio-targeting Theranostics, Guangxi Medical University, China.
² Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, Xiamen, Fujian, China.
³ School of Medicine, Xiamen University, Xiamen, Fujian, China.
⁴ School of Medicine, Guangxi University, Nanning, Guangxi, China.
⁵ Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
⁶ Medical Center, Duke University, Durham, NC.
⁷ Department of Surgery, Robert-Wood-Johnson Medical School University Hospital, Rutgers University, The State University of New Jersey, New Brunswick, NJ.

Abstract

Purpose: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors. The malignant biological behavior of HCC is closely related to epithelial-mesenchymal transition (EMT), and EMT plays an important role in the progression, migration and metastasis of HCC. P21-activated kinase 3 (PAK3) is a serine/threonine protein kinase, and PAK3 affects the EMT, proliferation, metastasis and invasion of HCC. Methods: In this study, the relationship between PAK3 and HCC was first analyzed by bioinformatics, and then, the expression of PAK3 in clinical samples was detected by immunohistochemistry (IHC), quantitative real-time PCR (qRT-PCR) and Western blotting. Subsequently, the expression of PAK3 was further confirmed in HCC cells. In addition, after the overexpression or knockdown of PAK3 in cells, the proliferation, migration and invasion abilities of these cells were assessed by Cell Counting Kit-8 (CCK-8), wound healing and Transwell assays, and the results were confirmed in vivo experiments in mice. In addition, we also verified that PAK3 affected the EMT and EMT-related pathway of HCC through qRT-PCR, Western blotting and immunofluorescence experiments. Results: Through database analysis, we found that PAK3 was highly expressed in HCC patients and was positively correlated with tumor stage and grade, suggesting that PAK3 expression was closely related to HCC occurrence and development. We subsequently confirmed that PAK3 was overexpressed in HCC clinical samples and HCC cell lines and that PAK3 promoted the proliferation, migration and invasion of HCC cells in vitro. Finally, we found that PAK3 regulated EMT-related molecule expression and EMT-related TGF-β/smad signaling pathway. Conclusion: High expression of PAK3 enhances the invasion of HCC and regulates EMT, suggesting that PAK3 may be a potential target for the treatment of HCC.

Keywords: EMT; HCC; PAK3; smad.