J Cancer 2020; 11(15):4397-4405. doi:10.7150/jca.43459

Research Paper

Loss of PDK4 expression promotes proliferation, tumorigenicity, motility and invasion of hepatocellular carcinoma cells

Yu-Juan Qin1,3,4*, Tao-Yan Lin1,5*, Xiao-Lin Lin1*, Yu Liu3, Wen-Tao Zhao6, Xiao-Yan Li3, Mei Lian3, Heng-Wei Chen3, Yong-Long Li3, Xiao-Ling Zhang7, Dong Xiao1,3✉, Jun-Shuang Jia1✉, Yan Sun2✉

1. Guangdong Provincial Key Laboratory of Cancer Immunotherapy Research and Guangzhou Key Laboratory of Tumor Immunology Research, Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
2. Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China
3. Institute of Comparative Medicine & Laboratory Animal Center, Southern Medical University, Guangzhou 510515, China
4. Department of Radiology, The 5th Affiliated Hospital of Sun Yat-Sen University, Zhuhai 519000, China
5. Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
6. Department of Medical Oncology, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming 650118, China
7. Department of Physiology, Faculty of Basic Medical Sciences, Guilin Medical University, Guilin 541004, China
* First Authors

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Qin YJ, Lin TY, Lin XL, Liu Y, Zhao WT, Li XY, Lian M, Chen HW, Li YL, Zhang XL, Xiao D, Jia JS, Sun Y. Loss of PDK4 expression promotes proliferation, tumorigenicity, motility and invasion of hepatocellular carcinoma cells. J Cancer 2020; 11(15):4397-4405. doi:10.7150/jca.43459. Available from http://www.jcancer.org/v11p4397.htm

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Although the roles and underlying mechanisms of other PDK family members (i.e., PDK1, PDK2 and PDK3) in tumor progression have been extensively investigated and are well understood, the functions and underlying molecular mechanisms of pyruvate dehydrogenase kinase 4 (PDK4) in the tumorigenesis and progression of various cancers [including hepatocellular carcinoma (HCC)] remain largely unknown. In this study, we examined the expression profile of PDK4 in HCC clinical tissue specimens and the roles of PDK4 in the proliferation, tumorigenicity, motility and invasion of HCC cells. The immunohistochemistry (IHC) and quantitative real-time PCR (qRT-PCR) results revealed that PDK4 was significantly downregulated in the cohort of HCC clinical specimens. Additionally, PDK4 protein was found in both the nucleus and cytoplasm of HCC cells based on an immunofluorescence (ICC) assay, and PDK4 protein was also found in the nucleus and cytoplasm of cancer cells contained in HCC clinical specimens based on IHC. The CCK-8 assay and cell colony formation assay demonstrated that stable depletion of endogenous PDK4 by lentivirus-mediated RNA interference (RNAi) markedly promoted the proliferation of HCC cell lines (i.e., BEL-7402 and BEL-7404 cells) in vitro, while PDK4 silencing significantly enhanced the tumorigenic ability of BEL-7404 cells in vivo. In addition to enhance proliferation and tumorigenesis induced by PDK4 silencing, additional studies demonstrated that knockdown of PDK4 led to increase migration and invasion of BEL-7402 and BEL-7404 cells in vitro. Taken together, these findings suggest that the loss of PDK4 expression contributes to HCC malignant progression.

Keywords: Hepatocellular carcinoma, Pyruvate dehydrogenase kinase 4, Cell proliferation, Migration, Invasion