TPI1-reduced extracellular vesicles mediated by Rab20 downregulation promotes aerobic glycolysis to drive hepatocarcinogenesis.

Abstract

Rab GTPases are major mediators that ensure the proper spatiotemporal regulation of intracellular trafficking. Functional impairment and altered expression of Rab proteins have been revealed in various human cancers. There is an emerging evidence about the role of Rab proteins in the biogenesis of extracellular vesicles (EVs). In hepatocellular carcinoma (HCC), using RNA sequencing comparing expression profiles of adjacent non-tumorous tissues and HCC, Rab20 is identified to be the most frequently downregulated Rab member in HCC. Functionally, restoration of Rab20 in metastatic HCC cells results in the release of EVs with a diminished activity to promote cell growth, motility and metastasis. Conversely, EVs released from normal liver cells with Rab20 knockdown loses suppressive effect on HCC cell growth and motility. Proteomic profiling revealed the level of triosephosphate isomerase 1 (TPI1), a glycolytic enzyme, in EVs to be positively associated with Rab20 expression of the releasing cells. TPI1 targeted to be expressed in EVs released by Rab20 knockdown cells compromises the oncogenic activity of EVs. Besides, EVs released by TPI1 knockdown cells recapitulates the promoting effect of EVs derived from HCC cells with Rab20 underexpression. Aerobic glycolysis is beneficial to the survival and proliferation of tumour cells. Here, we observed that the enhanced cell growth and motility are driven by the enhanced aerobic glycolysis induced by EVs with reduced TPI1. The addition of glycolytic inhibitor blocks the promoting effect of EVs with reduced TPI1. Taken together, our study provides a mechanistic link among tumour cell-derived EVs and glucose metabolism in HCC with Rab20 deregulation.

• Authors: Bonnie Hei Man Liu, Sze Keong Tey, Xiaowen Mao, Angel Po Yee Ma, Cherlie Lot Sum Yeung, Samuel Wan Ki Wong, Tung Him Ng, Yi Xu, Yue Yao, Eva Yi Man Fung, Kel Vin Tan, Pek-Lan Khong, Daniel Wai-Hung Ho, Irene Oi-Lin Ng, Alexander Hin Ning Tang, Shao Hang Cai, Jing Ping Yun, Judy Wai Ping Yam
• Journal: Journal of extracellular vesicles (J Extracell Vesicles) Vol. 10 Issue 10 Pg. e12135 (08 2021) ISSN: 2001-3078 [Print] United States
• PMID: 34401050 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 The Authors. Journal of Extracellular Vesicles published by Wiley Periodicals, LLC on behalf of the International Society for Extracellular Vesicles.

Chemical References

• Rab20 protein, human
• rab GTP-Binding Proteins
• Triose-Phosphate Isomerase

Topics

• Carcinogenesis (metabolism)
• Carcinoma, Hepatocellular (genetics, metabolism)
• Cell Line, Tumor
• Cell Movement
• Extracellular Vesicles (metabolism)
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• Gene Knockdown Techniques
• Glycolysis
• Humans
• Liver Neoplasms (genetics, metabolism)
• Sequence Analysis, RNA
• Triose-Phosphate Isomerase (genetics, metabolism)
• rab GTP-Binding Proteins (genetics, metabolism)