2. Academic Validation
  3. Oxidative stress induces extracellular vesicle release by upregulation of HEXB to facilitate tumour growth in experimental hepatocellular carcinoma

Oxidative stress induces extracellular vesicle release by upregulation of HEXB to facilitate tumour growth in experimental hepatocellular carcinoma

  • J Extracell Vesicles. 2024 Jul;13(7):e12468. doi: 10.1002/jev2.12468.
Jiufei Duan 1,  Zhao Huang 2,  Siyuan Qin 1,  Bowen Li 1,  Zhe Zhang 3,  Rui Liu 4,  Kui Wang 1,  Edouard C Nice 5,  Jingwen Jiang 2,  Canhua Huang 1
Affiliations

Affiliations

  • 1 Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, P.R. China.
  • 2 West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, P.R. China.
  • 3 MOE Joint International Research Laboratory of Pancreatic Diseases, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
  • 4 State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, P.R. China.
  • 5 Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.
PMID: 38944674 DOI: 10.1002/jev2.12468
Abstract

Extracellular vesicles (EVs) play a crucial role in triggering tumour-aggressive behaviours. However, the energetic process by which tumour cells produce EVs remains poorly understood. Here, we demonstrate the involvement of β-hexosaminidase B (HEXB) in mediating EV release in response to oxidative stress, thereby promoting the development of hepatocellular carcinoma (HCC). Mechanistically, Reactive Oxygen Species (ROS) stimulate the nuclear translocation of transcription factor EB (TFEB), leading to the upregulation of both HEXB and its antisense lncRNA HEXB-AS. HEXB-AS can bind HEXB to form a protein/RNA complex, which elevates the protein stability of HEXB. The stabilized HEXB interacts with lysosome-associated membrane glycoprotein 1 (LAMP1), disrupting lysosome-multivesicular body (MVB) fusion, which protects EVs from degradation. Knockdown of HEXB efficiently inhibits EV release and curbs HCC growth both in vitro and in vivo. Moreover, targeting HEXB by M-31850 significantly inhibits HCC growth, especially when combined with GW4869, an inhibitor of exosome release. Our results underscore the critical role of HEXB as a modulator that promotes EV release during HCC development.

Keywords

EV secretion; hepatocellular carcinoma; lysosome; β‐hexosaminidase B (HEXB).

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