2. Academic Validation
  3. Osteopontin promotes hepatocellular carcinoma progression through inducing JAK2/STAT3/NOX1-mediated ROS production

Osteopontin promotes hepatocellular carcinoma progression through inducing JAK2/STAT3/NOX1-mediated ROS production

  • Cell Death Dis. 2022 Apr 13;13(4):341. doi: 10.1038/s41419-022-04806-9.
Qipeng Wu 1,  Le Li 1,  Chunmeng Miao 1,  Muhammad Hasnat 2,  Lixin Sun 1,  Zhenzhou Jiang 3 4,  Luyong Zhang 5 6
Affiliations

Affiliations

  • 1 New drug screening center, State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, China Pharmaceutical University, Nanjing, 210009, China.
  • 2 Institute of Pharmaceutical Sciences, University of Veterinary and Animal Sciences, Lahore, 54000, Pakistan.
  • 3 New drug screening center, State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, China Pharmaceutical University, Nanjing, 210009, China. beaglejiang@cpu.edu.cn.
  • 4 Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, Nanjing, 210009, China. beaglejiang@cpu.edu.cn.
  • 5 New drug screening center, State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, China Pharmaceutical University, Nanjing, 210009, China. lyzhang@cpu.edu.cn.
  • 6 The Center for Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou, 510006, China. lyzhang@cpu.edu.cn.
PMID: 35418176 DOI: 10.1038/s41419-022-04806-9
Abstract

Osteopontin (OPN) is a multifunctional cytokine that can impact Cancer progression. Therefore, it is crucial to determine the key factors involved in the biological role of OPN for the development of treatment. Here, we investigated that OPN promoted hepatocellular carcinoma (HCC) cell proliferation and migration by increasing Reactive Oxygen Species (ROS) production and disclosed the underlying mechanism. Knockdown of OPN suppressed ROS production in vitro and in vivo, whereas treatment with human recombinant OPN produced the opposite effect. N-Acetyl-L-cysteine (NAC, ROS scavenger) partially blocked HCC cell proliferation and migration induced by OPN. Mechanistically, OPN induced ROS production in HCC cells by upregulating the expression of NADPH Oxidase 1 (NOX1). NOX1 knockdown in HCC cells partially abrogated the cell proliferation and migration induced by OPN. Moreover, inhibition of JAK2/STAT3 phosphorylation effectively decreased the transcription of NOX1, upregulated by OPN. In addition, NOX1 overexpression increased JAK2 and STAT3 phosphorylation by increasing ROS production, creating a positive feedback loop for stimulating JAK2/STAT3 signaling induced by OPN. This study for the first time demonstrated that HCC cells utilized OPN to generate ROS for tumor progression, and disruption of OPN/NOX1 axis might be a promising therapeutic strategy for HCC.

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