The Natural Compound Dehydrocrenatidine Attenuates Nicotine-Induced Stemness and Epithelial-Mesenchymal Transition in Hepatocellular Carcinoma by Regulating a7nAChR-Jak2 Signaling Pathways.

Autor: Li CL; Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.; Department of Surgery, Pojen General Hospital, Taipei City 105, Taiwan., Wang CC; Department of Surgery, Pojen General Hospital, Taipei City 105, Taiwan., Pai HT; Department of Surgery, Pojen General Hospital, Taipei City 105, Taiwan., Tu SL; Department of Surgery, Pojen General Hospital, Taipei City 105, Taiwan., Hou PY; Department of Surgery, Pojen General Hospital, Taipei City 105, Taiwan., Huang CY; Department of Surgery, Taipei Medical University, Shuang Ho Hospital, New Taipei City 235, Taiwan.; Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.; Department of Pathology, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan.; Division of Colorectal Surgery, Department of Surgery, Taipei Medical University Shuang Ho Hospital, New Taipei City 235041, Taiwan., Huang MT; Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.; Department of Surgery, Xin Tai General Hospital, New Taipei City 235, Taiwan., Chang YJ; Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.; Department of Pathology, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan.; Cancer Research Center and Translational Laboratory, Department of Medical Research, Taipei Medical University Hospital, Taipei Medical University, Taipei 110, Taiwan.; Cell Physiology and Molecular Image Research Center, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan.
Jazyk: angličtina
Zdroj: Disease markers [Dis Markers] 2022 Jan 24; Vol. 2022, pp. 8316335. Date of Electronic Publication: 2022 Jan 24 (Print Publication: 2022).
DOI: 10.1155/2022/8316335
Abstrakt: Background: Exposure to nicotine has been observed associated with tumor progression, metastasis, and therapy resistance of many cancers. Hepatocellular carcinoma (HCC) is one major cancer related to the liver and the most difficult to treat malignancies worldwide. The underlying mechanism of nicotine in the stimulation of HCC tumorigenesis is still not studied well.
Methods: Classically, nicotine binds to nicotinic acetylcholine receptors (nAChRs) and induces many downstream cancer-associated signaling pathways. Big data analysis is used to explore the importance of a7nAChR-Jak2 axis in the progression of hepatocellular carcinoma. Bioinformatic analysis was performed to determine gene associated with a7nAChR-Jak2 axis of HCC patients. Biological importance of a7nAChR-Jak2 axis was investigated in vitro (Hun7 and HepG2 cell lines), and athymic nude mouse models bearing HepG2-HCC cells xenografts were established in vivo .
Result: We found that nicotine exposure stimulated the HCC tumorigenicity by inducing the expression of one of the key nAChRs subunit that is α 7nAChR as well as the expression of Janus kinase (JAK)-2. In both the in vitro and in vivo studies, the reduced overexpression of α 7nAChR and increased sensitization of HCC towards treatment is observed with dehydrocrenatidine (DHCT), a novel and potent JAK family kinase inhibitor. Interestingly, DHCT treatment results in the reduction of the epithelial-mesenchymal transition process which leads to a significant reduction of clonogenicity, migratory, and invasive ability of HCC cells. Moreover, DHCT treatment also inhibits the cancer stem cell phenotype by inhibiting the tumor-sphere formation and reducing the number of ALDH1+ cells population in nicotine-stimulated HCC cells.
Conclusions: Taken together, the presented results indicate the positive effect of inhibition of nicotine induced overexpression of α 7nAChR and JAK2, unique to HCC. Thus, these findings suggest the nicotine effect on HCC progression via α 7nAChR-mediated JAK2 signaling pathways, and DHCT treatment enhances the therapeutic potential of HCC patients via overcoming/reversing the effect of nicotine in HCC patients.
Competing Interests: We confirm that we have no known conflicts of interest associated with this publication, and no significant financial support for this work could have influenced its outcome.
(Copyright © 2022 Ching-Li Li et al.)
Databáze: MEDLINE
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