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

Ching Li Li, Chien Che Wang, Hsin Te Pai, Stan Ley Tu, Pin Yuan Hou, Chien Yu Huang, Ming Te Huang, Yu Jia Chang

研究成果: 雜誌貢獻文章同行評審

4 引文 斯高帕斯(Scopus)

摘要

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 a7nAChR as well as the expression of Janus kinase (JAK)-2. In both the in vitro and in vivo studies, the reduced overexpression of a7nAChR 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 a7nAChR and JAK2, unique to HCC. Thus, these findings suggest the nicotine effect on HCC progression via a7nAChR-mediated JAK2 signaling pathways, and DHCT treatment enhances the therapeutic potential of HCC patients via overcoming/reversing the effect of nicotine in HCC patients.
原文英語
文章編號8316335
期刊Disease Markers
2022
DOIs
出版狀態已發佈 - 2022

ASJC Scopus subject areas

  • 分子生物學
  • 遺傳學
  • 臨床生物化學
  • 生物化學(醫學)

指紋

深入研究「The Natural Compound Dehydrocrenatidine Attenuates Nicotine-Induced Stemness and Epithelial-Mesenchymal Transition in Hepatocellular Carcinoma by Regulating a7nAChR-Jak2 Signaling Pathways」主題。共同形成了獨特的指紋。

引用此