4.5 Article

Sophoridine suppresses lenvatinib-resistant hepatocellular carcinoma growth by inhibiting RAS/MEK/ERK axis via decreasing VEGFR2 expression

期刊

JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
卷 25, 期 1, 页码 549-560

出版社

WILEY
DOI: 10.1111/jcmm.16108

关键词

hepatocellular carcinoma; lenvatinib resistance; sophoridine; VEGFR2

资金

  1. Key R&D Program of Lishui City [2019ZDYF09, 2019ZDYF17]
  2. Jointly Built Key projects of provincial and ministry of the National Health Commission [WKJ-ZJ-1932]
  3. National Natural Science Foundation of China [81803778]
  4. Public Welfare Technology Research Program of Zhejiang Province [LGD19H160002]

向作者/读者索取更多资源

Development of LR HCC cell lines showed that up-regulated VEGFR2 expression is a sign of lenvatinib resistance, while Sophoridine was found to restore sensitivity of lenvatinib against LR HCC cells.
Hepatocellular carcinoma (HCC) is one of the most lethal cancer types with insufficient approved therapies, among which lenvatinib is a newly approved multi-targeted tyrosine kinase inhibitor for frontline advanced HCC treatment. However, resistance to lenvatinib has been reported in HCC treatment recently, which limits the clinical benefits of lenvatinib. This study aims to investigate the underlying mechanism of lenvatinib resistance and explore the potential drug to improve the treatment for lenvatinib-resistant (LR) HCC. Here, we developed two human LR HCC cell lines by culturing with long-term exposure to lenvatinib. Results showed that the vascular endothelial growth factor receptors (VEGFR)2 expression and its downstream RAS/MEK/ERK signalling were obviously up-regulated in LR HCC cells, whereas the expression of VEGFR1, VEGFR3, FGFR1-4 and PDGFR alpha/beta showed no difference. Furthermore, ETS-1 was identified to be responsible for VEGFR2 mediated lenvatinib resistance. The cell models were further used to explore the potential strategies for restoration of sensitivity of lenvatinib. Sophoridine, an alkaloid extraction, inhibited the proliferation, colony formation, cell migration and increased apoptosis of LR HCC cells. In vivo and in vitro results showed Sophoridine could further sensitize the therapeutic of lenvatinib against LR HCC. Mechanism studies revealed that Sophoridine decreased ETS-1 expression to down-regulate VEGFR2 expression along with downstream RAS/MEK/ERK axis in LR HCC cells. Hence, our study revealed that up-regulated VEGFR2 expression could be a predicator of the resistance of lenvatinib treatment against HCC and provided a potential candidate to restore the sensitivity of lenvatinib for HCC treatment.

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