2. Academic Validation
  3. Lenvatinib inhibited HCC cell migration and invasion through regulating the transcription and ubiquitination of UHRF1 and DNMT1

Lenvatinib inhibited HCC cell migration and invasion through regulating the transcription and ubiquitination of UHRF1 and DNMT1

  • Biochem Pharmacol. 2023 Mar 7;115489. doi: 10.1016/j.bcp.2023.115489.
Ting Fang 1,  Zhen Jiao 1,  Yuting You 1,  Jiahao Cao 1,  Chuanzheng Wang 1,  Jingjing Liu 2,  Wenxiu Zhao 3
Affiliations

Affiliations

  • 1 Xiamen Key Laboratory of Translational Medical of Digestive System Tumor, Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361004, P. R. China.
  • 2 Xiamen Key Laboratory of Intestinal Microbiome and Human Health, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361004, P. R. China. Electronic address: jingjingliu@xmu.edu.cn.
  • 3 Xiamen Key Laboratory of Translational Medical of Digestive System Tumor, Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361004, P. R. China. Electronic address: wxzhao@xmu.edu.cn.
PMID: 36893815 DOI: 10.1016/j.bcp.2023.115489
Abstract

Hepatocellular carcinoma (HCC) is one of the most common causes of malignancy-related deaths. Lenvatinib, as a multi-targeted tyrosine kinase inhibitor, has gained increasing attention for its antitumor activity. However, the effect and mechanisms of Lenvatinib on HCC metastasis are virtually unknown. In this study, we revealed that Lenvatinib inhibited HCC cell motility and epithelial mesenchymal transition (EMT), along with cell adhesion and extension. Concomitant high DNMT1 and UHRF1 mRNA levels were in HCC patients and indicated worse prognosis. On the one hand, Lenvatinib modulated the transcription of UHRF and DNMT1via negatively regulation of ERK/MAPK pathway. On the Other hand, Lenvatinib downregulated DNMT1 and UHRF1 expression by promoting their protein degradation through ubiquitin-proteasome pathway, consequently, resulting in upregulation of E-Cadherin. Moreover, Lenvatinib attenuated Huh7 cell adhesion and metastasis in vivo. Our findings provided insight into the intriguing molecular mechanisms regarding the anti-metastasis effect of Lenvatinib in HCC.

Keywords

DNMT1; ERK/MAPK; Lenvatinib; UHRF1; hepatocellular carcinoma.

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