LOXL3‐promoted hepatocellular carcinoma progression via promotion of Snail1/USP4‐mediated epithelial‐mesenchymal transition

• DOI: 10.1002/tox.23617
• Publication Date: 2022-07-16T14:21:18Z
• Authors: Rong Li; Runze Shang; Shunle Li; Yifan Ren; Lin Shen; Longbao Yang; Shuo Chen; Xi Chen; Junhui Li; Meng Xu
• Keywords: 0301 basic medicine; Carcinoma, Hepatocellular; Epithelial-Mesenchymal Transition; Liver Neoplasms; 3. Good health; Gene Expression Regulation, Neoplastic; Transforming Growth Factor beta1; 03 medical and health sciences; Cell Movement; Cell Line, Tumor; Humans; Amino Acid Oxidoreductases; Snail Family Transcription Factors; Ubiquitin-Specific Proteases

AbstractLysyl‐oxidase‐like 3 (LOXL3) was reported to be essential in epithelial‐mesenchymal transition (EMT) of cancers. However, the role of LOXL3 in hepatocellular carcinoma (HCC) remained unclear. In this study, we explored clinical significance, biological functions, and regulatory mechanisms of LOXL3 in HCC. Our study found that LOXL3 expression was markedly associated with the tumor size and clinical stage of HCC, and it was highly expressed in tumor tissues of metastatic HCC patients. High expression of LOXL3 predicted a poor prognosis of HCC. TGF‐β1 treatment elevated LOXL3 protein expression and cell invasion, and reduced cell apoptosis in HCC cell lines (SMMC‐7721 and Huh‐7), while downregulation of LOXL3 reversed the promotive effects of TGF‐β1 treatment on LOXL3 protein expression and cell invasion, and the inhibitory effect on cell apoptosis. Mechanistically, LOXL3 interacted with snail family transcriptional repressor 1 (Snail1) through STRING database and RIP assay, and Snail1 bound to ubiquitin‐specific peptidase 4 (USP4) promoter by JASPAR database, luciferase reporter gene and Co‐IP assays. Overexpression of USP4 reversed the inhibitory effect of LOXL3 silence on EMT in HCC cells through deubiquitinating and stabilizing the expression of Snail1. Moreover, LOXL3‐promoted HCC EMT through Wnt/β‐catenin/Snail1 signaling pathway. In vivo study revealed that silence of LOXL3‐inhibited HCC tumor growth. In conclusion, LOXL3 silence inhibited HCC invasion and EMT through Snail1/USP4‐mediated circulation loop and Wnt/β‐catenin signaling pathway.