In Vivo Study Revealed Pro-tumorigenic Effect of CMTM3 in Hepatocellular Carcinoma Involving the Regulation of Peroxisome Proliferator-activated Receptor Gamma (PPARγ)

Overview

Journal Cell Oncol (Dordr)

Publisher Springer

Date 2022 Oct 25

PMID 36284038

Authors

Jiahui Wang

Hongjin Chu

Zhixin Wang

Xuebo Wang

Xuexia Liu

Zhan Song

Fujun Liu

Affiliations

Soon will be listed here.

Abstract

Purpose: To clarify the ambiguity of the function of CMTM3 in the development of hepatocellular carcinoma (HCC) and explore its molecular mechanism.

Methods: The Cmtm3-KO C57BL/6 mouse strain was established using CRISPR-Cas9. Acute liver damage and HCC models were induced by peritoneal injection of 100 or 25 mg/kg.BW N-Nitrosodiethylamine (DEN) to male mice. Liver function and histology were evaluated by blood serum levels of AST and ALT, and HE staining. Gene and protein expression in liver tissues was investigated by RNA-seq, RT-qPCR, Western blotting, immunohistochemistry, and immunofluorescence. Protein-protein interactions were studied by STRING and topological measures. The mRNA expression of CMTM3 and PPARs and patient survival were analyzed using the UALCAN database.

Results: Global knockout of Cmtm3 in KO mice was successfully confirmed. Cmtm3 knockout alleviated DEN-induced acute damage to liver histological integrity and liver function, reduced DNA damage and apoptosis, and also caused a significantly reduced number (WT: 8.7 ± 5.5 vs. KO: 2.7 ± 3.1, P = 0.0394) and total size of tumors (WT: 130.9 ± 181.8 mm vs. KO: 9.3 ± 11.5 mm, P = 0.026) in the liver. Mechanistically, Cmtm3 knockout resulted in reduced expression and inactivation of Pparγ and its downstream lipid metabolism genes (e.g. Adipoq) upon DEN intoxication. CMTM3 and PPARγ were both overexpressed in HCC, and higher levels of both genes were associated with worse overall survival of HCC patients.

Conclusion: This study clarified the pro-tumorigenesis role of CMTM3 in HCC in vivo, possibly through the upregulation of PPARγ and activation of the PPAR pathway.

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