Systemic TM4SF5 overexpression in ApcMin/+ mice promotes hepatic portal hypertension associated with fibrosis

Joohyeong Lee, Eunmi Kim, Min Kyung Kang, Jihye Ryu, Ji Eon Kim, Eun Ae Shin, Yangie Pinanga, Kyung hee Pyo, Haesong Lee, Eun Hae Lee, Heejin Cho, Jayeon Cheon, Wonsik Kim, Eek Hoon Jho, Semi Kim, Jung Weon Lee

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


Mutation of the gene for adenomatous polyposis coli (APC), as seen in ApcMin/+ mice, leads to intestinal adenomas and carcinomas via stabilization of β-catenin. Transmembrane 4 L six family member 5 (TM4SF5) is involved in the development of non-alcoholic fatty liver disease, fibrosis, and cancer. However, the functional linkage between TM4SF5 and APC or β-catenin has not been investigated for pathological outcomes. After interbreeding ApcMin/+ with TM4SF5-overexpressing transgenic (TgTM4SF5) mice, we explored pathological outcomes in the intestines and livers of the offspring. The intestines of 26-week-old dual-transgenic mice (ApcMin/+:TgTM4SF5) had intramucosal adenocarcinomas beyond the single-crypt adenomas in ApcMin/+ mice. Additional TM4SF5 overexpression increased the stabilization of β-catenin via reduced glycogen synthase kinase 3β (GSK3β) phosphorylation on Ser9. Additionally, the livers of the dualtransgenic mice showed distinct sinusoidal dilatation and features of hepatic portal hypertension associated with fibrosis, more than did the relatively normal livers in ApcMin/+ mice. Interestingly, TM4SF5 overexpression in the liver was positively linked to increased GSK3β phosphorylation (opposite to that seen in the colon), β-catenin level, and extracellular matrix (ECM) protein expression, indicating fibrotic phenotypes. Consistent with these results, 78-week-old TgTM4SF5 mice similarly had sinusoidal dilatation, immune cell infiltration, and fibrosis. Altogether, systemic overexpression of TM4SF5 aggravates pathological abnormalities in both the colon and the liver.

Original languageEnglish
Pages (from-to)609-614
Number of pages6
JournalBMB Reports
Issue number12
StatePublished - 2022


  • Adenomatous polyposis coli
  • Colon adenocarcinoma
  • Hepatic portal hypertension
  • Tetraspan(in)
  • Β-catenin


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