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KMID : 0624620220550120609
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BMB Reports
2022 Volume.55 No. 12 p.609 ~ p.614
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Systemic TM4SF5 overexpression in ApcMin/+ mice promotes hepatic portal hypertension associated with fibrosis
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Lee Joo-Hyeong
Kim Eun-Mi
Kang Min-Kyung
Ryu Ji-Hye
Kim Ji-Eon
Shin Eun-Ae
Pinanga Yangie
Pyo Kyung-Hee
Lee Hae-Song
Lee Eun-Hae
Cho Hee-Jin
Cheon Ja-Yeon
Kim Won-Sik
Jho Eek-Hoon
Kim Se-Mi
Lee Jung-Weon
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Abstract
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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 dual-transgenic 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.
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KEYWORD
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Adenomatous polyposis coli, Colon adenocarcinoma, Hepatic portal hypertension, Tetraspan(in), β-catenin
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