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

Mutation of the gene for adenomatous polyposis coli (APC), as seen in Apc(Min/+) mice, leads to intestinal adenomas and carcinomas via stabilization of ss-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 ss-catenin has not been investigated for pathological outcomes. After interbreeding Apc(Min/+) with TM4SF5-overexpressing transgenic (Tg(TM4SF5)) mice, we explored pathological outcomes in the intestines and livers of the offspring. The intestines of 26-week-old dual-transgenic mice (Apc(Min/+):Tg(TM4SF5)) had intramucosal adenocarcinomas beyond the single-crypt adenomas in Apc(Min/+) mice. Additional TM4SF5 overexpression increased the stabilization of ss-catenin via reduced glycogen synthase kinase 3 ss (GSK3 ss) 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 Apc(Min/+) mice. Interestingly, TM4SF5 overexpression in the liver was positively linked to increased GSK3 ss phosphorylation (opposite to that seen in the colon), ss-catenin level, and extracellular matrix (ECM) protein expression, indicating fibrotic phenotypes. Consistent with these results, 78-week-old Tg(TM4SF5) 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.

Automated summary

Overexpression of TM4SF5 exacerbates pathological abnormalities in both the colon and liver, including intestinal adenomas, carcinomas, sinusoidal dilatation, and fibrosis.