Somatic mutations of the β-catenin gene are frequent in mouse and human hepatocellular carcinomas

TLDR

Hepatocellular carcinoma is the most common primary liver cancer, yet the molecular events driving its development remain largely unknown, and the Wnt‑β‑catenin pathway—activated in colon cancer and melanoma—has not been examined in HCC. The authors investigated β‑catenin in transgenic mouse HCC models driven by c‑myc or H‑ras, finding that point mutations or deletions disrupt its signaling function and promote tumorigenesis. Activating β‑catenin mutations were present in 50 % of mouse tumors and 26 % of human HCCs, leading to nuclear accumulation of β‑catenin and indicating that Wnt‑β‑catenin dysregulation is a key event in liver cancer in both species.

Abstract

Hepatocellular carcinoma (HCC) is the major primary malignant tumor in the human liver, but the molecular changes leading to liver cell transformation remain largely unknown. The Wnt-β-catenin pathway is activated in colon cancers and some melanoma cell lines, but has not yet been investigated in HCC. We have examined the status of the β-catenin gene in different transgenic mouse lines of HCC obtained with the oncogenes c- myc or H- ras . Fifty percent of the hepatic tumors in these transgenic mice had activating somatic mutations within the β-catenin gene similar to those found in colon cancers and melanomas. These alterations in the β-catenin gene (point mutations or deletions) lead to a disregulation of the signaling function of β-catenin and thus to carcinogenesis. We then analyzed human HCCs and found similar mutations in eight of 31 (26%) human liver tumors tested and in HepG2 and HuH6 hepatoma cells. The mutations led to the accumulation of β-catenin in the nucleus. Thus alterations in the β-catenin gene frequently are selected for during liver tumorigenesis and suggest that disregulation of the Wnt-β-catenin pathway is a major event in the development of HCC in humans and mice.