TIP30 deficiency increases susceptibility to tumorigenesis.

TIP30, also called CC3 or Htatip2, is a putative metastasis suppressor that promotes apoptosis and inhibits angiogenesis. Although TIP30 has several characteristic features of a tumor suppressor in in vitro analyses, tumor development as a result of TIP30 inactivation has not been demonstrated in vivo, and abnormal expression of TIP30 in human cancer has not been reported. Using genetically engineered mice and cells deficient in TIP30, we show that TIP30-deficient mice have a high incidence of hepatocellular carcinoma and other tumors, and loss of TIP30 enhances susceptibility of fibroblasts to transformation by the SV40 large T antigen. Furthermore, immunohistochemical analysis indicates that reduced TIP30 expression is associated with 33% of human hepatocellular carcinomas. Some of these carcinomas harbor missense mutations in the Tip30 gene, which cause abnormal expression of TIP30. Together, these results demonstrate that the Tip30 gene is a tumor susceptibility gene playing an important role in the suppression of hepatocarcinogenesis.