Expression of T-cell lymphoma invasion and metastasis 2 (TIAM2) promotes proliferation and invasion of liver cancer.

ABSTRACT

The T-cell lymphoma invasion and metastasis 2 (TIAM2) gene is the homolog of human TIAM1, a Rac-specific guanine nucleotide exchange factor that plays important roles in neuron development and human malignancies. Although the role of TIAM1 is well characterized, the physiological and pathological functions of TIAM2 remain unknown. In our study, human cDNA and protein panels were evaluated for endogenous expression of TIAM2. Four hepatocellular carcinoma (HCC) cell lines and 91 HCC samples were used to demonstrate expression of TIAM2S (the short form of TIAM2) in cancer cells. In addition, HepG2 cells stably expressing TIAM2S were used for tumorigenic assays in both cellular and mouse models. We demonstrate that endogenous TIAM2S was induced in several human cancers including HCC. TIAM2S expression was undetectable in normal human liver but was induced in all HCC cell lines and in 86% (78/91) of HCC biopsies. TIAM2S expression was positively associated with TIAM1 expression, hepatitis B virus (HBV) infection and metastatic phenotype. Expression of recombinant TIAM2S in HepG2 cells promoted growth and invasiveness. In vivo study using a xenografted mouse model demonstrated that induced endogenous expression of TIAM2S converted non-invasive human HCC cells into highly aggressive vascular tumors. Further examination revealed that TIAM2S expression resulted in up-regulation of N-cadherin and vimentin, and in redistribution of E-cadherin. These findings show, for the first time, that human TIAM2S is involved in HCC pathogenesis, and that increased expression of TIAM2S promotes epithelial-to-mesenchymal transition and results in proliferation and invasion in liver cancer cells.