Overexpression of TG-Interacting Factor Is Associated with Worse Prognosis in Upper Urinary Tract Urothelial Carcinoma

Prognostic outcome prediction would be useful for the treatment of patients with upper urinary tract urothelial carcinoma (UC). However, its prognostic biomarkers are not well established so far. According to the results of analysis of 168 human upper urinary tract UC specimens, overexpressed TG-interacting factor (TGIF) in nuclei of tumor tissues is significantly correlated with poor progression-free survival and higher cancer-related death. When both TGIF and p21 expression are altered, these patients had an even worse prognosis than those with one or no marker altered. Furthermore, to elucidate the role of TGIF in the progression of UC, overexpression of TGIF in RT4 or TSGH8301 cells was performed, and the results revealed that TGIF can significantly increase migration/invasion ability, matrix metalloproteinase expression, and invadopodia formation via the phosphatidylinositol 3-kinase-AKT pathway. In contrast, knockdown of TGIF with its specific short hairpin RNA inhibited the invasion ability of T24 cells. Besides, TGIF could inhibit p21(WAF/CIP1) expression, up-regulate cyclin D1 expression, and phosphorylate retinoblastoma to promote G1-S transition and cellular proliferation. In conclusion, we demonstrated that TGIF contributes to the progression of urothelial carcinoma via the phosphatidylinositol 3-kinase-AKT pathway. It may serve as an attractive therapeutic or prognostic target for selected patients with upper urinary tract UC. (Am J Pathol 2012, 181:1044-1055; http://dx.doi.org/10.1016/j.ajpath.2012.05.024)