TSSC3 overexpression associates with growth inhibition, apoptosis induction and enhances chemotherapeutic effects in human osteosarcoma
Menée in vitro et in vivo, cette étude suggère que le gène TSSC3, impliqué dans la voie de l'apoptose, exerce une fonction de suppresseur de tumeurs dans les ostéosarcomes
Loss of expression of TSSC3, an apoptosis-related imprinted gene, has been reported in several cases of malignant tumors. However, the roles and mechanisms of TSSC3 in human osteosarcoma remain to be defined. In this study, we found TSSC3 to be down-regulated during osteosarcoma transformation and progression in osteosarcoma cell lines and tissues. The SaOS2 cell line was used to further evaluate the precise role of TSSC3 in osteosarcoma development. Overexpression of TSSC3 markedly reduced cell vitality and growth, colony formation, Ki67 expression, as well as cell cycle arrest in the G0/G1 phase. Consistently, TSSC3 overexpression was associated with increased apoptosis assayed by annexinV/PI and TUNEL staining. Subcutaneous injection of TSSC3 overexpressing SaOS2 cells into athymic nude mice showed that TSSC3 also inhibited tumorigenesis through growth inhibition and apoptosis induction in vivo. Further mechanistic studies revealed that the mitochondrial apoptosis pathway was required for TSSC3-mediated cell apoptosis. These findings support a suppressor role for TSSC3 in osteosracoma development by regulating apoptosis. In addition, constitutive TSSC3 expression greatly enhanced the sensitivity of human osteosarcoma cells to the chemotherapeutic drugs cisplatin and epirubicin. Conversely, TSSC3 knockdown increased SaOS2 cell growth and decreased apoptosis in vitro and in vivo, and reduced sensitivity of the cells to chemotherapy. This is the first study to demonstrate that TSSC3 has a potent tumor-suppressor role in osteosarcoma, likely by inhibition of growth and induction of apoptosis via the mitochondrial apoptosis pathway.
http://carcin.oxfordjournals.org/content/early/2011/10/20/carcin.bgr232.abstract