HAb18G/CD147 promotes radioresistance in hepatocellular carcinoma cells: a potential role for integrin β1 signaling
Menée in vitro et à l'aide d'une xénogreffe de carcinome hépatocellulaire sur un modèle murin, cette étude met en évidence un mécanisme par lequel l'expression de HAb18G/CD147 confère une radiorésistance aux cellules tumorales en agissant sur la voie de signalisation de l'intégrine bêta
Radiotherapy has played a limited role in the treatment of hepatocellular carcinoma (HCC) due to the risk of tumor radioresistance. A previous study in our lab confirmed that CD147 interacts with integrin β1 and plays an important role in modulating the malignant properties of HCC cells. In this study, we further evaluated the role of CD147 in the radioresistance of HCC and as a potential target for improving radiosensitivity. Upon irradiation, the colony formation, apoptosis, cell cycle distribution, migration and invasion of SMMC-7721, CD147-knockout SMMC-7721, HepG2 and CD147-knockdown HepG2 cells were determined. A nude mouse xenograft model and a metastatic model of HCC were used to detect the role of CD147 in radioresistance in vivo. Deletion of HAb18G/CD147 significantly enhanced the radiosensitivity of SMMC-7721 and HepG2 cells, and knocking out HAb18G/CD147 in SMMC-7721 cells attenuated irradiation-enhanced migration and invasion. The knockout and antibody blockade of CD147 decreased the tumor growth and metastatic potentials of HCC cells under irradiation. CD147-deleted SMMC-7721 cells showed diminished levels of calpain, cleaved talin, active integrin β1 and decreased p-FAK (Tyr397) and p-Akt (Ser473) levels. FAK and PI3K inhibitors, as well as integrin β1 antibodies, increased the radiation-induced apoptosis of SMMC-7721 cells. Our data provide evidence for CD147 as an important determinant of radioresistance via the regulation of integrin β1 signaling. Inhibition of the HAb18G/CD147-integrin interaction may improve the efficiency of radiosensitivity and provide a potential new approach for HCC therapy.
http://mct.aacrjournals.org/content/early/2014/12/20/1535-7163.MCT-14-0618.abstract