HAb18G/CD147 Promotes Radioresistance in Hepatocellular Carcinoma Cells: A Potential Role for Integrin b1 Signaling

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 laboratory confirmed that CD147 interacts with integrin b1 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, CD147knockout SMMC-7721, HepG2, and CD147-knockdown HepG2 cells were determined. A nude mouse xenograft model and a metastaticmodel ofHCCwere 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 andmetastatic potentials of HCC cells under irradiation. CD147deleted SMMC-7721 cells showed diminished levels of calpain, cleaved talin, active integrin b1, and decreased p-FAK (Tyr397) and p-Akt (Ser473) levels. FAK and PI3K inhibitors, as well as integrin b1 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 b1 signaling. Inhibition of the HAb18G/CD147 integrin interaction may improve the efficiency of radiosensitivity and provide a potential newapproach forHCC therapy.MolCancer Ther; 14(2); 553–63. 2014 AACR.