Gastric cancer is characterized by the presence of high invasion ability, hypoxia and chemoresistance. Previous studies reported that liver X receptor α (LXRα) was involved in epithelial-mesenchymal transition (EMT) of gastric cancer cells. However, hypoxia-mediated EMT and the role of LXRα in gastric cancer remained elusive. In this study, we demonstrated that LXRa mRNA and protein levels were up-regulated by hypoxia treatment and LXRα played an important role in HIF-1 dimer induced-EMT. The putative HIF-1α binding site was identified in the LXRa promoter. Expression of LXRα and HIF-1α was significantly up-regulated in gastric cancer tissues compared to that in normal tissues. More importantly, we noticed that the expression of LXRα and HIF-1α was significantly correlated. Taken together, these data suggested that LXRα is regulated by the activity and accumulation of HIF-1α and contributes to EMT of gastric cancer cells. This suggests that targeting LXRα might be a potential approach for improving survival of gastric cancer patients.
Adjuvant therapy and radiotherapy improves the survival of patients with metastatic and locally advanced gastric cancer (GC). However, the resistance to radiotherapy limits its clinical usage. Rhotekin 2 (RTKN2) functions as an oncogene and confers resistance to ultraviolet B-radiation and apoptosis- inducing agents. Here, the role of RTKN2 in radiosensitivity of GC cell lines was investigated. RTKN2 was found to be elevated in GC tissues and cells. A series of functional assays revealed that overexpression of RTKN2 induced GC cell proliferation, promoted GC cell migration and invasion, while inhibiting GC cell apoptosis. However, silence of RTKN2 promoted GC cell apoptosis, while repressing GC cell proliferation, invasion and migration. GC cells were exposed to irradiation, and data from cell survival and apoptotic assays showed that knock-down of RTKN2 enhanced radiosensitivity of GC through up-regulation of apoptosis and down-regulation of proliferation in irradiation-exposed GC cells. Moreover, the protein expression of β-catenin and c-Myc in GC cells was enhanced by RTKN2 over-expression, but reduced by RTKN2 silence. Interference of RTKN2 down-regulated nuclear β-catenin expression, while up-regulating cytoplasmic β-catenin in GC. In conclusion, RTKN2 contributed to cell growth and radioresistance in GC through activation of Wnt/β-catenin signalling.