Abstract
Lung cancer remains the leading cause of cancer mortality in the world. Metastatic property is one of the major reasons for treatment failure in lung cancer patients. Tumor microenvironment plays a key role in shaping tumor progression. In solid tumors, a decreased oxygen and nutrient supply creates a hypoxic microenvironment in the central region, which elicits a set of genes to endow cancer cells with increased survival or proliferation abilities. On the other hand, TGF-beta, which is often released by tumor stroma cells, attenuates cell proliferation but induces invasion of lung cancer. How cancer cells are shaped by tumor microenvironment with elevated proliferation and invasion abilities are elusive. Here, we report that CITED2, a MYC interacting transcriptional modulator, responds to hypoxia induction and TGF-beta suppression to orchestrate cellular proliferation and invasion, respectively. We observed that hypoxia induced CITED2 expression in a group of lung cancer cells, the proliferation and survival of which were dependent on CITED2 signaling. TGF-beta stimulation inhibited CITED2 expression, causing decreased cell proliferation. Nonetheless, hypoxia potentiated TGF-beta mediated invasion and rendered cell resistant to TGF-beta induced cell growth arrest by elevating CITED2 dependent signaling. Our findings provide that CITED2 functions as an oncogeneic switch for hypoxia and TGF-beta mediated proliferation and invasion in lung cancer, deserving additional evaluation as a biomarker for lung cancer progression.