In the present study, we elucidated a novel mechanism underpinning the impact of the absence of HTATIP2 expression on the activation of HIF signaling that mediates tumor adaptation to hypoxia and subsequently promotes aggressive tumor growth and resistance to therapy in a murine xenograft model of A549 human lung adenocarcinoma, which represents the most common subtype of non-small cell lung carcinoma (NSCLC). The gene discussed is HTATIP2; the disease is non-small cell lung carcinoma.