PTGS2 and colorectal carcinoma: Other components implicated in the CIN pathway include the Hypoxia Inducible Factor (HIF)-1 and HIF-2, which function as essential mediators of cellular response to hypoxia and increase the expression of different genes involved in angiogenesis, cell survival, and glucose metabolism, by influencing different pathways, including mTOR. An over-expression of HIF1α, a key regulatory subunit of HIF1 and HIF2, has been reported to directly upregulate COX-2 expression in CRC by binding with COX-2 [55,56].