In summary, HIF-1A, p53-induced miR-34a, and the IRE1A-XBP-1(S) pathway form a double-negative feedback regulatory loop under hypoxic conditions, wherein activation of HIF-1A/IRE1A induces XBP-1(S) by repressing miR-34a to promote EMT, metastasis, autophagy and chemo-resistance in colorectal cancer cells that have undergone inactivation of p53. Here, ERN1 is linked to colorectal cancer.