Hypoxia Induces Drug Resistance in Colorectal Cancer through the HIF-1α/miR-338-5p/IL-6 Feedback Loop

Hypoxia is associated with poor prognosis and therapeutic resistance in cancer patients. Accumulating evidence has shown that microRNA (miRNA) plays an important role in the acquired drug resistance in colorectal carcinoma (CRC). However, the role of miRNA in hypoxia-induced CRC drug resistance remains to be elucidated. Here, we identified a hypoxia-triggered feedback loop that involves hypoxia-inducible transcription factor 1 alpha (HIF-1 alpha)-mediated repression of miR-338-5p and confers drug resistance in CRC. In this study, the unbiased miRNA array screening revealed that miR-338-5p is downregulated in both hypoxic CRC cell lines tested. Repression of miR-338-5p was required for hypoxia-induced CRC drug resistance. Furthermore, we identified interleukin-6 (IL-6), which mediates STAT3/Bcl2 activation under hypoxic conditions, as a direct miR-338-5p target. The resulting HIF-1 alpha/miR-338-5p/IL-6 feedback loop was necessary for drug resistance in colon cancer cell lines. Using CRC patient samples, we found miR-338-5p has a negative correlation with HIF-1 alpha and IL-6. Finally, in a xenograft model, overexpressing miR-338-5p in CRC cells and HIF-1 alpha inhibitor PX-478 were able to enhance the sensitivity of CRC to oxaliplatin (OXA) via suppressing the HIF-1 alpha/miR-338-5p/IL-6 feedback loop in vivo. Taken together, our results uncovered an HIF-1 alpha/miR-338-5p/IL-6 feedback circuit that is critical in hypoxia-mediated drug resistance in CRC; targeting each member of this feedback loop could potentially reverse hypoxia-induced drug resistance in CRC.