P53‑microRNA interactions regulate the response of colorectal tumor cells to oxaliplatin under normoxic and hypoxic conditions

Abstract

Oxaliplatin (OXA)-containing regimens are used as first-line chemotherapy in colorectal cancer (CRC). However, OXA resistance remains a major challenge in CRC treatment. CRC cells that adapt to hypoxia can potentially develop OXA resistance, and the underlying molecular mechanisms still need to be further investigated. In the current study, the OXA drug sensitivity of two CRC cell lines, HCT116 (TP53 ^WT) and HT29 (TP53 ^MT), was compared under both normoxic and hypoxic conditions. It was found that under normoxic condition, HCT116 cells showed significantly higher OXA sensitivity than HT29 cells. However, both cell lines showed remarkable OXA resistance under hypoxic conditions. It was also revealed that P53 levels were increased after OXA and hypoxia treatment in HCT116 cells but not in HT29 cells. Notably, knocking down P53 ^WT decreased normoxic but increased hypoxic OXA sensitivity in HCT116 cells, which did not exist in HT29 cells. Molecular analysis indicated that P53 ^WT activated microRNA (miR)-26a and miR-34a in OXA treatment and activated miR-23a in hypoxia treatment. Cell proliferation experiments indicated that a high level of miR-23a decreased OXA sensitivity and that a high level of miR-26a or miR-34a increased OXA sensitivity in HCT116 cells. Additionally, it was demonstrated that miR-26a, miR-34a and miR-23a affect cell apoptosis through regulation of MCL-1, EZH2, BCL-2, SMAD 4 and STAT3. Taken together, the present findings revealed the dual function of P53 in regulating cellular chemo-sensitivity and highlighted the role of P53-miR interactions in the response of CRC cells to OXA chemotherapy under normoxic and hypoxic conditions.