Abstract

Objective: We investigated mechanisms of colorectal cancer (CRC) chemoresistance to first-line chemotherapy (capecitabine plus oxaliplatin (XELOX)) and identified two putative chemoresistant microRNAs, miR-1914* and -1915, that are downregulated in plasma samples from patients with chemoresistant CRC.

Methods: A number of plasma samples from CRC patients were analyzed for the levels of miR-1914* and - 1915. Effects of stable and transient expression of 2 microRNAs in human chemoresistant CRC cell lines were analyzed. Tumor formation and chemoresistance in HCT116/5-Fu/OXA that did or did not express 2 microRNAs were analyzed in mice. Nuclear factor I/X (NFIX) was predicted to target the gene of 2 miRNAs and verified in vivo and in vitro.

Results: Plasma levels of miR-1914* and -1915 in chemoresistant CRC patients were different than levels in responders, and associated with clinical response. Overexpression of miR-1914* and -1915 in chemoresistant CRC cells reduced resistance to 5-FU and Oxaliplatin in vitro. The microRNAs suppressed chemoresistance in CRC tumors in mice by affecting cell growth, invasion, apoptosis and tumor suppressor function. miR-1914* and -1915 interacted with the 3’-untranslated region of NFIX and reduced NFIX its level in chemoresistant CRC cells. Overexpression of NFIX did not inhibit chemoresistant CRC cell motility and chemoresistant proteins when miR-1914* and -1915 were transfected.

Conclusion: Plasma miR-1914* and -1915 interact with NFIX RNA and reduce its level in chemoresistant CRC cells to first-line chemotherapy. Up-regulation of miR-1914* and -1915 decreased the chemoresistance abilities of chemoresistant CRC cells. The plasma miR-1914* and -1915 may play a role in colorectal cancer therapy and diagnosis.

Keywords: Colorectal cancer, chemotherapy resistance, non-coding RNA, plasma.