High expression of microRNA‐625‐3p is associated with poor response to first‐line oxaliplatin based treatment of metastatic colorectal cancer

Abstract

The backbone of current cytotoxic treatment of metastatic colorectal cancer (mCRC) consists of a fluoropyrimidine together with either oxaliplatin (XELOX/FOLFOX) or irinotecan (XELIRI/FOLFIRI). With an overall objective response rate of approximately 50% for either treatment combination, a major unsolved problem is that no predictors of response to these treatments are available. To address this issue, we profiled 742 microRNAs in laser-capture microdissected cancer cells from responding and non-responding patients receiving XELOX/FOLFOX as first-line treatment for mCRC, and identified, among others, high expression of miR-625-3p, miR-181b and miR-27b to be associated with poor clinical response. In a validation cohort of 94 mCRC patients treated first-line with XELOX, high expression of miR-625-3p was confirmed to be associated with poor response (OR = 6.25, 95%CI [1.8; 21.0]). Independent analyses showed that miR-625-3p was not dysregulated between normal and cancer samples, nor was its expression associated with recurrence of stage II or III disease, indicating that miR-625-3p solely is a response marker. Finally, we also found that these miRNAs were up-regulated in oxaliplatin resistant HCT116/oxPt (miR-625-3p, miR-181b and miR-27b) and LoVo/oxPt (miR-181b) colon cancer cell lines as compared with their isogenic parental cells. Altogether, our results suggest an association between miR-625-3p and response to first-line oxaliplatin based chemotherapy of mCRC.

Induction of Epithelial-Mesenchymal Transition and Down-Regulation of miR-200c and miR-141 in Oxaliplatin-Resistant Colorectal Cancer Cells

“…14) Several in vitro studies showed that L-OHP resistance is linked to the expression of miRNAs, such as miR-27b, miR-143, miR-181b, miR-203, and miR-1915. [15][16][17][18] Furthermore, the responses of patients with CRC to L-OHPbased chemotherapy have been associated with the up-regulated expression of miR-148a, miR-181b, and miR-625-3p. 17,19) However, these miRNAs may not be directly linked to EMT caused by the acquisition of L-OHP resistance in CRC cells because they have no binding sites to the 3′-untranslated region of ZEB1.…”

MicroRNAs as potential therapeutic targets to predict responses to oxaliplatin in colorectal cancer: From basic evidence to therapeutic implication

“…Further cohort study in 94 metastatic CRC patients treated first‐line with XELOX showed that high expression of miR‐625‐3p was confirmed to be associated with a poor clinical response. Their findings suggested that miR‐625‐3p may be a marker of responsiveness . Another study of the expression levels of 1,200 human miRNAs in colon cancer tissues, using laser capture microdissection and miRNA profiling arrays showed a low level of miR‐4299 expression and the high levels of miR‐196b expression are related to advance OS in colon cancer patients treated with XELOX .…”

MicroRNAs as Regulators, Biomarkers and Therapeutic Targets in the Drug Resistance of Colorectal Cancer

“…Boisen et al reported that high expression of miR-196b-5p and miR-592 predicted improved prognosis of mCRC patients receiving XELOX therapy, while high miR-664-3p and low miR-455-5p levels were correlated with improved outcome under XELOX plus bevacizumab treatment [78]. By using laser capture microdissected cancer cells from responsive and non-responsive patients receiving XELOX/FOLFOX, Rasmussen et al found that high level of miR-625-3p was associated with poor response but was not associated with disease recurrence, indicating that miR-625-3p is solely a response biomarker for XELOX/FOLFOX treatment in mCRC patients [79].…”