Hsa-miR-31-3p Expression Is Linked to Progression-free Survival in Patients with KRAS Wild-type Metastatic Colorectal Cancer Treated with Anti-EGFR Therapy

Abstract

Purpose: To identify microRNAs (miRNA) that predict response to anti-EGFR antibodies in patients with wild-type KRAS metastatic colorectal cancer (mCRC).Experimental Design: miRNA profiling was performed in a training set of 87 patients with mCRC refractory to chemotherapy treated with anti-EGFR antibodies. This included 33 fresh-frozen (FF) and 35 formalin-fixed paraffin-embedded (FFPE) samples retrospectively collected and 19 prospectively collected FF samples. An independent validation cohort consisting of 19 FF and 26 FFPE prospectively collected samples from patients with mCRC treated with anti-EGFR antibodies was used to confirm our findings.Results: After screening the expression of 1,145 miRNAs in FF samples from the training set, we identified that hsa-miR-31-3p expression level was significantly associated with progression-free survival (PFS). Statistical models based on miRNA expression discriminated between high and low risk of progression for both FF and FFPE samples. These models were confirmed in the validation cohort for both FF [HR, 4.1; 95% confidence interval (CI), 1.1-15.3; P < 0.04] and FFPE samples (HR, 2.44; 95% CI, 1.1-5.4; P ¼ 0.028). The percentage of variation of RECIST criteria in the validation series was significantly associated with the expression level of hsa-miR-31-3p (r 2 ¼ 0.49; P ¼ 0.0035) and risk status determined by hsa-miR-31-3p expression level (P ¼ 0.02, Kruskal-Wallis rank test). Nomograms were built and validated to predict PFSdepending on hsa-miR-31-3p expression level. Following in vitro studies, we identified 47 genes regulated by hsa-miR-31-3p. Conclusion: Hsa-miR-31-3p seems to be a new mCRC biomarker whose expression level allows for the identification of patients with wild-type KRAS mCRC who are more likely to respond to anti-EGFR therapy.

Expression deregulation of mir31 and CXCL12 in two types of oral precancers and cancer: importance in progression of precancer and cancer

“…In contrast, it is also reported to be down-regulated in cancer and prevent metastasis in cancer cells12. Like miR-31, expression of miR-31* is also up-regulated in cancer and two pre-cancer tissues in this study like a report in another study13, but its expression was found to be significantly associated with progression free survival of metastatic colorectal cancer14. MiR-7 is a known OncomiR and its expression was up-regulated in cancer, leukoplakia and lichen planus tissues in this study, like in different cancers from other report15.…”

Epigenetic Alterations in Colorectal Cancer: Emerging Biomarkers

“…Furthermore, both expression and methylation levels of miR-148a are linked with lack of response to 5-FU and oxaliplatin chemotherapies in advanced CRC patients 273 . A recent comprehensive array-based interrogation of tumor tissues collected from KRAS wild-type metastatic CRC (mCRC) patients treated with anti-EGFR therapy identified miR-31-3p as a negative predictor of progression free survival (PFS) 274 .…”

Comprehensive Analysis of miRNome Alterations in Response to Sorafenib Treatment in Colorectal Cancer Cells

“…Interestingly, microRNA-31 has been shown to activate RAS signaling by repressing RAS p21 GTPase activating protein 1 [44]. More evidence for the involvement of miR-31-3p in RAS signaling and EGFR inhibitor resistance came from a number of other studies, which make this microRNA a potential biomarker for future evaluation in prospective clinical trials [45,46,47,48]. Though we did not detect increased apoptosis activation in our cell models, there have been some reports about the pro-apoptotic effect of sorafenib in liver cancer in in vivo models [49].…”