MicroRNA expression profiling identifies miR-31-5p/3p as associated with time to progression in wild-type RAS metastatic colorectal cancer treated with cetuximab

Abstract

The aim of our study was to investigate whether microRNAs (miRNAs) could serve as predictive biomarkers to anti-EGFR therapy (cetuximab, panitumumab) in patients with RAS wild-type (wt-RAS) metastatic colorectal cancer (mCRC). Historical cohort of 93 patients with mCRC (2006–2009) was included and further divided into exploratory and validation cohorts. MiRNAs expression profiling was performed on the exploratory cohort of 41 wt-KRAS mCRC patients treated with cetuximab to identify miRNAs associated with time to progression (TTP). The validation was performed on two independent cohorts: 28 patients of wt-RAS mCRC treated with cetuximab and 24 patients of wt-RAS mCRC treated with panitumumab. We identified 9 miRNAs with significantly different expression between responders and non-responders to cetuximab therapy (P ≤ 0.01). These 9 miRNAs were further evaluated in two independent cohorts of patients and miR-31-3p (P < 0.001) and miR-31-5p (P < 0.001) were successfully confirmed as strongly associated with TTP in wt-RAS mCRC patients treated with cetuximab but not panitumumab. When evaluated on the complete cohort of cetuximab patients (N = 69), miR-31-3p (HR, 5.10; 95% CI, 2.52–10.32; P < 0.001) and miR-31-5p (HR, 4.80; 95% CI, 2.50–9.24; P < 0.001) were correlated with TTP on the comparable level of significance. There was no difference in miR-31-5p/3p expression levels in RAS mutated and wild-type tumor samples. MiR-31-5p/3p are promising predictive biomarkers of cetuximab response in wt-RAS mCRC patients.

Klf4 inhibits tumor growth and metastasis by targeting microRNA-31 in human hepatocellular carcinoma

“…Numerous studies have shed light on tumor-targeting therapies using miRNAs as a novel diagnostic and therapeutic tools (7,8,12,25,28). In the present study, the downregulation of Klf4 and miR-31 was consistently observed in HCC tissues and they may thus serve as potential diagnostic markers and therapeutic targets for HCC.…”

“…miR-31 has been found to be significantly overexpressed in colorectal cancer (12), squamous cell carcinoma of the tongue (13), head and neck squamous cell carcinoma (14), lung cancer (15) and esophageal squamous cell carcinoma (16); it has been found to be downregulated in bladder tumors (17), prostate carcinoma (18), gastric cancer (19), HCC (20), breast cancer (21) and serous ovarian carcinoma (22). Studies have suggested that Kruppel (or Krüppel)-like factor 4 (Klf4), a zinc-finger transcription factor, functions as a tumor suppressor or an oncogene.…”

Genome-Wide miRNA Analysis Identifies miR-188-3p as a Novel Prognostic Marker and Molecular Factor Involved in Colorectal Carcinogenesis

“…Some of them, for instance miR-221-5p (22), have been previously proposed as prognostic factors in other colorectal cancer studies. miR-331-3p has been linked to progression-free survival in patients with KRAS wild-type mCRC treated with anti-EGFR therapy in two independent studies (23, 24), and miR-497-5p has been involved in the regulation of the endogenous insulin-like growth factor receptor 1 expression, as well as cell survival, proliferation, and invasion (25). Our findings from the TCGA dataset substantiate their involvement in colorectal carcinogenesis.…”

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].…”