Association of miR-125b, miR-17 and let-7c Dysregulations With Response to Anti-epidermal Growth Factor Receptor Monoclonal Antibodies in Patients With Metastatic Colorectal Cancer

Abstract

Background/Aim: MicroRNAs (miRs) play an important role in the regulation of cancer-related processes and are promising candidates for cancer biomarkers. The aim of the study was to evaluate the association of response to anti-EGFR monoclonal antibodies (mAbs) with selected miR expression profiles, including miR-125b, let-7c, miR-99a, miR-17, miR-143 and miR-145 in metastatic colorectal cancer (mCRC) patients. Patients and Methods: This retrospective study included 46 patients with mCRC harbouring wild-type RAS gene treated with cetuximab or panitumumab combined with chemotherapy in first-or second-line therapy. The miR expression was assessed using qRT-PCR. Results: Down-regulation of miR-125b and let-7c and up-regulation of miR-17 were found in the tumour tissue (p=0.0226, p=0.0040, p<0.0001). Objective response rate (ORR) was associated with up-regulation of miR-125b (p=0.0005). Disease control rate (DCR) was associated with up-regulation of miR-125b and let-7c (p=0.0383 and p=0.0255) and down-regulation of miR-17 (p=0.0464). MiR-125b showed correlation with progression-free and overall survival (p=0.055 and p=0.006). Conclusion: The results show that up-regulation of miR-125b is associated with higher ORR and DCR and longer survival; let-7c up-regulation and miR-17 downregulation are associated with higher DCR in mCRC patients treated with anti-EGFR mAbs. Colorectal cancer (CRC) is one of the most common malignancies whose incidence has been increasing in developed countries (1). Clinical trials have provided evidence for the efficacy and safety of monoclonal antibodies (mAbs) targeting the epidermal growth factor receptor (EGFR) represented by cetuximab and panitumumab, in the treatment of patients with metastatic CRC (mCRC). Both agents have been widely used in mCRC patients with tumours harbouring a wild-type RAS gene. Despite the standard use of RAS gene mutations as effective biomarkers predictive of resistance to anti-EGFR mAbs, there is a large proportion of patients with tumours harbouring a wild-type RAS gene who obtain poor benefit from this systemic treatment (2-9). There is therefore an urgent need for novel complementary predictive and prognostic biomarkers. MicroRNAs (miRs) are small non-coding RNAs, consisting of approximately 18-25 nucleotides that play an important role in the regulation of target gene expression. MiRs are involved in the regulation of key cancer-related processes including proliferation, differentiation, apoptosis, cell adhesion and angiogenesis (10). The role of miRs as biomarkers useful in diagnostics or prognostic estimation in cancer patients has been extensively studied.

Prognostic value of BRAF/MIR‐17 signature and B‐Raf protein expression in patients with colorectal cancer: A pilot study

“…37,38 The present overall analysis found no significant difference between cancerous and non-cancerous specimens in terms of MIR-17 expression, which contrasts with other studies that showed significant upregulation of this microRNA in CRC tissues. 37,39,40 This difference could be due to the Further work on larger samples in the same population will be required to confirm this finding.…”

“…39,46 Recently, Fiala et al reported miR-17 deregulation as one of the promising predictive biomarkers associated with an unfavorable response to anti-epidermal growth factor receptor (EGFR) monoclonal antibody therapy in metastatic CRC patients. 40 Additionally, Ast et al specified matrix metallopeptidase 2 (MMP2), fascin actin-bundling protein 1 (FSCN1), laminin subunit gamma 1 (LAMC1), transforming growth factor-beta 1 (TGFB1), dystonin (DST), ETS proto-oncogene 1 (ETS1), fibrillin 1 (FBN1), fibroblast growth factor 2 (FGF2), fibronectin 1 (FN1), integrin subunit alpha V (ITGAV), ITGB1, peroxidasin (PXDN), and TIMP metallopeptidase inhibitor 2 (TIMP2) as potential targets in extracellular matrix remodeling that could mediate some of the essential roles miR-17 play in cancer, including CRC. 47 Interestingly, a recent functional study by Han et al identified the primary miR-17 processing could be regulated via the circular non-coding RNA "circLONP2,"…”

Integrated whole transcriptome and small RNA analysis revealed multiple regulatory networks in colorectal cancer

“…We identified a number of other different interactions of SNHG5 with miRNAs including hsa-let-7c-5p, hsa-miR-363-3p, hsa-miR-125b-2-3p, hsa-miR-214-3p, hsa-miR-9–5-p, hsa-miR-132-3p, hsa-miR-29c-3p, and hsa-miR-10a-5p , amongst others, while other groups have also reported on the significance of SNHG5 in CRC 42 . Elevated expression of the downregulated miR-let-7c in CRC was found to be associated with higher disease control rate (DCR) in metastatic CRC patients treated with anti-EGFR mAbs 43 , 44 . The upregulation of miR-let-7c via the silencing of Lin28 in another study, promoting apoptosis in CRC cells, indicating the Lin28/let‑7c axis as a potential route for novel therapeutic target in CRC 45 .…”

Promotion or remission: a role of noncoding RNAs in colorectal cancer resistance to anti-EGFR therapy

“…In KRAS-mutated patients, high levels of Let-7 were significantly associated with better survival under Cetuximab treatment [ 73 ], suggesting that Let-7 helps identify patients with KRAS mutations that may still be possible subpopulations that benefit from EGFR inhibitors. In the case of receiving anti-EGFR mAbs treatment, the progression-free survival (PFS) and OS of patients with high Let-7a and Let-7c expression are superior to those with low expression of Let-7a and Let-7c [ 73 , 74 ]. The researchers considered that Let-7c may modulate the sensitivity of mCRC patients to anti-EGFR drugs by interfering with the primary resistance mechanism of Cetuximab or Panitumumab, and has application potential in screening mCRC patients sensitive to anti-EGFR therapy [ 47 ].…”