MicroRNA-7expression in colorectal cancer is associated with poor prognosis and regulates cetuximab sensitivity viaEGFRregulation

Abstract

MicroRNA-7 (miR-7) has been reported to be a tumor suppressor in all malignancies including colorectal cancer (CRC). However, its significance for CRC clinical outcomes has not yet been explored. The potential for miR-7 to act as a tumor suppressor by coordinately regulating the epidermal growth factor receptor (EGFR) signaling pathway at several levels was examined. We investigated the tumor inhibitory effect of miR-7 in CRC, with particular focus on the relationship between miR-7 and the EGFR pathway. Quantitative reverse transcription-PCR was used to evaluate miR-7 expression in 105 CRC cases to determine the clinicopathologic significance of this miRNA. The regulation of EGFR by miR-7 was examined with miR-7 precursor-transfected cells. Furthermore, we investigated whether miR-7 suppresses proliferation of CRC cells in combination with cetuximab, a monoclonal antibody against EGFR. Multivariate analysis indicated that low miR-7 expression was an independent prognostic factor for poor survival (P = 0.0430). In vitro assays showed that EGFR and RAF-1 are direct targets of miR-7, which potently suppressed the proliferation of CRC cells, and, interestingly, that the growth inhibitory effect of each of these was enhanced by cetuximab. miR-7 is a meaningful prognostic marker. Furthermore, these data indicate that miR-7 precursor, alone or in combination with cetuximab, may be useful in therapy against CRC.

Development of a deregulating MicroRNA panel for the detection of early relapse in postoperative colorectal cancer patients

“…Yin et al identified miR-141 as a potential circulating biomarker for metastasis [44], consistent with our findings of high miR-141 expression in early relapsed CRC patients. Previous studies have shown that miR-7 functions as a tumor suppresser in CRC by targeting oncogenic YY1 and XRCC2 [45][46][47]. By contrast, we found that the upregulation of miR-7 was more frequent in early relapsed CRC patients.…”

CiRS‐7 targeting miR‐7 modulates the progression of non‐small cell lung cancer in a manner dependent on NF‐κB signalling

“…For instance, ciRS‐7, the natural antisense transcript of cerebellar degeneration‐associated protein 1 (CRD1), contained approximately 70 MREs of miR‐7 24, 32, 36. Its high expression within cytoplasms could effectively lower miR‐7 activity through binding to it, thereby down‐regulating the expressions of insulin‐like growth factor‐1 receptor (IGF1R), epidermal growth factor receptor (EGFR) and focal adhesion kinase (FAK) 37, 38, 39…”

Role of microRNA-7 in digestive system malignancy

“…In contrast, using the same method, Suto et al [26] discovered that miR-7 level was higher in CRC tissue than in adjacent normal tissue, induced by EGFR mutations. However, it was found that the aforementioned results would be opposite when the EGFR protein expression was positive in CRC.…”

“…MiR-7 is a tumor suppressor, which is mediated through the YY1-P53-Wnt signaling pathway, and plays pivotal roles in many cellular processes, such as development, differentiation, proliferation and apoptosis [37] . By targeting EGFR and v-raf-1 murine leukemia viral oncogene homolog 1 (RAF-1), a low level of miR-7 suggests poor prognosis for CRC, and miR-7 precursor, alone or in combination with a monoclonal antibody, could be a novel therapy against CRC [26] . XRCC2 (X-ray repair complementing defective repair in Chinese hamster cells 2) participates in homologous recombination, and its relationship with miR-7 has been studied.…”