MicroRNA-337 inhibits colorectal cancer progression by directly targeting KRAS and suppressing the AKT and ERK pathways

Abstract

Colorectal cancer (CRC) is the third most common cancer and the fourth most common cause of cancer-related death worldwide. Tumour progression and development in CRC is a multi-step process involving a large number of genetic and epigenetic alterations. Previous studies indicated that abnormally expressed microRNAs play critical roles in CRC through regulation of oncogenic and tumour-suppressor genes. Hence, determination of the function of microRNAs may provide novel therapeutic targets for CRC diagnosis and treatments. MicroRNA-337 (miR-337) has been reported to be downregulated in several cancer types. However, the expression, function and underlying mechanisms of miR-337 in CRC have not been clearly elucidated. In this study, miR-337 was significantly decreased in CRC tissues and cell lines. Low miR-337 expression level was correlated with lymph node metastasis, distant metastasis and TNM stage of CRC patients. In addition, upregulation of miR-337 suppressed cell proliferation and invasion and promoted apoptosis in CRC. Based on bioinformatics analysis, we assumed that Kirsten rat sarcoma viral oncogene homolog (KRAS) was directly modulated by miR-337 in CRC. Luciferase reporter assay demonstrated the direct interaction between miR-337 and 3'-UTR of KRAS mRNA. Furthermore, reverse transcription-quantitative polymerase chain reaction and western blot analysis indicated that miR-337 could negatively regulate endogenous KRAS expression in CRC cells at both mRNA and protein levels. Moreover, KRAS was highly expressed in CRC tissues and inversely correlated with miR-337 expression in CRC tissues. KRAS knockdown recapitulates effects similar to those induced by miR-337 overexpression in CRC cells, whereas KRAS overexpression partially restored the tumour suppressive effects of miR-337. Besides, ectopic expression of miR-337 inactivates the AKT and ERK signalling pathways in CRC. These results suggested that miR-337 may act as a tumour suppressor during the process of CRC malignant transformation by interacting with KRAS.