Department of Oncology, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China.
Department of Hematology, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China.
Oncol Rep. 2017 Nov;38(5):3187-3196. doi: 10.3892/or.2017.5997. Epub 2017 Sep 25.
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.
结直肠癌（CRC）是全球第三大常见癌症，也是第四大常见癌症相关死亡原因。CRC 中的肿瘤进展和发展是一个多步骤过程，涉及大量的遗传和表观遗传改变。先前的研究表明，异常表达的 microRNAs 通过调节致癌和肿瘤抑制基因在 CRC 中发挥关键作用。因此，确定 microRNAs 的功能可能为 CRC 的诊断和治疗提供新的治疗靶点。microRNA-337（miR-337）在几种癌症类型中表达下调。然而，miR-337 在 CRC 中的表达、功能和潜在机制尚未明确阐明。在本研究中，miR-337 在 CRC 组织和细胞系中显著下调。miR-337 低表达水平与 CRC 患者的淋巴结转移、远处转移和 TNM 分期相关。此外，上调 miR-337 抑制 CRC 细胞增殖和侵袭，促进细胞凋亡。基于生物信息学分析，我们假设 Kirsten 大鼠肉瘤病毒致癌基因同源物（KRAS）在 CRC 中直接受 miR-337 调节。荧光素酶报告基因检测证实 miR-337 与 KRAS mRNA 的 3'UTR 直接相互作用。此外，逆转录-定量聚合酶链反应和 Western blot 分析表明，miR-337 可在 CRC 细胞中负调控 KRAS 内源性表达，在 mRNA 和蛋白水平上均有作用。此外，KRAS 在 CRC 组织中高表达，与 CRC 组织中 miR-337 的表达呈负相关。在 CRC 细胞中敲低 KRAS 可重现 miR-337 过表达引起的类似作用，而 KRAS 过表达部分恢复了 miR-337 的肿瘤抑制作用。此外，miR-337 的异位表达可使 CRC 中的 AKT 和 ERK 信号通路失活。这些结果表明，miR-337 通过与 KRAS 相互作用，可能在 CRC 恶性转化过程中发挥肿瘤抑制作用。
