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MicroRNA-485 在结直肠癌中通过直接靶向 GAB2 发挥肿瘤抑制作用。

MicroRNA-485 plays tumour-suppressive roles in colorectal cancer by directly targeting GAB2.

机构信息

Department of Colorectal Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, Liaoning 110042, P.R. China.

出版信息

Oncol Rep. 2018 Jul;40(1):554-564. doi: 10.3892/or.2018.6449. Epub 2018 May 17.

Abstract

Colorectal cancer (CRC) is reported to be the third most common cancer and the fourth leading cause of cancer-related deaths around the world. MicroRNA-485 (miR-485) has been reported to be aberrantly expressed and play important roles in several types of human malignancy. However, the expression level, biological functions and underlying molecular mechanisms of miR-485 in CRC remain unclear. Therefore, the aim of the present study was to determine miR-485 expression levels and their clinical significance in CRC and to explore the functions and underlying mechanisms of miR-485 in this disease. In the present study, miR-485 was lowly expressed in CRC tissues and cell lines. Decreased miR-485 expression was associated with tumour size, lymph node metastasis, distant metastasis and TNM stage. Functional assays indicated that upregulation of miR-485 impaired CRC cell proliferation, invasion and induced cell apoptosis. Grb2-associated binding 2 (GAB2) was identified as a direct target of miR-485 in CRC. GAB2 was upregulated in CRC tissues and was negatively correlated with the miR-485 expression level. Furthermore, GAB2 knockdown simulated the tumour-suppressing roles of miR-485 overexpression in CRC cells. Moreover, restored GAB2 expression reversed the effects of miR-485 overexpression in CRC cells. In addition, miR-485 suppressed the AKT and ERK signalling pathways in CRC by directly targeting GAB2. Collectively, these findings demonstrate that miR-485 may play tumour suppressive roles in CRC by directly targeting GAB2 and indirectly regulating AKT and ERK signalling pathways, suggesting that miR-485 may be a potential therapeutic target for patients with this disease.

摘要

结直肠癌(CRC)据报道是全球第三大常见癌症和第四大癌症相关死亡原因。microRNA-485(miR-485)已被报道存在异常表达,并在多种人类恶性肿瘤中发挥重要作用。然而,miR-485 在 CRC 中的表达水平、生物学功能和潜在分子机制仍不清楚。因此,本研究旨在确定 miR-485 在 CRC 中的表达水平及其临床意义,并探讨 miR-485 在该疾病中的功能和潜在机制。在本研究中,miR-485 在 CRC 组织和细胞系中低表达。miR-485 表达降低与肿瘤大小、淋巴结转移、远处转移和 TNM 分期有关。功能测定表明,上调 miR-485 可损害 CRC 细胞增殖、侵袭并诱导细胞凋亡。Grb2 相关结合蛋白 2(GAB2)被鉴定为 CRC 中 miR-485 的直接靶标。GAB2 在 CRC 组织中上调,与 miR-485 的表达水平呈负相关。此外,GAB2 敲低模拟了 miR-485 过表达在 CRC 细胞中的肿瘤抑制作用。此外,恢复 GAB2 表达逆转了 miR-485 过表达对 CRC 细胞的作用。此外,miR-485 通过直接靶向 GAB2 抑制 CRC 中的 AKT 和 ERK 信号通路。总之,这些发现表明,miR-485 通过直接靶向 GAB2 并间接调节 AKT 和 ERK 信号通路,在 CRC 中可能发挥肿瘤抑制作用,表明 miR-485 可能是该疾病患者的潜在治疗靶点。

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