miR-143-3p 通过靶向 KRAS 抑制胰腺导管腺癌的肿瘤发生。

MiR-143-3p suppresses tumorigenesis in pancreatic ductal adenocarcinoma by targeting KRAS.

机构信息

Department of Liver Surgery & Liver Transplantation Centre, West China Hospital of Sichuan University, Chengdu 610041, China.

出版信息

Biomed Pharmacother. 2019 Nov;119:109424. doi: 10.1016/j.biopha.2019.109424. Epub 2019 Sep 12.

DOI:10.1016/j.biopha.2019.109424

PMID:31521891

Abstract

BACKGROUND

Pancreatic ductal adenocarcinoma (PDAC) is a malignant tumor with high mortality and metastasis, which is difficult to diagnose and treat. MicroRNA-143-3p (miR-143-3p) acts as a tumor suppressor in various cancers. However, its role in pancreatic ductal adenocarcinoma has not been explored. Here we examined the potential role and mechanism of miR-143-3p in PDAC.

METHODS

The levels of miR-143-3p and KRAS mRNA in matched PDAC and normal tissues as well as PDAC cell lines were determined by quantitative RT-PCR. The effect of miR-143-3p on cell proliferation was evaluated by Cell Counting Kit-8 assay, colony-forming assay and a mouse subcutaneous transplantation model. Transwell assay, wound healing assay and a mouse orthotopic implantation model were conducted to examine the role of miR-143-3p on cell migratory and invasive capacities. The target gene and mechanisms of miR-143-3p were explored by qRT-PCR, western blot and luciferase assays.

RESULTS

The expression of miR-143-3p was down-regulated in PDAC tissues compared with the paired adjacent normal tissues. Cell proliferative, migratory and invasive capacities in PDAC cells were significantly decreased by miR-143-3p up-regulation. Moreover, we identified KRAS as a direct target of miR-143-3p, revealed its expression to be inversely correlated with miR-143-3p in PDAC samples. Up-regulated expression of KRAS partially reversed the phenotypes induced by miR-143-3p overexpression. What's more, KRAS could activate the ERK signaling pathway, which is associated with tumorigenesis.

CONCLUSIONS

MiR-143-3p may suppress tumorigenesis in PDAC by targeting KRAS. This might provide a theoretical basis for miR-143-3p in treatment of pancreatic cancer.

摘要

背景

胰腺导管腺癌（PDAC）是一种死亡率和转移性高的恶性肿瘤，难以诊断和治疗。microRNA-143-3p（miR-143-3p）在各种癌症中充当肿瘤抑制因子。然而，其在胰腺导管腺癌中的作用尚未得到探索。在这里，我们研究了 miR-143-3p 在 PDAC 中的潜在作用和机制。

方法

通过定量 RT-PCR 测定匹配的 PDAC 和正常组织以及 PDAC 细胞系中 miR-143-3p 和 KRAS mRNA 的水平。通过细胞计数试剂盒-8 测定法、集落形成测定法和小鼠皮下移植模型评估 miR-143-3p 对细胞增殖的影响。通过 Transwell 测定法、划痕愈合测定法和小鼠原位植入模型研究 miR-143-3p 对细胞迁移和侵袭能力的作用。通过 qRT-PCR、western blot 和荧光素酶测定法探索 miR-143-3p 的靶基因和机制。

结果

与配对的相邻正常组织相比，PDAC 组织中 miR-143-3p 的表达下调。miR-143-3p 上调可显著降低 PDAC 细胞的增殖、迁移和侵袭能力。此外，我们确定 KRAS 是 miR-143-3p 的直接靶基因，表明其在 PDAC 样本中的表达与 miR-143-3p 呈负相关。KRAS 的上调表达部分逆转了 miR-143-3p 过表达诱导的表型。更重要的是，KRAS 可以激活与肿瘤发生相关的 ERK 信号通路。