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首页> 外文期刊>Oncogene >MiR-19a/miR-96-mediated low expression of KIF26A suppresses metastasis by regulating FAK pathway in gastric cancer
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MiR-19a/miR-96-mediated low expression of KIF26A suppresses metastasis by regulating FAK pathway in gastric cancer

机译：MiR-19a/miR-96 介导的 KIF26A 低表达通过调节胃癌 FAK 通路抑制转移

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摘要

Gastric cancer (GC) is one of the most common malignant neoplasms. Invasion and metastasis are the main causes of GC-related deaths. Recently, kinesins were discovered to be involved in tumor development. The aim of this study was to elucidate the roles of kinesin superfamily protein 26A (KIF26A) in GC and its underlying molecular mechanism in regulating tumor invasion and metastasis. Using real-time quantitative polymerase chain reaction (qPCR) and immunohistochemistry (IHC), we showed that KIF26A expression was lower in GC tissues without lymph node metastasis (LNM) than in nontumorous gastric mucosa, and even lower in GC tissues with LNM than in GC tissues without LNM. Functional experiments showed that KIF26A inhibited migration and invasion of GC cells. We further identified focal-adhesion kinase (FAK), phosphatidylinositol 3-kinase regulatory subunit alpha (PI3KR1), VAV3, Rac1 and p21-activated kinase 2, and beta-PAK (PAK3) as downstream effectors of KIF26A in the focal-adhesion pathway, and we found that KIF26A could regulate FAK mRNA expression through inhibiting c-MYC by MAPK pathway. c-MYC could bind to the promoter of FAK and activate FAK transcription. Moreover, we found that KIF26A-mediated inactivation of the focal-adhesion pathway could reduce the occurrence of the epithelial-to-mesenchymal transition (EMT) by increasing expression of E-cadherin and reducing that of Snail. Luciferase assays and Western blotting revealed that miR-19a and miR-96 negatively regulate KIF26A. Finally, we found that decreased expression of KIF26A has been positively correlated with histological differentiation, Lauren classification, LNM, distal metastasis, and clinical stage, as well as poor survival in patients with GC. These data indicate that KIF26A could inhibit GC migration and invasion by regulating the focal-adhesion pathway and repressing the occurrence of EMT.
机译：胃癌（GC）是最常见的恶性肿瘤之一。侵袭和转移是GC相关死亡的主要原因。最近，驱动蛋白被发现参与肿瘤的发展。本研究旨在阐明驱动蛋白超家族蛋白26A（KIF26A）在GC中的作用及其在调控肿瘤侵袭和转移中的潜在分子机制。使用实时定量聚合酶链反应 （qPCR） 和免疫组化 （IHC），我们发现 KIF26A 在无淋巴结转移 （LNM） 的 GC 组织中的表达低于非肿瘤性胃粘膜，在有 LNM 的 GC 组织中甚至低于没有 LNM 的 GC 组织。功能实验表明，KIF26A抑制GC细胞的迁移和侵袭。我们进一步鉴定了黏着斑激酶（FAK）、磷脂酰肌醇3-激酶调节亚基α（PI3KR1）、VAV3、Rac1和p21活化激酶2以及β-PAK（PAK3）作为KIF26A在黏着斑途径中的下游效应子，我们发现KIF26A可以通过MAPK通路抑制c-MYC来调节FAK mRNA的表达。c-MYC可以与FAK的启动子结合并激活FAK转录。此外，我们发现KIF26A介导的黏着斑途径失活可以通过增加E-钙粘蛋白的表达和减少Snail的表达来减少上皮间充质转化（EMT）的发生。荧光素酶测定和蛋白质印迹显示 miR-19a 和 miR-96 负调控 KIF26A。最后，我们发现 KIF26A 表达降低与 GC 患者的组织学分化、Lauren 分型、LNM、远端转移和临床分期以及生存率低呈正相关。这些数据表明，KIF26A可以通过调节黏着斑途径和抑制EMT的发生来抑制GC迁移和侵袭。

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