Key Laboratory for Experimental Teratology of the Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Shandong University, Jinan, PR China.
Department of Pathology, Qilu Hospital, Shandong University, Jinan, PR China.
Oncogene. 2021 Apr;40(14):2524-2538. doi: 10.1038/s41388-020-01610-7. Epub 2021 Mar 5.
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 β-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.
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，发现驱动蛋白参与了肿瘤的发展。本研究旨在阐明驱动蛋白超家族蛋白 26A（KIF26A）在 GC 中的作用及其在调节肿瘤侵袭和转移中的潜在分子机制。通过实时定量聚合酶链反应（qPCR）和免疫组织化学（IHC），我们显示无淋巴结转移（LNM）的 GC 组织中 KIF26A 的表达低于非肿瘤性胃黏膜，而有 LNM 的 GC 组织中 KIF26A 的表达甚至低于无 LNM 的 GC 组织。功能实验表明，KIF26A 抑制 GC 细胞的迁移和侵袭。我们进一步鉴定了粘着斑激酶（FAK）、磷脂酰肌醇 3-激酶调节亚基α（PI3KR1）、VAV3、Rac1 和 p21 激活激酶 2 以及β-PAK（PAK3）作为 KIF26A 在粘着斑途径中的下游效应物，并且发现 KIF26A 可以通过 MAPK 途径抑制 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 介导的粘着斑途径失活可以通过增加 E-钙黏蛋白的表达和减少 Snail 的表达来减少上皮间质转化（EMT）的发生。荧光素酶测定和 Western blot 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 分类、LNM、远端转移和临床分期以及较差的生存有关。这些数据表明，KIF26A 通过调节粘着斑通路和抑制 EMT 的发生来抑制 GC 的迁移和侵袭。
