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MiR-19a/miR-96-mediated low expression of KIF26A suppresses metastasis by regulating FAK pathway in gastric cancer

Oncogene volume 40, pages 2524–2538 (2021)Cite this article

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Abstract

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.

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Fig. 1: KIF26A is underexpressed in human GC.
Fig. 2: KIF26A inhibited cell migration and invasion of GC cell lines.
Fig. 3: KIF26A demonstrated no effect on cell proliferation or apoptosis in GC cells.
Fig. 4: KIF26A suppresses migration and invasion via inactivation of the FAK–PI3KR1–VAV3–Rac1–PAK3 axis in the focal-adhesion pathway.
Fig. 5: KIF26A influences the expression of E-cadherin and Snail.
Fig. 6: miR-19a and miR-96 negatively regulate the expression of KIF26A.

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Acknowledgements

This study was supported by the National Natural Science Foundation of China (Grant No. 81872362 and 82072665) and the Taishan Scholars Program of Shandong Province (Grant No. ts201511096).

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Authors and Affiliations

  1. Key Laboratory for Experimental Teratology of the Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Shandong University, Jinan, PR China

    Ran-Ran Ma, Hui Zhang, Hong-Fang Chen, Guo-Hao Zhang, Ya-Ru Tian & Peng Gao

  2. Department of Pathology, Qilu Hospital, Shandong University, Jinan, PR China

    Ran-Ran Ma, Hui Zhang & Peng Gao

  3. Department of Pathology, Yidu Central Hospital of Weifang, Weifang, PR China

    Hong-Fang Chen

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PG performed the conception and design of this manuscript. R-RM and HZ, H-FC, G-HZ, Y-RT collected clinical samples. R-RM conducted experiments and analyzed data. PG and R-RM performed the manuscript writing. All authors read and approved the final manuscript.

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Correspondence to Peng Gao.

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Ma, RR., Zhang, H., Chen, HF. et al. MiR-19a/miR-96-mediated low expression of KIF26A suppresses metastasis by regulating FAK pathway in gastric cancer. Oncogene 40, 2524–2538 (2021). https://doi.org/10.1038/s41388-020-01610-7

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