University of Oulu

Zhang, K., Myllymäki, S., Gao, P., Devarajan, R., Kytölä, V., Nykter, M., Wei, G., Manninen, A. (2017) Oncogenic K-Ras upregulates ITGA6 expression via FOSL1 to induce anoikis resistance and synergizes with αV-Class integrins to promote EMT. Oncogene, 36 (41), 5681-5694. doi:10.1038/onc.2017.177

Oncogenic K-Ras upregulates ITGA6 expression via FOSL1 to induce anoikis resistance and synergizes with αV-Class integrins to promote EMT

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Author: Zhang, K1; Myllymäki, S-M1; Gao, P1;
Organizations: 1Biocenter Oulu, Centre of Excellence in Cell-Extracellular Matrix Research, Faculty of Biochemistry and Molecular Medicine, University of Oulu
2Prostate Cancer Research Center, Institute of Biomedical Technology and BioMediTech, University of Tampere and Tampere University Hospital
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 5.6 MB)
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Language: English
Published: Springer Nature, 2017
Publish Date: 2017-11-28


In many cancer types, integrin-mediated signaling regulates proliferation, survival and invasion of tumorigenic cells. However, it is still unclear how integrins crosstalk with oncogenes to regulate tumorigenesis and metastasis. Here we show that oncogenic K-RasV12 upregulates α6-integrin expression in Madin–Darby canine kidney (MDCK) cells via activation of the mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK)/Fos-related antigen 1-signaling cascade. Activated α6-integrins promoted metastatic capacity and anoikis resistance, and led to perturbed growth of MDCK cysts. Transcriptomic analysis of K-RasV12-transformed MDCK cells also revealed robust downregulation of αV-class integrins. Re-expression of αV-integrin in K-RasV12-transformed MDCK cells synergistically upregulated the expression of Zinc finger E-box-binding homeobox 1 and Twist-related protein 1 and triggered epithelial-mesenchymal transition leading to induced cell motility and invasion. These results delineate the signaling cascades connecting oncogenic K-RasV12 with α6- and αV-integrin functions to modulate cancer cell survival and tumorigenesis, and reveal new possible strategies to target highly oncogenic K-RasV12 mutants.

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Series: Oncogene
ISSN: 0950-9232
ISSN-E: 1476-5594
ISSN-L: 0950-9232
Volume: 36
Issue: 41
Pages: 5681 - 5694
DOI: 10.1038/onc.2017.177
Type of Publication: A1 Journal article – refereed
Field of Science: 3122 Cancers
Funding: This work was funded by Academy of Finland (251314, 135560, 263770, 140974/AM, 284618 and 279760/GHW).
Academy of Finland Grant Number: 251314
Detailed Information: 251314 (Academy of Finland Funding decision)
135560 (Academy of Finland Funding decision)
263770 (Academy of Finland Funding decision)
140974 (Academy of Finland Funding decision)
284618 (Academy of Finland Funding decision)
279760 (Academy of Finland Funding decision)
Dataset Reference: Supplementary information:
Copyright information: © The Author(s) 2017. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material.