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
|Author:||Zhang, K1; Myllymäki, S-M1; Gao, P1;|
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
|Online Access:||PDF Full Text (PDF, 5.6 MB)|
|Persistent link:|| http://urn.fi/urn:nbn:fi-fe2017112855098
|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.
|Pages:||5681 - 5694|
|Type of Publication:||
A1 Journal article – refereed
|Field of Science:||
This work was funded by Academy of Finland (251314, 135560, 263770, 140974/AM, 284618 and 279760/GHW).
|Academy of Finland Grant Number:||
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)
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