Zhang K, Myllymäki S-M, Gao P, Devarajan R, Kytölä V, Nykter M, Wei G-H, Manninen A
Biocenter Oulu, Centre of Excellence in Cell-Extracellular Matrix Research, Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland.
Prostate Cancer Research Center, Institute of Biomedical Technology and BioMediTech, University of Tampere and Tampere University Hospital, Tampere, Finland.
Oncogene. 2017 Oct 12;36(41):5681-5694. doi: 10.1038/onc.2017.177. Epub 2017 Jun 12.
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-Ras 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-Ras-transformed MDCK cells also revealed robust downregulation of αV-class integrins. Re-expression of αV-integrin in K-Ras-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-Ras with α6- and αV-integrin functions to modulate cancer cell survival and tumorigenesis, and reveal new possible strategies to target highly oncogenic K-Ras mutants.
在许多癌症类型中，整合素介导的信号传导调节致瘤细胞的增殖、存活和侵袭。然而，整合素如何与癌基因相互作用以调节肿瘤发生和转移仍不清楚。在此，我们表明致癌性K-Ras通过激活丝裂原活化蛋白激酶/细胞外信号调节激酶（ERK）/Fos相关抗原1信号级联反应，上调了Madin-Darby犬肾（MDCK）细胞中α6-整合素的表达。活化的α6-整合素促进了转移能力和失巢凋亡抗性，并导致MDCK囊肿生长紊乱。对K-Ras转化的MDCK细胞进行转录组分析还发现αV类整合素显著下调。在K-Ras转化的MDCK细胞中重新表达αV-整合素可协同上调锌指E盒结合同源框1和Twist相关蛋白1的表达，并引发上皮-间质转化，导致细胞运动性和侵袭性增强。这些结果描绘了连接致癌性K-Ras与α6-和αV-整合素功能以调节癌细胞存活和肿瘤发生的信号级联反应，并揭示了针对高度致癌性K-Ras突变体的新的可能策略。
