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RCP induces Slug expression and cancer cell invasion by stabilizing β1 integrin

A Correction to this article was published on 24 January 2019

Abstract

Rab coupling protein (RCP)-induced tumor cell migration has been implicated in tumor pathophysiology and patient outcomes. In the present study, we demonstrate that RCP stabilizes β1 integrin leading to increased β1 integrin levels and activation of a signaling cascade culminating in Slug induction, epithelial-to-mesenchymal transition and increased invasion. Ectopic expression of RCP induced Slug expression. Silencing β1 integrin efficiently inhibited RCP-induced Slug expression and subsequent cancer cell invasion. Conversely, ectopic expression of β1 integrin was sufficient to induce Slug expression. Pharmacological inhibition of integrin linked kinase (ILK), EGFR and NF-κB, as well as transfection of a dominant-negative mutant of Ras (RasN17), significantly inhibited RCP-induced Slug expression and cancer cell invasion. Strikingly, ectopic expression of RCP was sufficient to enhance metastasis of ovarian cancer cells to the lung. Collectively, we demonstrate a mechanism by which RCP promotes cancer cell aggressiveness through sequential β1 integrin stabilization, activation of an ILK/EGFR/Ras/NF-κB signaling cascade and subsequent Slug expression.

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References

  1. Tomaskovic-Crook E, Thompson EW, Thiery JP . Epithelial to mesenchymal transition and breast cancer. Breast Cancer Res 2009; 11: 213.

    Article  Google Scholar 

  2. Lo HW, Hsu SC, Xia W, Cao X, Shih JY, Wei Y et al. Epidermal growth factor receptor cooperates with signal transducer and activator of transcription 3 to induce epithelial-mesenchymal transition in cancer cells via up-regulation of TWIST gene expression. Cancer Res 2007; 67: 9066–9076.

    Article  CAS  Google Scholar 

  3. Oft M, Peli J, Rudaz C, Schwarz H, Beug H, Reichmann E . TGF-beta1 and Ha-Ras collaborate in modulating the phenotypic plasticity and invasiveness of epithelial tumor cells. Genes Dev 1996; 10: 2462–2477.

    Article  CAS  Google Scholar 

  4. Dong P, Karaayvaz M, Jia N, Kaneuchi M, Hamada J, Watari H et al. Mutant p53 gain-of-function induces epithelial-mesenchymal transition through modulation of the miR-130b-ZEB1 axis. Oncogene 2013; 32: 3286–3295.

    Article  CAS  Google Scholar 

  5. de Herreros AG, Peiro S, Nassour M, Savagner P . Snail family regulation and epithelial mesenchymal transitions in breast cancer progression. J Mammary Gland Biol Neoplasia 2010; 15: 135–147.

    Article  Google Scholar 

  6. Casas E, Kim J, Bendesky A, Ohno-Machado L, Wolfe CJ, Yang J . Snail2 is an essential mediator of Twist1-induced epithelial mesenchymal transition and metastasis. Cancer Res 2011; 71: 245–254.

    Article  CAS  Google Scholar 

  7. Alves CC, Carneiro F, Hoefler H, Becker KF . Role of the epithelial-mesenchymal transition regulator Slug in primary human cancers. Front Biosci (Landmark Ed) 2009; 14: 3035–3050.

    Article  Google Scholar 

  8. Come C, Magnino F, Bibeau F, De Santa Barbara P, Becker KF, Theillet C et al. Snail and slug play distinct roles during breast carcinoma progression. Clin Cancer Res 2006; 12: 5395–5402.

    Article  CAS  Google Scholar 

  9. Elloul S, Elstrand MB, Nesland JM, Trope CG, Kvalheim G, Goldberg I et al. Snail, Slug, and Smad-interacting protein 1 as novel parameters of disease aggressiveness in metastatic ovarian and breast carcinoma. Cancer 2005; 103: 1631–1643.

    Article  CAS  Google Scholar 

  10. Zhang J, Liu X, Datta A, Govindarajan K, Tam WL, Han J et al. RCP is a human breast cancer-promoting gene with Ras-activating function. J Clin Invest 2009; 119: 2171–2183.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Morello V, Cabodi S, Sigismund S, Camacho-Leal MP, Repetto D, Volante M et al. Beta1 integrin controls EGFR signaling and tumorigenic properties of lung cancer cells. Oncogene 2011; 30: 4087–4096.

    Article  CAS  Google Scholar 

  12. Jacquemet G, Green DM, Bridgewater RE, von Kriegsheim A, Humphries MJ, Norman JC et al. RCP-driven alpha5beta1 recycling suppresses Rac and promotes RhoA activity via the RacGAP1-IQGAP1 complex. J Cell Biol 2013; 202: 917–935.

    Article  CAS  Google Scholar 

  13. Mills GB, Jurisica I, Yarden Y, Norman JC . Genomic amplicons target vesicle recycling in breast cancer. J Clin Invest 2009; 119: 2123–2127.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Rainero E, Caswell PT, Muller PA, Grindlay J, McCaffrey MW, Zhang Q et al. Diacylglycerol kinase alpha controls RCP-dependent integrin trafficking to promote invasive migration. J Cell Biol 2012; 196: 277–295.

    Article  CAS  Google Scholar 

  15. Muller PA, Caswell PT, Doyle B, Iwanicki MP, Tan EH, Karim S et al. Mutant p53 drives invasion by promoting integrin recycling. Cell 2009; 139: 1327–1341.

    Article  Google Scholar 

  16. Caswell PT, Chan M, Lindsay AJ, McCaffrey MW, Boettiger D, Norman JC . Rab-coupling protein coordinates recycling of alpha5beta1 integrin and EGFR1 to promote cell migration in 3D microenvironments. J Cell Biol 2008; 183: 143–155.

    Article  CAS  Google Scholar 

  17. Rhee CM, Ravel VA, Ayus JC, Sim JJ, Streja E, Mehrotra R et al. Pre-dialysis serum sodium and mortality in a national incident hemodialysis cohort. Nephrol Dial Transplant 2015; 31: 992–1001.

    Article  Google Scholar 

  18. Zhang C, Carl TF, Trudeau ED, Simmet T, Klymkowsky MW . An NF-kappaB and slug regulatory loop active in early vertebrate mesoderm. PloS one 2006; 1: e106.

    Article  Google Scholar 

  19. Choi MJ, Cho KH, Lee S, Bae YJ, Jeong KJ, Rha SY et al. hTERT mediates norepinephrine-induced Slug expression and ovarian cancer aggressiveness. Oncogene 2015; 34: 3402–3412.

    Article  CAS  Google Scholar 

  20. Sakai D, Tanaka Y, Endo Y, Osumi N, Okamoto H, Wakamatsu Y . Regulation of Slug transcription in embryonic ectoderm by beta-catenin-Lef/Tcf and BMP-Smad signaling. Dev Growth Differ 2005; 47: 471–482.

    Article  CAS  Google Scholar 

  21. Lambertini E, Franceschetti T, Torreggiani E, Penolazzi L, Pastore A, Pelucchi S et al. SLUG: a new target of lymphoid enhancer factor-1 in human osteoblasts. BMC. Mol Biol 2010; 11: 13.

    Google Scholar 

  22. Krishnan M, Lapierre LA, Knowles BC, Goldenring JR . Rab25 regulates integrin expression in polarized colonic epithelial cells. Mol Biol Cell 2013; 24: 818–831.

    Article  CAS  Google Scholar 

  23. Toguri JT, Moxsom R, Szczesniak AM, Zhou J, Kelly ME, Lehmann C . Cannabinoid 2 receptoractivation reduces leukocyte adhesion and improves capillary perfusionin the iridial microvasculature during systemic inflammation. Clin Hemorheol Microcirc 2015; 61: 237–249.

    Article  CAS  Google Scholar 

  24. Braune S, Zhou S, Groth B, Jung F . Quantification of adherent platelets on polymer-based biomaterials. Comparison of colorimetric and microscopic assessment. Clin Hemorheol Microcirc 2015; 61: 225–236.

    Article  CAS  Google Scholar 

  25. Ju L, Zhou C . Integrin beta 1 enhances the epithelial-mesenchymal transition in association with gefitinib resistance of non-small cell lung cancer. Cancer Biomark 2013; 13: 329–336.

    Article  CAS  Google Scholar 

  26. Arboleda MJ, Lyons JF, Kabbinavar FF, Bray MR, Snow BE, Ayala R et al. Overexpression of AKT2/protein kinase Bbeta leads to up-regulation of beta1 integrins, increased invasion, and metastasis of human breast and ovarian cancer cells. Cancer Res 2003; 63: 196–206.

    CAS  PubMed  Google Scholar 

  27. Yao ES, Zhang H, Chen YY, Lee B, Chew K, Moore D et al. Increased beta1 integrin is associated with decreased survival in invasive breast cancer. Cancer Res 2007; 67: 659–664.

    Article  CAS  Google Scholar 

  28. Lee MY, Chou CY, Tang MJ, Shen MR . Epithelial-mesenchymal transition in cervical cancer: correlation with tumor progression, epidermal growth factor receptor overexpression, and snail up-regulation. Clin Cancer Res 2008; 14: 4743–4750.

    Article  CAS  Google Scholar 

  29. Moro L, Dolce L, Cabodi S, Bergatto E, Boeri Erba E, Smeriglio M et al. Integrin-induced epidermal growth factor (EGF) receptor activation requires c-Src and p130Cas and leads to phosphorylation of specific EGF receptor tyrosines. J Biol Chem 2002; 277: 9405–9414.

    Article  CAS  Google Scholar 

  30. Azimifar SB, Bottcher RT, Zanivan S, Grashoff C, Kruger M, Legate KR et al. Induction of membrane circular dorsal ruffles requires co-signalling of integrin-ILK-complex and EGF receptor. J Cell Sci 2012; 125: 435–448.

    Article  CAS  Google Scholar 

  31. Lee M, Lee HJ, Seo WD, Park KH, Lee YS . Sialylation of integrin beta1 is involved in radiation-induced adhesion and migration in human colon cancer cells. Int J Radiat Oncol Biol Phys 2010; 76: 1528–1536.

    Article  CAS  Google Scholar 

  32. Park SY, Jeong KJ, Panupinthu N, Yu S, Lee J, Han JW et al. Lysophosphatidic acid augments human hepatocellular carcinoma cell invasion through LPA1 receptor and MMP-9 expression. Oncogene 2011; 30: 1351–1359.

    Article  CAS  Google Scholar 

  33. Jeong KJ, Park SY, Cho KH, Sohn JS, Lee J, Kim YK et al. The Rho/ROCK pathway for lysophosphatidic acid-induced proteolytic enzyme expression and ovarian cancer cell invasion. Oncogene 2012; 31: 4279–4289.

    Article  CAS  Google Scholar 

  34. Kenny HA, Kaur S, Coussens LM, Lengyel E . The initial steps of ovarian cancer cell metastasis are mediated by MMP-2 cleavage of vitronectin and fibronectin. J Clin Invest 2008; 118: 1367–1379.

    Article  CAS  Google Scholar 

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Acknowledgements

This study was supported by a grant from Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (NRF-2014R1A2A1A11051091).

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Correspondence to H Y Lee.

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Hwang, M., Cho, K., Jeong, K. et al. RCP induces Slug expression and cancer cell invasion by stabilizing β1 integrin. Oncogene 36, 1102–1111 (2017). https://doi.org/10.1038/onc.2016.277

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