Lung cancer is the leading cause of cancer death in the United States and around the world. Recent studies indicate that cancer-associated fibroblasts (CAFs) are involved in tumor growth, invasion and metastasis, however, the underling mechanisms remain unclear. In the present study, we investigated the role of interaction of interleukin 32 (IL-32) with integrin on the metastatic potential of lung cancer cells and related CAF pathway. We found that IL-32, an ‘RGD’ motif–containing cytokine, was found to be abundantly expressed in CAFs. Integrin β3 turned out to be up-regulated in non-small lung cancer (NSCLC) during epithelial–mesenchymal transition (EMT). CAF-derived IL-32 specifically bound to integrin β3 through the RGD motif, thus activating intracellular downstream p38 MAPK signalling in NSCLC cells. This signalling increased the expression of EMT markers and promoted tumor cell invasion. While, inhibition of IL-32 led to specific inactivation of p38 MAPK signalling in tumor cells. Furthermore, blockage of the p38 MAPK pathway also diminished IL-32-induced expression of EMT markers and NSCLC cell invasion and metastasis.
Keywords:NSCLC; MAPK; CAF; RGD
Copyright © 2018 by The American Society for BioMedicine and BM-Publisher, Inc.
1. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin 2015;65:87-108.
2. Moon YW, Jeung HC, Rha SY, et al. Changing patterns of prognosticators during 15-year follow-up of advanced gastric cancer after radical gastrectomy and adjuvant chemotherapy: a 15-year follow-up study at a single korean institute. Annals of surgical oncology 2007;14:2730-2737.
3. Thiery JP. Epithelial-mesenchymal transitions in tumour progression. Nature reviews Cancer 2002;2:442-454.
4. Yang J, Weinberg RA. Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Developmental cell 2008;14:818-829.
5. Zeisberg M, Neilson EG. Biomarkers for epithelial-mesenchymal transitions. J Clin Invest 2009;119:1429-1437.
6. Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 2015;136:E359-386.
7. Yousif NG. Fibronectin promotes migration and invasion of ovarian cancer cells through up‐regulation of FAK–PI 3 K/A kt pathway. Cell biology international 2014;38:85-91.
8. Herbst RS, Heymach JV, Lippman SM. Lung cancer. N Engl J Med 2008;359:1367-1380.
9. Mego M, Mani SA, Cristofanilli M. Molecular mechanisms of metastasis in breast cancer—clinical applications. Nat Rev Clin Oncol 2010;7:693-701.
10. Quail DF, Joyce JA. Microenvironmental regulation of tumor progression and metastasis. Nat Med 2013;19:1423-1437.
11. Augsten M. Cancer-associated fibroblasts as another polarized cell type of the tumor microenvironment. Front Oncol 2014;4:62.
12. Kalluri R. The biology and function of fibroblasts in cancer. Nat Rev Cancer 2016;16:582-598.
13. Kalluri R, Zeisberg M. Fibroblasts in cancer. Nat Rev Cancer 2006;6:392-401.
14. Lohr M, Schmidt C, Ringel J, et al. Transforming growth factor-beta1 induces desmoplasia in an experimental model of human pancreatic carcinoma. Cancer Res 2001;61:550-555.
15. Wang X, Yang S, Zheng E, Xiao P, Zheng-Yu Li. Interleukin-10 inhibits ovarian cancer cells growth via down regulation of inflammatory cytokine production. American Journal of BioMedicine 2014;2(8): 940-951.
16. Aoyagi Y, Oda T, Kinoshita T, Nakahashi C, Hasebe T, Ohkohchi N, Ochiai A. Overexpression of TGF-beta by infiltrated granulocytes correlates with the expression of collagen mRNA in pancreatic cancer. Br J Cancer 2004;91:1316-1326.
17. Bronzert DA, Pantazis P, Antoniades HN, Kasid A, Davidson N, Dickson RB, Lippman ME. Synthesis and secretion of platelet-derived growth factor by human breast cancer cell lines. Proc Natl Acad Sci U S A 1987;84:5763-5767.
18. Zhuang J, Lu Q, Shen B, Huang X, Shen L, Zheng X, Huang R, Yan J, Guo H. TGFbeta1 secreted by cancer-associated fibroblasts induces epithelial-mesenchymal transition of bladder cancer cells through lncRNA-ZEB2NAT. Scientific Rep 2015;5:11924.
19. Kojima Y, Acar A, Eaton EN,et al. Autocrine TGF-beta and stromal cell-derived factor-1 (SDF-1) signaling drives the evolution of tumor-promoting mammary stromal myofibroblasts. Proc Natl Acad Sci U S A 2010;107:20009-20014.
20. Fang WB, Mafuvadze B, Yao M, Zou A, Portsche M, Cheng N. TGF-beta negatively regulates CXCL1 chemokine expression in mammary fibroblasts through enhancement of Smad2/3 and suppression of HGF/c-Met signaling mechanisms. PLoS One 2015;10:e0135063.
21. Tsai C, Kim H, Adriennea J. Critical role of IL-32 invasion and metastasis of colonic cancer through upregulation of matrix metalloproteinase (MMP)-2. American Journal of BioMedicine 2018;6(10):661-684.
22. Taguchi A, Kawana K, Tomio K, Yamashita A, Isobe Y, Nagasaka K, Koga K, Inoue T, Nishida H, Kojima S, Adachi K, Matsumoto Y, Arimoto T, et al. Matrix metalloproteinase (MMP)-9 in cancer-associated fibroblasts (CAFs) is suppressed by omega-3 polyunsaturated fatty acids in vitro and in vivo. PLoS One 2014;9:e89605.
23. Zheng X, Carstens JL, Kim J, et al. Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer. Nature 2015;527:525-530.
24. Bae YK, Choi JE, Kang SH, Lee SJ. Epithelial-Mesenchymal Transition Phenotype Is Associated with Clinicopathological Factors That Indicate Aggressive Biological Behavior and Poor Clinical Outcomes in Invasive Breast Cancer. J Breast Cancer 2015;18:256-263.
25. Gupta GP, Massague J. Cancer metastasis: building a framework. Cell 2006;127(4):679-695.
26. Chambers AF, Groom AC, MacDonald IC. Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer 2002;2(8):563-572.
27. Vitolo D, Ciocci L, Deriu G, et al. Laminin alpha2 chain-positive vessels and epidermal growth factor in lung neuroendocrine carcinoma: a model of a novel cooperative role of laminin-2 and epidermal growth factor in vessel neoplastic invasion and metastasis. Am J Pathol 2006;168(3):991-1003.
28. Lam TK, Gallicchio L, Lindsley K, et al. Cruciferous vegetable consumption and lung cancer risk: a systematic review. Cancer Epidemiol Biomarkers Prev 2009;18(1):184-195.
29. Wu X, Zhou QH, Xu K. Are isothiocyanates potential anti-cancer drugs? Acta Pharmacol Sin 2009;30(5):501-512.
30. AI-Timimi AH, Yousif NG. Immunohistochemical determination of estrogen and progesterone receptors in breast cancer: pathological correlation and prognostic indicators. American Journal of BioMedicine 2014;2(12):295-312.https://doi.org/10.18081/2333-5106/014-12/1229-1239
READ THE FULL ARTICLE
1. Access this article through OpenAthens
3. Purchase this article at rate $55.00 and received Full-Text/PDF
You will have online immediate access to article following the completion of this purchase and you may download and print a copy of each article for your personal use. Use the coding below to purchase your article as PDF by credit card, debit card, will be asked to supply your billing card information. Before continue with your purchase please read carefully the BM-Publisher terms and conditions of purchase.
For any technique error please contact us and will be response to sending purchase article by email.
Who Can Become a Reviewer?
Any expert in the article's research field can become a reviewer with American Journal of Biomedicine. Editors might ask you to look at a specific aspect of an article,...
Thank you for visiting American Journal of BioMedicine. * = Required fields
[contact-form-7 404 "Not Found"]
American Journal of BioMedicine Volume 6, Issue 8, pages 685-697
Received April 11, 2018; accepted October 19, 2018; published October 31, 2018
How to cite this article
Shete S, Kim Q, Wu X, Wang X, Dong Q. IL-32 promotes lung cancer cell invasion and metastasis through p38 MAPK signaling pathway: Cancer-associated fibroblast-derived. American Journal of BioMedicine 2018;6(10):685-697.
Case report outline