根據統計癌症是近年來最為常見的疾病之一，癌症可以藉由血液循環或是淋巴系統擴散到身體的其他部位，進而增加癌症致死率。在癌症易好發轉移的部位當中，骨頭轉移是很常見的現象，當癌細胞轉移到骨頭當中時，不僅會造成骨質侵蝕(osteolysis)，往往也會對病人造成極大的疼痛。介白素二十(Interleukin-20，IL-20)是隸屬於介白素十(Interleukin-10，IL-10)家族當中的一員，而IL-20可以透過與其受體IL-20R1/IL-20R2的作用，進一步往下進行訊息傳遞。過去研究顯示，IL-20在牛皮癬、類風溼性關節炎甚至是癌症…等疾病當中都有參與。在先前實驗室所發表的文獻當中，IL-20單株抗體7E對於乳癌所導致的癌症骨侵蝕現象，具有良好的抑制效果。然而我們並不清楚7E對於其他癌症所引發的骨侵蝕現象是否也能具有類似的保護效果。因此，我們利用五種不同的癌細胞：「前列腺癌、食道癌、口腔癌、骨肉瘤、多發性骨髓瘤」來建立癌症骨侵蝕的動物實驗模式，經由骨質密度分析我們發現7E對於前列腺癌以及食道癌所導致骨侵蝕現象具有良好的抑制效果，但是在口腔癌、骨肉瘤以及多發性骨髓瘤則沒有看到明顯的保護效果。在前列腺癌細胞當中，IL-20能促進其sRANKL、cathepsin G 以及cathepsin K基因的表現量，也能促進sRANKL蛋白的產生。前列腺癌細胞的條件培養液，也可以抑制前驅成骨細胞的細胞增生現象。此外，7E也能抑制前列癌細胞的細胞增生、細胞遷徙以及細胞集落的形成。而IL-20也可以誘導前列腺癌細胞內的P-38、Erk1/2、Akt以及NFκB等訊息傳遞分子的磷酸化，更可以促進與癌症轉移相關(STAT3、 vimentin、fibronectin、N-cadherin)基因的表現。此外在食道癌細胞中，7E也可以抑制其細胞增生、細胞遷徙以及細胞集落的形成。從以上的實驗結果，我們證實7E對於前列腺癌以及食道癌所引發的骨侵蝕具有良好的保護效果，這些結果顯示7E在癌症所引發的骨侵蝕現象具有治療潛力。

Cancer is the most common disease in the world. It may also spread to distant parts of the body and increase the mortality. Bone is one of the site for cancer metastasis. Cancer cells in the bone reduce bone mineral density and induce pain in patients. IL-20 is a cytokine belonging to the IL-10 family. IL-20 binds to a heterodimer receptor complex IL-20R1/IL-20R2 mediating its signal transduction. Previous studies showed that IL-20 is involved in several diseases, such as psoriasis, rheumatoid arthritis and cancer. In our previous study, anti-IL-20 monoclonal antibody 7E suppressed breast cancer-induced osteolysis. To investigate whether 7E can suppress other cancer cells-induced osteolysis, we used five different kinds of cancers: prostate cancer, esophageal cancer, oral cancer, osteosarcoma and multiple myeloma to establish cancer-induced osteolysis animal models. Our result showed that 7E suppressed prostate cancer and esophageal cancer induced osteolysis. However, 7E did not suppress osteolysis in oral cancer, osteosarcoma and multiple myeloma. Furthermore, IL-20 increased gene expression of sRANKL, cathepsin G and cathepsin K and sRANKL protein expression in prostate cancer cell. Condition medium of prostate cancer cell suppressed pre-osteoblast proliferation. 7E also suppressed prostate cancer cell proliferation, migration and colony formation. IL-20 also induced phosphorylation of P-38, Erk1/2, Akt and NFκB in prostate cancer cell. In addition, IL-20 upregulated STAT3, vimentin, fibronectin and N-cadherin gene expression. 7E also suppressed esophageal cancer cell proliferation, migration and colony formation. Our study provides the evidence that 7E has a protective function in prostate and esophageal cancer-induced osteolysis in animal model and anti-IL-20 monoclonal antibody 7E may have therapeutic potential in cancer-induced osteolysis.

1. E. I. Buchbinder, D. F. McDermott, Interferon, Interleukin-2, and Other Cytokines. Hematology/oncology clinics of North America 28, 571-583 (2014).
2. R. Sabat, IL-10 family of cytokines. Cytokine & growth factor reviews 21, 315-324 (2010).
3. A. Zdanov, Structural analysis of cytokines comprising the IL-10 family. Cytokine & growth factor reviews 21, 325-330 (2010).
4. U. M. Wegenka, IL-20: biological functions mediated through two types of receptor complexes. Cytokine & growth factor reviews 21, 353-363 (2010).
5. C. C. Wei, Y. H. Hsu, H. H. Li, Y. C. Wang, M. Y. Hsieh, W. Y. Chen, C. H. Hsing, M. S. Chang, IL-20: biological functions and clinical implications. Journal of biomedical science 13, 601-612 (2006).
6. A. Zdanov, Structural features of the interleukin-10 family of cytokines. Current pharmaceutical design 10, 3873-3884 (2004).
7. B. E. Rich, IL-20: a new target for the treatment of inflammatory skin disease. Expert opinion on therapeutic targets 7, 165-174 (2003).
8. R. Sabat, S. Philipp, C. Hoflich, S. Kreutzer, E. Wallace, K. Asadullah, H. D. Volk, W. Sterry, K. Wolk, Immunopathogenesis of psoriasis. Experimental dermatology 16, 779-798 (2007).
9. K. Stenderup, C. Rosada, A. Worsaae, J. T. Clausen, T. Norman Dam, Interleukin-20 as a target in psoriasis treatment. Annals of the New York Academy of Sciences 1110, 368-381 (2007).
10. A. Michalak-Stoma, A. Pietrzak, J. C. Szepietowski, A. Zalewska-Janowska, T. Paszkowski, G. Chodorowska, Cytokine network in psoriasis revisited. European cytokine network 22, 160-168 (2011).
11. R. Kleemann, S. Zadelaar, T. Kooistra, Cytokines and atherosclerosis: a comprehensive review of studies in mice. Cardiovascular research 79, 360-376 (2008).
12. R. X. Leng, H. F. Pan, J. H. Tao, D. Q. Ye, IL-19, IL-20 and IL-24: potential therapeutic targets for autoimmune diseases. Expert opinion on therapeutic targets 15, 119-126 (2011).
13. F. Brennan, J. Beech, Update on cytokines in rheumatoid arthritis. Current opinion in rheumatology 19, 296-301 (2007).
14. Y. H. Hsu, C. H. Hsing, C. F. Li, C. H. Chan, M. C. Chang, J. J. Yan, M. S. Chang, Anti-IL-20 monoclonal antibody suppresses breast cancer progression and bone osteolysis in murine models. Journal of immunology (Baltimore, Md. : 1950) 188, 1981-1991 (2012).
15. Y. H. Hsu, C. C. Wei, D. B. Shieh, C. H. Chan, M. S. Chang, Anti-IL-20 monoclonal antibody alleviates inflammation in oral cancer and suppresses tumor growth. Molecular cancer research : MCR 10, 1430-1439 (2012).
16. B. Kahn, J. Collazo, N. Kyprianou, Androgen Receptor as a Driver of Therapeutic Resistance in Advanced Prostate Cancer. International journal of biological sciences 10, 588-595 (2014).
17. N. Rucci, A. Angelucci, Prostate Cancer and Bone: The Elective Affinities. 2014, 167035 (2014).
18. J. H. Noguez, C. R. Fantz, Pathology Consultation on Prostate-Specific Antigen Testing. American journal of clinical pathology 142, 7-15 (2014).
19. M. F. Berry, Esophageal cancer: staging system and guidelines for staging and treatment. Journal of thoracic disease 6, S289-297 (2014).
20. M. Pazianas, S. van der Geest, P. Miller, Bisphosphonates and bone quality. BoneKEy reports 3, 529 (2014).
21. M. Capulli, R. Paone, N. Rucci, Osteoblast and osteocyte: Games without frontiers. Archives of biochemistry and biophysics, (2014).
22. G. Y. Rochefort, The osteocyte as a therapeutic target in the treatment of osteoporosis. Therapeutic advances in musculoskeletal disease 6, 79-91 (2014).
23. M. T. Drake, Osteoporosis and cancer. Current osteoporosis reports 11, 163-170 (2013).
24. Y. H. Hsu, W. Y. Chen, C. H. Chan, C. H. Wu, Z. J. Sun, M. S. Chang, Anti-IL-20 monoclonal antibody inhibits the differentiation of osteoclasts and protects against osteoporotic bone loss. The Journal of experimental medicine 208, 1849-1861 (2011).
25. G. Bhutani, M. C. Gupta, Emerging therapies for the treatment of osteoporosis. Journal of mid-life health 4, 147-152 (2013).
26. T. J. Wilson, K. C. Nannuru, M. Futakuchi, A. Sadanandam, R. K. Singh, Cathepsin G enhances mammary tumor-induced osteolysis by generating soluble receptor activator of nuclear factor-kappaB ligand. Cancer research 68, 5803-5811 (2008).
27. A. Nickel, S. C. Stadler, Role of epigenetic mechanisms in epithelial-to-mesenchymal transition of breast cancer cells. Translational research : the journal of laboratory and clinical medicine, (2014).
28. S. J. Lee, K. H. Kim, K. K. Park, Mechanisms of fibrogenesis in liver cirrhosis: The molecular aspects of epithelial-mesenchymal transition. World journal of hepatology 6, 207-216 (2014).
29. M. K. Wendt, N. Balanis, C. R. Carlin, W. P. Schiemann, STAT3 and epithelial-mesenchymal transitions in carcinomas. Jak-stat 3, e28975 (2014).
30. M. Shiota, J. L. Bishop, K. M. Nip, A. Zardan, A. Takeuchi, T. Cordonnier, E. Beraldi, J. Bazov, L. Fazli, K. Chi, M. Gleave, A. Zoubeidi, Hsp27 regulates epithelial mesenchymal transition, metastasis, and circulating tumor cells in prostate cancer. Cancer research 73, 3109-3119 (2013).