Suppression of mucin 2 promotes interleukin-6 secretion and tumor growth in an orthotopic immune-competent colon cancer animal model

Shan,Yan-Shen; Hsu,Hui-Ping; Lai,Ming-Derg; Yen,Meng-Chi; Fang,Jung-Hua; Weng,Tzu-Yang; Chen,Yi-Ling

doi:10.3892/or.2014.3544

Suppression of mucin 2 promotes interleukin-6 secretion and tumor growth in an orthotopic immune-competent colon cancer animal model

Authors:
- Yan-Shen Shan
- Hui-Ping Hsu
- Ming-Derg Lai
- Meng-Chi Yen
- Jung-Hua Fang
- Tzu-Yang Weng
- Yi-Ling Chen
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Affiliations: Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan, R.O.C., Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan, R.O.C., Laboratory Animal Center, College of Medicine, National Cheng Kung University, Tainan, Taiwan, R.O.C., Department of Senior Citizen Service Management, Chia Nan University of Pharmacy and Science, Tainan, Taiwan, R.O.C.
Published online on: October 13, 2014 https://doi.org/10.3892/or.2014.3544
Pages: 2335-2342
Copyright: © Shan et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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Abstract

Mucin 2 (MUC2) is the major secreted mucin of the large intestine and is expressed by adenomas and mucinous carcinomas. Since colon cancer is associated with a proinflammatory microenvironment and dysregulated MUC2 expression, the aim of this study was to characterize the effects of MUC2 gene expression in colon tumor progression using colonic cancer cells. CT26 colon cancer cells were stably transfected with MUC2 siRNA (MUC2 RNAi) or a control construct containing a nonspecific sequence (scrambled RNAi). Expression of MUC2 was significantly decreased in the MUC2 RNAi cell clones. Although MUC2 suppression did not affect the cell growth of colon cancer cells in vitro, MUC2 knockdown promoted tumor growth in an orthotopic colon cancer model in vivo. MUC2 silencing also increased interleukin (IL)-6 secretion by colon cancer cells. IL-6 neutralization attenuated tumor formation by MUC2 RNAi cells; it also increased CD8 T cell infiltration into the peritoneum. Taken together, to the best of our knowledge, this is the first study indicating that the immune response to cancer cells plays an important role in tumor growth regulated by MUC2. Furthermore, given the effects of MUC2 on IL-6 secretion, its targeting may represent a potentially useful strategy to treat colonic carcinomas.

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1	Hanski C, Hofmeier M, Schmitt-Gräff A, et al: Overexpression or ectopic expression of MUC2 is the common property of mucinous carcinomas of the colon, pancreas, breast, and ovary. J Pathol. 182:385–391. 1997. View Article : Google Scholar : PubMed/NCBI
2	Velcich A, Yang W, Heyer J, et al: Colorectal cancer in mice genetically deficient in the mucin Muc2. Science. 295:1726–1729. 2002. View Article : Google Scholar : PubMed/NCBI
3	Coussens LM and Werb Z: Inflammation and cancer. Nature. 420:860–867. 2002. View Article : Google Scholar : PubMed/NCBI
4	Piancatelli D, Romano P, Sebastiani P, Adorno D and Casciani CU: Local expression of cytokines in human colorectal carcinoma: evidence of specific interleukin-6 gene expression. J Immunother. 22:25–32. 1999. View Article : Google Scholar
5	Lieubeau B, Heymann MF, Henry F, Barbieux I, Meflah K and Grégoire M: Immunomodulatory effects of tumor-associated fibroblasts in colorectal-tumor development. Int J Cancer. 81:629–636. 1999. View Article : Google Scholar : PubMed/NCBI
6	Giri D, Ozen M and Ittmann M: Interleukin-6 is an autocrine growth factor in human prostate cancer. Am J Pathol. 159:2159–2165. 2001. View Article : Google Scholar : PubMed/NCBI
7	Adler HL, McCurdy MA, Kattan MW, Timme TL, Scardino PT and Thompson TC: Elevated levels of circulating interleukin-6 and transforming growth factor-beta 1 in patients with metastatic prostatic carcinoma. J Urol. 161:182–187. 1999. View Article : Google Scholar : PubMed/NCBI
8	Esfandi F, Mohammadzadeh Ghobadloo S and Basati G: Interleukin-6 level in patients with colorectal cancer. Cancer Lett. 244:76–78. 2006. View Article : Google Scholar : PubMed/NCBI
9	Galizia G, Orditura M, Romano C, et al: Prognostic significance of circulating IL-10 and IL-6 serum levels in colon cancer patients undergoing surgery. Clin Immunol. 102:169–178. 2002. View Article : Google Scholar : PubMed/NCBI
10	Ueda T, Shimada E and Urakawa T: Serum levels of cytokines in patients with colorectal cancer: possible involvement of interleukin-6 and interleukin-8 in hematogenous metastasis. J Gastroenterol. 29:423–429. 1994. View Article : Google Scholar : PubMed/NCBI
11	Kinoshita T, Ito H and Miki C: Serum interleukin-6 level reflects the tumor proliferative activity in patients with colorectal carcinoma. Cancer. 85:2526–2531. 1999. View Article : Google Scholar : PubMed/NCBI
12	Chung YC and Chang YF: Serum interleukin-6 levels reflect the disease status of colorectal cancer. J Surg Oncol. 83:222–226. 2003. View Article : Google Scholar : PubMed/NCBI
13	Li YY, Hsieh LL, Tang RP, Liao SK and Yeh KY: Macrophage-derived interleukin-6 up-regulates MUC1, but down-regulates MUC2 expression in the human colon cancer HT-29 cell line. Cell Immunol. 256:19–26. 2009. View Article : Google Scholar : PubMed/NCBI
14	Atsumi T, Singh R, Sabharwal L, et al: Inflammation amplifier, a new paradigm in cancer biology. Cancer Res. 74:8–14. 2014. View Article : Google Scholar : PubMed/NCBI
15	Lu TJ, Lai WY, Huang CY, et al: Inhibition of cell migration by autophosphorylated mammalian sterile 20-like kinase 3 (MST3) involves paxillin and protein-tyrosine phosphatase-PEST. J Biol Chem. 281:38405–38417. 2006. View Article : Google Scholar : PubMed/NCBI
16	Shan YS, Fang JH, Lai MD, et al: Establishment of an orthotopic transplantable gastric cancer animal model for studying the immunological effects of new cancer therapeutic modules. Mol Carcinog. 50:739–750. 2011. View Article : Google Scholar
17	Ancrile B, Lim KH and Counter CM: Oncogenic Ras-induced secretion of IL6 is required for tumorigenesis. Genes Dev. 21:1714–1719. 2007. View Article : Google Scholar : PubMed/NCBI
18	Fridlender ZG, Sun J, Kim S, et al: Polarization of tumor-associated neutrophil phenotype by TGF-beta: ‘N1’ versus ‘N2’ TAN. Cancer Cell. 16:183–194. 2009.PubMed/NCBI
19	Ajioka Y, Allison LJ and Jass JR: Significance of MUC1 and MUC2 mucin expression in colorectal cancer. J Clin Pathol. 49:560–564. 1996. View Article : Google Scholar : PubMed/NCBI
20	Yonezawa S, Sueyoshi K, Nomoto M, et al: MUC2 gene expression is found in noninvasive tumors but not in invasive tumors of the pancreas and liver: its close relationship with prognosis of the patients. Hum Pathol. 28:344–352. 1997. View Article : Google Scholar : PubMed/NCBI
21	Li A, Goto M, Horinouchi M, et al: Expression of MUC1 and MUC2 mucins and relationship with cell proliferative activity in human colorectal neoplasia. Pathol Int. 51:853–860. 2001. View Article : Google Scholar : PubMed/NCBI
22	Bresalier RS, Niv Y, Byrd JC, et al: Mucin production by human colonic carcinoma cells correlates with their metastatic potential in animal models of colon cancer metastasis. J Clin Invest. 87:1037–1045. 1991. View Article : Google Scholar
23	Blank M, Klussmann E, Krüger-Krasagakes S, et al: Expression of MUC2-mucin in colorectal adenomas and carcinomas of different histological types. Int J Cancer. 59:301–306. 1994. View Article : Google Scholar : PubMed/NCBI
24	Ohlsson L, Israelsson A, Oberg A, et al: Lymph node CEA and MUC2 mRNA as useful predictors of outcome in colorectal cancer. Int J Cancer. 130:1833–1843. 2012. View Article : Google Scholar : PubMed/NCBI
25	Kang H, Min BS, Lee KY, et al: Loss of E-cadherin and MUC2 expressions correlated with poor survival in patients with stages II and III colorectal carcinoma. Ann Surg Oncol. 18:711–719. 2011. View Article : Google Scholar : PubMed/NCBI
26	Elzagheid A, Emaetig F, Buhmeida A, et al: Loss of MUC2 expression predicts disease recurrence and poor outcome in colorectal carcinoma. Tumour Biol. 34:621–628. 2013. View Article : Google Scholar : PubMed/NCBI
27	Van der Sluis M, De Koning BA, De Bruijn AC, et al: Muc2-deficient mice spontaneously develop colitis, indicating that MUC2 is critical for colonic protection. Gastroenterology. 131:117–129. 2006.PubMed/NCBI
28	Eichbaum C, Meyer AS, Wang N, et al: Breast cancer cell-derived cytokines, macrophages and cell adhesion: implications for metastasis. Anticancer Res. 31:3219–3227. 2011.PubMed/NCBI
29	Luboshits G, Shina S, Kaplan O, et al: Elevated expression of the CC chemokine regulated on activation, normal T cell expressed and secreted (RANTES) in advanced breast carcinoma. Cancer Res. 59:4681–4687. 1999.PubMed/NCBI
30	Niwa Y, Akamatsu H, Niwa H, Sumi H, Ozaki Y and Abe A: Correlation of tissue and plasma RANTES levels with disease course in patients with breast or cervical cancer. Clin Cancer Res. 7:285–289. 2001.PubMed/NCBI
31	Zhang GJ and Adachi I: Serum interleukin-6 levels correlate to tumor progression and prognosis in metastatic breast carcinoma. Anticancer Res. 19:1427–1432. 1999.
32	Salgado R, Junius S, Benoy I, et al: Circulating interleukin-6 predicts survival in patients with metastatic breast cancer. Int J Cancer. 103:642–646. 2003. View Article : Google Scholar : PubMed/NCBI
33	Kishimoto T: The biology of interleukin-6. Blood. 74:1–10. 1989.
34	Jones SA, Scheller J and Rose-John S: Therapeutic strategies for the clinical blockade of IL-6/gp130 signaling. J Clin Invest. 121:3375–3383. 2011. View Article : Google Scholar : PubMed/NCBI
35	Yen MC, Lin CC, Chen YL, et al: A novel cancer therapy by skin delivery of indoleamine 2,3-dioxygenase siRNA. Clin Cancer Res. 15:641–649. 2009. View Article : Google Scholar : PubMed/NCBI
36	Lin CC, Chou CW, Shiau AL, et al: Therapeutic HER2/Neu DNA vaccine inhibits mouse tumor naturally overexpressing endogenous neu. Mol Ther. 10:290–301. 2004. View Article : Google Scholar : PubMed/NCBI