Expressions and significances of interleukin-6 and microsatellite instability in ulcerative colitis-associated colorectal cancer_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

YIN Dongzhi ¹ ,  ZUO Jian ¹ , YUAN Youneng ¹ , ZUO Yanni ¹ , LUO Haiping ¹ , WANG Yanwu ²

1. Department of Gastrointestinal Surgery, Huangshi Central Hospital (Affiliated Hospital of Hubei Polytechnic University), Edong Healthcare Group, Huangshi, Hubei 435000, P. R. China;
2. Department of Pathology, Huangshi Central Hospital (Affiliated Hospital of Hubei Polytechnic University), Edong Healthcare Group, Huangshi, Hubei 435000, P. R. China;

Corresponding author：

ZUO Jian, Email: 332702072@qq.com

Keywords：

ulcerative colitis-associated colorectal cancer; ulcerative colitis; sporadic colorectal cancer; microsatellite instability; interleukin-6

DOI：

10.7507/1007-9424.201910009

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Objective To analyze expressions of interleukin-6 (IL-6) and microsatellite instability (MSI) in ulcerative colitis-associated colorectal cancer (UC-CRC) and investigate role of IL-6 and MSI in carcinogenesis of patients with UC.Methods The postoperative pathological data of patients with UC-CRC and patients with sporadic colorectal cancer (SCRC) admitted by Edong Healthcare Group from January 2013 to January 2019 were analyzed retrospectively. The expressions of MMR proteins, including hMLH1, hPMS2, hMSH2, and hMSH6, were detected by the immunohistochemical method. The serum IL-6 levels of the patients with UC, UC-CRC, SCRC and control patients (non-UC, non-UC-CRC, non-SCRC) were detected. The correlation between the IL-6 and MMR protein expression in the cancer tissue was analyzed.Results There were 43 patients with UC, 17 UC-CRC, 55 SCRC, and 30 control patients. The total rate of MMR-deficient (dMMR) was 41.2% (7/17) in the patients with UC-CRC. There were significant correlations between the hMLH1 and hPMS2 protein expression deletion and between the hMSH2 and hMSH6 protein expression deletion (P<0.001). The serum level of IL-6 in the patients with UC-CRC was significantly higher than that in the patients with UC (t=4.97, P<0.001) and the patients with SCRC (t=5.26, P=0.006). The dMMR might be associated with the level of IL-6 in the patients with UC-CRC, which wasn’t associated with it in the patients with SCRC (r_s=0.04, P=0.77).Conclusions Similar to SCRC, MSI also plays a role in occurrence and development of UC-CRC. dMMR in patient with UC-CRC is more common in co-expression deficiency of hMLH1 and hPMS2, as did hMSH2 and hMSH6. IL-6 is not involved in mechanism of MSI-related canceration of colorectal cancer, but it is speculated that IL-6 might be involved in occurrence of MSI of UC-CRC.

Citation： YIN Dongzhi, ZUO Jian, YUAN Youneng, ZUO Yanni, LUO Haiping, WANG Yanwu. Expressions and significances of interleukin-6 and microsatellite instability in ulcerative colitis-associated colorectal cancer. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2020, 27(7): 841-845. doi: 10.7507/1007-9424.201910009 Copy

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2.	Gu M, Kim D, Bae Y, et al. Analysis of microsatellite instability, protein expression and methylation status of hMLH1 and hMSH2 genes in gastric carcinomas. Hepatogastroenterology, 2009, 56(91-92): 899-904.
3.	Lynch HT, de la Chapelle A. Hereditary colorectal cancer. N Engl J Med, 2003, 348(10): 919-932.
4.	Fujiwara I, Yashiro M, Kubo N, et al. Ulcerative colitis-associated colorectal cancer is frequently associated with the microsatellite instability pathway. Dis Colon Rectum, 2008, 51(9): 1387-1394.
5.	Delahunty R, Mcmurrick P, Carne P, et al. Screening for mismatch repair deficiency in colorectal cancer. Asia Pac Clin Oncol, 2015, 11(S3): 52.
6.	Chung YC, Chang YF. Serum interleukin-6 levels reflect the disease status of colorectal cancer. J Surg Oncol, 2003, 83(4): 222-226.
7.	Tseng-Rogenski SS, Hamaya Y, Choi DY, et al. Interleukin 6 alters localization of hMSH3, leading to DNA mismatch repair defects in colorectal cancer cells. Gastroenterology, 2015, 148(3): 579-589.
8.	银东智, 沈世强. 溃疡性结肠炎相关结直肠癌的诊断与治疗. 中华消化外科杂志, 2018, 17(6): 637-639.
9.	Gorman J, Greene EC. Target search dynamics during post-replicative mismatch repair. Cell Cycle, 2013, 12(4): 537-538.
10.	Pino MS, Chung DC. Microsatellite instability in the management of colorectal cancer. Expert Rev Gastroenterol Hepatol, 2011, 5(3): 385-399.
11.	Vindigni SM, Kaz AM. Universal screening of colorectal cancers for Lynch syndrome: Challenges and opportunities. Dig Dis Sci, 2016, 61(4): 969-976.
12.	Amira AT, Mouna T, Ahlem B, et al. Immunohistochemical expression pattern of MMR protein can specifically identify patients with colorectal cancer microsatellite instability. Tumour Biol, 2014, 35(7): 6283-6291.
13.	Edelbrock MA, Kaliyaperumal S, Williams KJ. Structural, molecular and cellular functions of MSH2 and MSH6 during DNA mismatch repair, damage signaling and other noncanonical activities. Mutat Res, 2013, 743-744: 53-66.
14.	Jess T, Loftus EV Jr, Velayos FS, et al. Risk of intestinal cancer in inflammatory bowel disease: a population-based study from Olmsted county, Minnesota. Gastroenterology, 2006, 130(4): 1039-1046.
15.	Yang H, Li Y, Wu W, et al. The incidence of inflammatory bowel disease in Northern China: a prospective population-based study. PLoS One, 2014, 9(7): e101296.
16.	Eaden JA, Abrams KR, Mayberry JF. The risk of colorectal cancer in ulcerative colitis: a meta-analysis. Gut, 2001, 48(4): 526-535.
17.	Vagefi PA, Longo WE. Colorectal cancer in patients with inflammatory bowel disease. Clin Colorectal Cancer, 2005, 4(5): 313-319.
18.	Leedham SJ, Graham TA, Oukrif D, et al. Clonality, founder mutations, and field cancerization in human ulcerative colitis-associated neoplasia. Gastroenterology, 2009, 136(2): 542-550.
19.	Ullman TA, Itzkowitz SH. Intestinal inflammation and cancer. Gastroenterology, 2011, 140(6): 1807-1816.
20.	Park WS, Pham T, Wang C, et al. Loss of heterozygosity and microsatellite instability in non-neoplastic mucosa from patients with chronic ulcerative colitis. Int J Mol Med, 1998, 2(2): 221-224.
21.	Roessner A, Kuester D, Malfertheiner P, et al. Oxidative stress in ulcerative colitis-associated carcinogenesis. Pathol Res Pract, 2008, 204(7): 511-524.
22.	Simmonds NJ, Allen RE, Stevens TR, et al. Chemiluminescence assay of mucosal reactive oxygen metabolites in inflammatory bowel disease. Gastroenterology, 1992, 103(1): 186-196.
23.	Fournier BM, Parkos CA. The role of neutrophils during intestinal inflammation. Mucosal Immunol, 2012, 5(4): 354-366.
24.	Barzilai A, Yamamoto K. DNA damage responses to oxidative stress. DNA Repair (Amst), 2004, 3(8-9): 1109-1115.
25.	De Simone V, Franzè E, Ronchetti G, et al. Th17-type cytokines, IL-6 and TNF-α synergistically activate STAT3 and NF-kB to promote colorectal cancer cell growth. Oncogene, 2015, 34(27): 3493-3503.
26.	Klampfer L. Cytokines, inflammation and colon cancer. Curr Cancer Drug Targets, 2011, 11(4): 451-464.

1. Markowitz SD, Bertagnolli MM. Molecular origins of cancer: Molecular basis of colorectal cancer. N Engl J Med, 2009, 361(25): 2449-2460.
2. Gu M, Kim D, Bae Y, et al. Analysis of microsatellite instability, protein expression and methylation status of hMLH1 and hMSH2 genes in gastric carcinomas. Hepatogastroenterology, 2009, 56(91-92): 899-904.
3. Lynch HT, de la Chapelle A. Hereditary colorectal cancer. N Engl J Med, 2003, 348(10): 919-932.
4. Fujiwara I, Yashiro M, Kubo N, et al. Ulcerative colitis-associated colorectal cancer is frequently associated with the microsatellite instability pathway. Dis Colon Rectum, 2008, 51(9): 1387-1394.
5. Delahunty R, Mcmurrick P, Carne P, et al. Screening for mismatch repair deficiency in colorectal cancer. Asia Pac Clin Oncol, 2015, 11(S3): 52.
6. Chung YC, Chang YF. Serum interleukin-6 levels reflect the disease status of colorectal cancer. J Surg Oncol, 2003, 83(4): 222-226.
7. Tseng-Rogenski SS, Hamaya Y, Choi DY, et al. Interleukin 6 alters localization of hMSH3, leading to DNA mismatch repair defects in colorectal cancer cells. Gastroenterology, 2015, 148(3): 579-589.
8. 银东智, 沈世强. 溃疡性结肠炎相关结直肠癌的诊断与治疗. 中华消化外科杂志, 2018, 17(6): 637-639.
9. Gorman J, Greene EC. Target search dynamics during post-replicative mismatch repair. Cell Cycle, 2013, 12(4): 537-538.
10. Pino MS, Chung DC. Microsatellite instability in the management of colorectal cancer. Expert Rev Gastroenterol Hepatol, 2011, 5(3): 385-399.
11. Vindigni SM, Kaz AM. Universal screening of colorectal cancers for Lynch syndrome: Challenges and opportunities. Dig Dis Sci, 2016, 61(4): 969-976.
12. Amira AT, Mouna T, Ahlem B, et al. Immunohistochemical expression pattern of MMR protein can specifically identify patients with colorectal cancer microsatellite instability. Tumour Biol, 2014, 35(7): 6283-6291.
13. Edelbrock MA, Kaliyaperumal S, Williams KJ. Structural, molecular and cellular functions of MSH2 and MSH6 during DNA mismatch repair, damage signaling and other noncanonical activities. Mutat Res, 2013, 743-744: 53-66.
14. Jess T, Loftus EV Jr, Velayos FS, et al. Risk of intestinal cancer in inflammatory bowel disease: a population-based study from Olmsted county, Minnesota. Gastroenterology, 2006, 130(4): 1039-1046.
15. Yang H, Li Y, Wu W, et al. The incidence of inflammatory bowel disease in Northern China: a prospective population-based study. PLoS One, 2014, 9(7): e101296.
16. Eaden JA, Abrams KR, Mayberry JF. The risk of colorectal cancer in ulcerative colitis: a meta-analysis. Gut, 2001, 48(4): 526-535.
17. Vagefi PA, Longo WE. Colorectal cancer in patients with inflammatory bowel disease. Clin Colorectal Cancer, 2005, 4(5): 313-319.
18. Leedham SJ, Graham TA, Oukrif D, et al. Clonality, founder mutations, and field cancerization in human ulcerative colitis-associated neoplasia. Gastroenterology, 2009, 136(2): 542-550.
19. Ullman TA, Itzkowitz SH. Intestinal inflammation and cancer. Gastroenterology, 2011, 140(6): 1807-1816.
20. Park WS, Pham T, Wang C, et al. Loss of heterozygosity and microsatellite instability in non-neoplastic mucosa from patients with chronic ulcerative colitis. Int J Mol Med, 1998, 2(2): 221-224.
21. Roessner A, Kuester D, Malfertheiner P, et al. Oxidative stress in ulcerative colitis-associated carcinogenesis. Pathol Res Pract, 2008, 204(7): 511-524.
22. Simmonds NJ, Allen RE, Stevens TR, et al. Chemiluminescence assay of mucosal reactive oxygen metabolites in inflammatory bowel disease. Gastroenterology, 1992, 103(1): 186-196.
23. Fournier BM, Parkos CA. The role of neutrophils during intestinal inflammation. Mucosal Immunol, 2012, 5(4): 354-366.
24. Barzilai A, Yamamoto K. DNA damage responses to oxidative stress. DNA Repair (Amst), 2004, 3(8-9): 1109-1115.
25. De Simone V, Franzè E, Ronchetti G, et al. Th17-type cytokines, IL-6 and TNF-α synergistically activate STAT3 and NF-kB to promote colorectal cancer cell growth. Oncogene, 2015, 34(27): 3493-3503.
26. Klampfer L. Cytokines, inflammation and colon cancer. Curr Cancer Drug Targets, 2011, 11(4): 451-464.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Expressions and significances of interleukin-6 and microsatellite instability in ulcerative colitis-associated colorectal cancer

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