Expression change of cytokine and its correlation with expression of CD16a mRNA in tumor microenvironment of colorectal cancer_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

WANG Lei ^1,2 , CHEN Xi ^1,3 ,  YAN Dengguo ¹ , LIANG Zhengzi ¹ , CAO Feilong ^1,4 , ZHEN Yunhuan ¹ , LI Guosheng ¹ , CHENG Haiyu ¹

1. Department of Colorectal Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang 550004, P. R. China;
2. Department of General Surgery, Dazhou Central Hospital, Dazhou, Sichuan 635000, P. R. China;
3. Department of General Surgery, Liangping District People’s Hospital, Chongqing 405200, P. R. China;
4. Department of Surgery, Longnan People’s Hospital, Longnan, Jiangxi 341700, P. R. China;

Corresponding author：

YAN Dengguo, Email: dengguoy@163.com

Keywords：

colorectal cancer; CD16a; cytokine; tumor microenvironment

DOI：

10.7507/1007-9424.201907092

Video：

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Objective To explore the changes of cytokines in the tumor microenvironment of colorectal cancer and the relationship between the expression of CD16a mRNA and cytokines in the microenvironment.Methods RT-PCR and flow cytometry microsphere array (CBA) were used to detect the expressions of CD16a mRNA, as well as cytokines of Th1 ［interleukin (IL)-2, IL-12, and interferone-γ (IFN-γ)］, Th2 (IL-4, IL-6, and IL-10), tumor necrosis factor-α (TNF-α), and vascular endothelial growth factor (VEGF) in the tumor and the adjacent tissues of 42 patients with colorectal cancer, respectively, and the correlation between the expression of CD16a mRNA and cytokines in the microenvironment was analyzed.Results The expressions of IL-6, TNF-α, and VEGF in colorectal cancer tissues were significantly higher than those in the adjacent tissues (P<0.05). There was no significant difference in the expression of IL-2,IL-4, IL-10, IL-12, and IFN-γ between the two kinds of tissues (P>0.05). Clinicopathological factor analysis showed that, the levels of IL-6 and VEGF in the colorectal cancer patients with preoperative normal CEA were significantly higher than those with elevated CEA (P<0.05). Correlation analysis showed that the expression of IL-6 was negatively correlated with expression of CD16a mRNA (P<0.05).Conclusions The expressions of IL-6, TNF-α, and VEGF in tumor tissues were significantly higher than adjacent tissues, and the effect of angiogenic and immunosuppression were enhanced. The expression of CD16a mRNA in the microenvironment of colorectal cancer tumor is negatively correlated with the expression of IL-6.

Citation： WANG Lei, CHEN Xi, YAN Dengguo, LIANG Zhengzi, CAO Feilong, ZHEN Yunhuan, LI Guosheng, CHENG Haiyu. Expression change of cytokine and its correlation with expression of CD16a mRNA in tumor microenvironment of colorectal cancer. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2020, 27(3): 291-297. doi: 10.7507/1007-9424.201907092 Copy

1.	Tuccitto A, Shahaj E, Vergani E, et al. Immunosuppressive circuits in tumor microenvironment and their influence on cancer treatment efficacy. Virchows Arch, 2019, 474(4): 407-420.
2.	Cecchetti S, Spadaro F, Lugini L, et al. Functional role of phosphatidylcholine-specific phospholipase C in regulating CD16 membrane expression in natural killer cells. Eur J Immunol, 2007, 37(10): 2912-2922.
3.	Huang Y, Yin HJ, Ma XJ, et al. Correlation between FcγRⅢa and aortic atherosclerotic plaque destabilization in ApoE knockout mice and intervention effects of effective components of chuanxiong rhizome and red peony root. Chin J Integr Med, 2011, 17(5): 355-360.
4.	Chauhan AK, Chen C, Moore TL, et al. Induced expression of FcγRⅢa (CD16a) on CD4⁺, T cells triggers generation of IFN-γ^high, subset. J Biol Chem, 2015, 290(8): 5127-5140.
5.	颜登国, 王国栋, 程海玉. 基因芯片技术分析结直肠癌肝转移患者免疫基因表达的变化. 中国普外基础与临床杂志, 2012, 19(11): 1182-1186.
6.	Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods, 2001, 25(4): 402-408.
7.	Agarwal A, Agrawal U, Verma S, et al. Serum Th1 and Th2 cytokine balance in patients of superficial transitional cell carcinoma of bladder pre- and post-intravesical combination immunotherapy. Immunopharmacol Immunotoxicol, 2010, 32(2): 348-356.
8.	王静, 徐向上, 曹志新, 等. Th细胞因子在结直肠癌组织中的表达. 中华实验外科杂志, 2010, 27(1): 62-64.
9.	Balkwill F. Tumour necrosis factor and cancer. Nat Rev Cancer, 2009, 9(5): 361-371.
10.	Chung SS, Wu Y, Okobi Q, et al. Proinflammatory cytokines IL-6 and TNF-α increased telomerase activity through NF-κB/STAT1/STAT3 activation, and withaferin a inhibited the signaling in colorectal cancer cells. Mediators Inflamm, 2017, 2017: 5958429.
11.	Wang H, Wang HS, Zhou BH, et al. Epithelial-mesenchymal transition (EMT) induced by TNF-α requires AKT/GSK-3β-mediated stabilization of snail in colorectal cancer. PLoS One, 2013, 8(2): e56664.
12.	Al Obeed OA, Alkhayal KA, Al Sheikh A, et al. Increased expression of tumor necrosis factor-α is associated with advanced colorectal cancer stages. World J Gastroenterol, 2014, 20(48): 18390-18396.
13.	向本旭, 刘婷婷, 孙芳玲, 等. VEGF相关信号通路在血管新生中的研究进展. 中国比较医学杂志, 2015, 25(12): 81-86.
14.	Talmadge JE, Gabrilovich DI. History of myeloid-derived suppressor cells. Nat Rev Cancer, 2013, 13(10): 739-752.
15.	Nagasaki T, Hara M, Nakanishi H, et al. Interleukin-6 released by colon cancer-associated fibroblasts is critical for tumour angiogenesis: anti-interleukin-6 receptor antibody suppressed angiogenesis and inhibited tumour-stroma interaction. Br J Cancer, 2014, 110(2): 469-478.
16.	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.
17.	Bunt SK, Yang L, Sinha P, et al. Reduced inflammation in the tumor microenvironment delays the accumulation of myeloid-derived suppressor cells and limits tumor progression. Cancer Res, 2007, 67(20): 10019-10026.
18.	Tsukamoto H, Nishikata R, Senju S, et al. Myeloid-derived suppressor cells attenuate TH1 development through IL-6 production to promote tumor progression. Cancer Immunol Res, 2013, 1(1): 64-76.
19.	曾艳, 张力, 贺帅. 结直肠癌患者血清CEA和CA19-9水平与肝转移的关系. 癌症进展, 2019, 17(13): 1586-1589.
20.	朱攀, 雷蜜, 高波. 肿瘤标志物及血管新生因子与结直肠癌患者临床分期及肿瘤转移相关. 基础医学与临床, 2019, 39(1): 59-62.
21.	汤俊, 黄春锦, 陈玺. 老年结直肠癌患者血清内CEA、AFP、CA50、CA199和CA724的表达及意义. 实用癌症杂志, 2019, 34(3): 397-399, 406.
22.	闫先侠, 王传新, 牛爱军, 等. 结直肠癌及淋巴结组织CEA mRNA表达的实时荧光定量检测. 中华肿瘤防治杂志, 2008, 15(16): 1255-1258.
23.	陈岩松, 陈燕, 陈娜娟. 结直肠癌患者血清白细胞介素6水平及与肿瘤疗效关系. 标记免疫分析与临床, 2017, 24(11): 1274-1279.
24.	冯仕庭, 孙灿辉, 彭振鹏, 等. 结直肠癌MVD和VEGF与临床及病理诸因素的相关性研究. 中山大学学报: 医学科学版, 2009, 30(4S): 234-238.
25.	史艳侠, 张晓实, 夏建川, 等. B-NHL患者NK细胞中CD16ζ表达及利妥昔单抗与LAK细胞的联合抗瘤作用. 癌症, 2007, 26(8): 837-842.
26.	Kobayashi E, Motoi S, Sugiura M, et al. Antibody-dependent cellular cytotoxicity and cytokine/chemokine secretion by KHYG-1 cells stably expressing FcγRⅢA. Immunol Lett, 2014, 161(1): 59-64.
27.	Capuano C, Pighi C, Molfetta R, et al. Obinutuzumab-mediated high-affinity ligation of FcγRⅢA/CD16 primes NK cells for IFNγ production. Oncoimmunology, 2017, 6(3): e1290037.
28.	Li XY, Wu L, Li SW, et al. Effect of CD16a, the surface receptor of Kupffer cells, on the growth of hepatocellular carcinoma cells. Int J Mol Med, 2016, 37(6): 1465-1474.

1. Tuccitto A, Shahaj E, Vergani E, et al. Immunosuppressive circuits in tumor microenvironment and their influence on cancer treatment efficacy. Virchows Arch, 2019, 474(4): 407-420.
2. Cecchetti S, Spadaro F, Lugini L, et al. Functional role of phosphatidylcholine-specific phospholipase C in regulating CD16 membrane expression in natural killer cells. Eur J Immunol, 2007, 37(10): 2912-2922.
3. Huang Y, Yin HJ, Ma XJ, et al. Correlation between FcγRⅢa and aortic atherosclerotic plaque destabilization in ApoE knockout mice and intervention effects of effective components of chuanxiong rhizome and red peony root. Chin J Integr Med, 2011, 17(5): 355-360.
4. Chauhan AK, Chen C, Moore TL, et al. Induced expression of FcγRⅢa (CD16a) on CD4⁺, T cells triggers generation of IFN-γ^high, subset. J Biol Chem, 2015, 290(8): 5127-5140.
5. 颜登国, 王国栋, 程海玉. 基因芯片技术分析结直肠癌肝转移患者免疫基因表达的变化. 中国普外基础与临床杂志, 2012, 19(11): 1182-1186.
6. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods, 2001, 25(4): 402-408.
7. Agarwal A, Agrawal U, Verma S, et al. Serum Th1 and Th2 cytokine balance in patients of superficial transitional cell carcinoma of bladder pre- and post-intravesical combination immunotherapy. Immunopharmacol Immunotoxicol, 2010, 32(2): 348-356.
8. 王静, 徐向上, 曹志新, 等. Th细胞因子在结直肠癌组织中的表达. 中华实验外科杂志, 2010, 27(1): 62-64.
9. Balkwill F. Tumour necrosis factor and cancer. Nat Rev Cancer, 2009, 9(5): 361-371.
10. Chung SS, Wu Y, Okobi Q, et al. Proinflammatory cytokines IL-6 and TNF-α increased telomerase activity through NF-κB/STAT1/STAT3 activation, and withaferin a inhibited the signaling in colorectal cancer cells. Mediators Inflamm, 2017, 2017: 5958429.
11. Wang H, Wang HS, Zhou BH, et al. Epithelial-mesenchymal transition (EMT) induced by TNF-α requires AKT/GSK-3β-mediated stabilization of snail in colorectal cancer. PLoS One, 2013, 8(2): e56664.
12. Al Obeed OA, Alkhayal KA, Al Sheikh A, et al. Increased expression of tumor necrosis factor-α is associated with advanced colorectal cancer stages. World J Gastroenterol, 2014, 20(48): 18390-18396.
13. 向本旭, 刘婷婷, 孙芳玲, 等. VEGF相关信号通路在血管新生中的研究进展. 中国比较医学杂志, 2015, 25(12): 81-86.
14. Talmadge JE, Gabrilovich DI. History of myeloid-derived suppressor cells. Nat Rev Cancer, 2013, 13(10): 739-752.
15. Nagasaki T, Hara M, Nakanishi H, et al. Interleukin-6 released by colon cancer-associated fibroblasts is critical for tumour angiogenesis: anti-interleukin-6 receptor antibody suppressed angiogenesis and inhibited tumour-stroma interaction. Br J Cancer, 2014, 110(2): 469-478.
16. 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.
17. Bunt SK, Yang L, Sinha P, et al. Reduced inflammation in the tumor microenvironment delays the accumulation of myeloid-derived suppressor cells and limits tumor progression. Cancer Res, 2007, 67(20): 10019-10026.
18. Tsukamoto H, Nishikata R, Senju S, et al. Myeloid-derived suppressor cells attenuate TH1 development through IL-6 production to promote tumor progression. Cancer Immunol Res, 2013, 1(1): 64-76.
19. 曾艳, 张力, 贺帅. 结直肠癌患者血清CEA和CA19-9水平与肝转移的关系. 癌症进展, 2019, 17(13): 1586-1589.
20. 朱攀, 雷蜜, 高波. 肿瘤标志物及血管新生因子与结直肠癌患者临床分期及肿瘤转移相关. 基础医学与临床, 2019, 39(1): 59-62.
21. 汤俊, 黄春锦, 陈玺. 老年结直肠癌患者血清内CEA、AFP、CA50、CA199和CA724的表达及意义. 实用癌症杂志, 2019, 34(3): 397-399, 406.
22. 闫先侠, 王传新, 牛爱军, 等. 结直肠癌及淋巴结组织CEA mRNA表达的实时荧光定量检测. 中华肿瘤防治杂志, 2008, 15(16): 1255-1258.
23. 陈岩松, 陈燕, 陈娜娟. 结直肠癌患者血清白细胞介素6水平及与肿瘤疗效关系. 标记免疫分析与临床, 2017, 24(11): 1274-1279.
24. 冯仕庭, 孙灿辉, 彭振鹏, 等. 结直肠癌MVD和VEGF与临床及病理诸因素的相关性研究. 中山大学学报: 医学科学版, 2009, 30(4S): 234-238.
25. 史艳侠, 张晓实, 夏建川, 等. B-NHL患者NK细胞中CD16ζ表达及利妥昔单抗与LAK细胞的联合抗瘤作用. 癌症, 2007, 26(8): 837-842.
26. Kobayashi E, Motoi S, Sugiura M, et al. Antibody-dependent cellular cytotoxicity and cytokine/chemokine secretion by KHYG-1 cells stably expressing FcγRⅢA. Immunol Lett, 2014, 161(1): 59-64.
27. Capuano C, Pighi C, Molfetta R, et al. Obinutuzumab-mediated high-affinity ligation of FcγRⅢA/CD16 primes NK cells for IFNγ production. Oncoimmunology, 2017, 6(3): e1290037.
28. Li XY, Wu L, Li SW, et al. Effect of CD16a, the surface receptor of Kupffer cells, on the growth of hepatocellular carcinoma cells. Int J Mol Med, 2016, 37(6): 1465-1474.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Expression change of cytokine and its correlation with expression of CD16a mRNA in tumor microenvironment of colorectal cancer

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