CCL20及其受体CCR6与消化系肿瘤
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摘要
趋化因子是一种小的结构相关的趋化性细胞因子,不仅在炎症反应中起重要作用,而且与肿瘤的发生发展有关。趋化因子CCL20是趋化因子CC家族中的一员,趋化因子受体CCR6是目前发现的CCL20唯一受体。近年,越来越多研究表明,趋化因子CCL20及其受体CCR6与消化系肿瘤密切相关。然而,人们对CCL20及其受体CCR6在消化系肿瘤的作用机制尚未完全认识。本文就趋化因子CCL20及其受体CCR6在消化系肿瘤研究中的进展进行综述,以期更好地理解两者之间的关系,并为CCL20及其受体CCR6成为消化系肿瘤治疗靶点的可能性提供依据。
Chemokines area small structure-related chemotactic cytokines. They not only play important roles in inflammatory response but also associate with the development and progression of multiple tumors. Chemokine CCL20 is a member of the chemokine CC family,and chemokine receptor CCR6 is the unique receptor of CCL20. Recently,increasing data have shown that chemokine CCL20 and its receptor CCR6 are closely associated with digestive system tumors. However,the mechanismby which CCL20 and its receptor CCR6 contribute to the digestive system tumors remains undocumented. Herein,the roles of chemokine CCL20 and its receptor CCR6 in digestive system tumors are reviewed,and this may provide a potential basis for novel therapeuticstrategies.
Chemokines area small structure-related chemotactic cytokines. They not only play important roles in inflammatory response but also associate with the development and progression of multiple tumors. Chemokine CCL20 is a member of the chemokine CC family,and chemokine receptor CCR6 is the unique receptor of CCL20. Recently,increasing data have shown that chemokine CCL20 and its receptor CCR6 are closely associated with digestive system tumors. However,the mechanismby which CCL20 and its receptor CCR6 contribute to the digestive system tumors remains undocumented. Herein,the roles of chemokine CCL20 and its receptor CCR6 in digestive system tumors are reviewed,and this may provide a potential basis for novel therapeuticstrategies.
引文
[1]Frick VO,Rubie C,Keilholz U,et al.Chemokine/chemokine receptor pair CCL20/CCR6 in human colorectal malignancy:An overview[J].World Journal of Gastroenterology,2016,22(2):833-841.
[2]Yamazaki T,Yang XO,Chung Y,et al.CCR6 regulates the migration of inflammatory and regulatory T cells[J].Oxford University Press,2008:8391-8401.
[3]Chen W,Zheng R,Baade PD,et al,Cancer statistics in China,2015[J].Ca A Cancer Journal for Clinicians,2016,66(2):115.
[4]Sasaki K,Natsugoe S,Ishigami S,et al.Expression of CXCL12 and its receptor CXCR4 in esophageal squamous cell carcinoma[J].Oncology Reports,2009,21(1):65-71.
[5]Lu CL,Ji Y,Ge D,et al.The expression of CXCR4 and its relationship with matrix metalloproteinase-9/vascular endothelial growth factor in esophageal squamous cell cancer[J].Diseases of the E-sophagus,2011,24(4):283-290.
[6]Ogura M,Takeuchi H,Kawakubo H,et al.Clinical significance of CXCL-8/CXCR-2 network in esophageal squamous cell carcinoma[J].Surgery,2013,154(3):512-520.
[7]Sui P,Hu P,Zhang T,et al.High expression of CXCR-2 correlates with lymph node metastasis and predicts unfavorable prognosis in resected esophageal carcinoma[J].Medical Oncology,2014,31(2):1-6.
[8]Irino T,Takeuchi H,Matsuda S,et al.CC-chemokine receptor CCR7:A key molecule for lymph node metastasis in esophageal squamous cell carcinoma[J].BMC Cancer,2014,14(1):291.
[9]Engel LS,Chow WH,Vaughan TL,et al.Population attributable risks of esophageal and gastric cancers[J].Journal of the National Cancer Institute,2003,95(18):1404-1413.
[10]Liu J,Zheng X,Deng H,et al.Expression of CCR6 in esophageal squamous cell carcinoma and its effects on epithelial-to-mesenchymal transition[J].Oncotarget,2017,8(70):115244-115253.
[11]Verma R,Sharma PC.Next generation sequencing-based emerging trends in molecular biology of gastric cancer[J].Am J Cancer Res,2018,8(2):207-225.
[12]Siegel R,Ma J,Zou Z,et al.Cancer statistics,2014[J].CA Cancer J Clin,2014,64(1):9-29.
[13]Raja UM,Gopal G,Shirley S,et al.Immunohistochemical expression and localization of cytokines/chemokines/growth factors in gastric cancer[J].Cytokine,2017,89:82-90.
[14]Stec M,Szatanek R,Bajkrzyworzeka M,et al.Interactions of tumour-derived micro(nano)vesicles with human gastric cancer cells[J].Journal of Translational Medicine,2015,13(1):376.
[15]Zhang XG,Song BT,Liu FJ,et al.CCR6 overexpression predicted advanced biological behaviors and poor prognosis in patients with gastric cancer[J].Clinical&Translational Oncology,2016,18(7):700-707.
[16]Jing Yu,Deng Liang.Clinical significance of lymph node metastasis in gastric cancer[J].World Journal of Gastroenterology,2014,20(14):3967.
[17]Velho S,Fernandes MS,Leite M,et al.Causes and consequences of microsatellite instability in gastric carcinogenesis[J].World Journal of Gastroenterology,2014,20(44):16433-16442.
[18]Ohtani H,Nakayama T,Yoshie O.In situ expression of the CCL20-CCR6 axis in lymphocyte-rich gastric cancer and its potential role in the formation of lymphoid stroma[J].Pathology International,2011,61(11):645-651.
[19]Pituchnoworolska A,Drabik G,Szatanek R,et al.Immunophenotype of isolated tumour cells in the blood,bone marrow and lymph nodes of patients with gastric cancer[J].Polish Journal of Pathology,2007,58(2):93-97.
[20]Han G,Wu D,Yang Y,et al.CrkL meditates CCL20/CCR6-induced EMT in gastric cancer[J].Cytokine,2015,76(2):163-169.
[21]Chen JP,Wu MS,Kuo SH,et al.IL-22 negatively regulates helicobacter pylori-induced CCL20 expression in gastric epithelial cells[J].PLos One,2014,9(5):e97350.
[22]Chang Xiuli,Wang Liming,Zang Mengya,et al.,The relationship between CCL20-CCR6-Th17 axis and vascular invasion and metastasis of hepatocellular carcinoma[J].Chinese Journal of Cancer,2015,37(1):5-10.[畅秀丽,王黎明,臧梦雅,等.CCL20-CCR6-Th17轴与肝细胞癌血管浸润转移的关系[J].中华肿瘤杂志,2015,37(1):5-10.]
[23]Fujii H,Itoh Y,Yamaguchi K,et al.Chemokine CCL20 enhances the growth of HuH7 cells via phosphorylation of p44/42 MAPK in vitro[J].Biochem Biophys Res Commun,2004,322(3):1052-1058.
[24]Soliman HH,Nagy H,Kotb N,et al.The role of chemokine CC ligand 20 in patients with liver cirrhosis and hepatocellular carcinoma[J].International Journal of Biological Markers,2012,27(2):e125-131.
[25]Du D,Liu Y,Qian H,et al.The effects of the CCR6/CCL20 biological axis on the invasion and metastasis of hepatocellular carcinoma[J].International Journal of Molecular Sciences,2014,15(4):6441-6452.
[26]Hou KZ,Fu ZQ,Gong H.Chemokine ligand 20 enhances progression of hepatocellular carcinoma via epithelial-mesenchymal transition[J].World Journal of Gastroenterology,2015,21(2):475-483.
[27]Ye LY,Chen W,Bai XL,et al.Hypoxia-induced epithelial-to-mesenchymal transition in hepatocellular carcinoma induces an immunosuppressive tumor microenvironment to promote metastasis[J].Cancer Research,2016,76(4):818.
[28]He H,Wu J,Zang M,et al.CCR6+B lymphocytes responding to tumor cell-derived CCL20 support hepatocellular carcinoma progression via enhancing angiogenesis[J].American Journal of Cancer Research,2017,7(5):1151.
[29]Li WM,Liu HR.CCL20-CCR6 cytokine network facilitate treg activity in advanced grades and metastatic variants of hepatocellular carcinoma[J].Scandinavian Journal of Immunology,2016,83(1):33.
[30]Chen KJ,Lin SZ,Zhou L,et al.Selective recruitment of regulatory T cell through CCR6-CCL20 in hepatocellular carcinoma fosters tumor progression and predicts poor prognosis[J].PLo S One,2011,6(9):e24671.
[31]Rubie C,Frick VO,Ghadjar P,et al.CCL20/CCR6 expression profile in pancreatic cancer[J].Journal of Translational Medicine,2010,8(1):45.
[32]Liu B,Jia Y,Ma J,et al.Tumor-associated macrophage-derived CCL20 enhances the growth and metastasis of pancreatic cancer[J].Journal of Biochemistry,2016,48(12):1067-1074.
[33]Geismann C,Grohmann F,Dreher A,et al.Role of CCL20 mediated immune cell recruitment in NF-κB mediated TRAIL resistance of pancreatic cancer[J].Biochimica Biophysi Acta Mol Cell Res,2017,1864(5):782-796.
[34]Nandi B,Pai C,Huang Q,et al.CCR6,the sole receptor for the chemokine CCL20,promotes spontaneous intestinal tumorigenesis[J].PLo S One,2014,9(5):e97566.
[35]Frick VO,Rubie C,K9lsch K,et al.CCR6/CCL20 chemokine expression profile in distinct colorectal malignancies[J].Scandinavian Journal of Immunology,2013,78(3):298.
[36]Hu D,Du C,Xue W,et al.The expression of chemokine receptors CCR6,CXCR2 and CXCR4 is not organ-specific for distant metastasis in colorectal cancer:A comparative study[J].Histopathology,2013,63(2):167-173.
[37]Yang CC,Ogawa H,Dwinell MB,et al.Chemokine receptor CCR6transduces signals that activate p130Cas and alter c AMP-stimulated ion transport in human intestinal epithelial cells[J].Am JPhysiol Cell Physiol,2005,288(2):C321.
[38]Brand S,Olszak TF,Diebold J,et al.Cell differentiation dependent expressed CCR6 mediates ERK-1/2,SAPK/JNK,and Akt signaling resulting in proliferation and migration of colorectal cancer cells[J].Journal of Cellular Biochemistry,2006,97(4):709-723.
[39]Vicinus B,Rubie C,Faust SK,et al.miR-21 functionally interacts with the 3'UTR of chemokine CCL20 and down-regulates CCL20 expression in miR-21 transfected colorectal cancer cells[J].Cancer Letters,2012,316(1):105-112.
[40]Chen J,Chen Z.The effect of immune microenvironment on the progression and prognosis of colorectal cancer[J].Medical Oncology,2014,31(8):1-8.
[41]Liu J,Duan Y,Cheng X,et al.IL-17 is associated with poor prognosis and promotes angiogenesis via stimulating VEGF production of cancer cells in colorectal carcinoma[J].Biochemical&Biophysical Research Communications,2011,407(2):348-354.
[42]Chin CC,Chen CN,Kuo HC,et al.Interleukin-17 induces CCchemokine receptor 6 expression and cell migration in colorectal cancer cells[J].Journal of Cellular Physiology,2015,230(7):1430.
[43]Nandi B,Shapiro M,Samur MK,et al.Stromal CCR6 drives tumor growth in a murine transplantable colon cancer through recruitment of tumor-promoting macrophages[J].Oncoimmunology,2016,5(8):e1189052
[2]Yamazaki T,Yang XO,Chung Y,et al.CCR6 regulates the migration of inflammatory and regulatory T cells[J].Oxford University Press,2008:8391-8401.
[3]Chen W,Zheng R,Baade PD,et al,Cancer statistics in China,2015[J].Ca A Cancer Journal for Clinicians,2016,66(2):115.
[4]Sasaki K,Natsugoe S,Ishigami S,et al.Expression of CXCL12 and its receptor CXCR4 in esophageal squamous cell carcinoma[J].Oncology Reports,2009,21(1):65-71.
[5]Lu CL,Ji Y,Ge D,et al.The expression of CXCR4 and its relationship with matrix metalloproteinase-9/vascular endothelial growth factor in esophageal squamous cell cancer[J].Diseases of the E-sophagus,2011,24(4):283-290.
[6]Ogura M,Takeuchi H,Kawakubo H,et al.Clinical significance of CXCL-8/CXCR-2 network in esophageal squamous cell carcinoma[J].Surgery,2013,154(3):512-520.
[7]Sui P,Hu P,Zhang T,et al.High expression of CXCR-2 correlates with lymph node metastasis and predicts unfavorable prognosis in resected esophageal carcinoma[J].Medical Oncology,2014,31(2):1-6.
[8]Irino T,Takeuchi H,Matsuda S,et al.CC-chemokine receptor CCR7:A key molecule for lymph node metastasis in esophageal squamous cell carcinoma[J].BMC Cancer,2014,14(1):291.
[9]Engel LS,Chow WH,Vaughan TL,et al.Population attributable risks of esophageal and gastric cancers[J].Journal of the National Cancer Institute,2003,95(18):1404-1413.
[10]Liu J,Zheng X,Deng H,et al.Expression of CCR6 in esophageal squamous cell carcinoma and its effects on epithelial-to-mesenchymal transition[J].Oncotarget,2017,8(70):115244-115253.
[11]Verma R,Sharma PC.Next generation sequencing-based emerging trends in molecular biology of gastric cancer[J].Am J Cancer Res,2018,8(2):207-225.
[12]Siegel R,Ma J,Zou Z,et al.Cancer statistics,2014[J].CA Cancer J Clin,2014,64(1):9-29.
[13]Raja UM,Gopal G,Shirley S,et al.Immunohistochemical expression and localization of cytokines/chemokines/growth factors in gastric cancer[J].Cytokine,2017,89:82-90.
[14]Stec M,Szatanek R,Bajkrzyworzeka M,et al.Interactions of tumour-derived micro(nano)vesicles with human gastric cancer cells[J].Journal of Translational Medicine,2015,13(1):376.
[15]Zhang XG,Song BT,Liu FJ,et al.CCR6 overexpression predicted advanced biological behaviors and poor prognosis in patients with gastric cancer[J].Clinical&Translational Oncology,2016,18(7):700-707.
[16]Jing Yu,Deng Liang.Clinical significance of lymph node metastasis in gastric cancer[J].World Journal of Gastroenterology,2014,20(14):3967.
[17]Velho S,Fernandes MS,Leite M,et al.Causes and consequences of microsatellite instability in gastric carcinogenesis[J].World Journal of Gastroenterology,2014,20(44):16433-16442.
[18]Ohtani H,Nakayama T,Yoshie O.In situ expression of the CCL20-CCR6 axis in lymphocyte-rich gastric cancer and its potential role in the formation of lymphoid stroma[J].Pathology International,2011,61(11):645-651.
[19]Pituchnoworolska A,Drabik G,Szatanek R,et al.Immunophenotype of isolated tumour cells in the blood,bone marrow and lymph nodes of patients with gastric cancer[J].Polish Journal of Pathology,2007,58(2):93-97.
[20]Han G,Wu D,Yang Y,et al.CrkL meditates CCL20/CCR6-induced EMT in gastric cancer[J].Cytokine,2015,76(2):163-169.
[21]Chen JP,Wu MS,Kuo SH,et al.IL-22 negatively regulates helicobacter pylori-induced CCL20 expression in gastric epithelial cells[J].PLos One,2014,9(5):e97350.
[22]Chang Xiuli,Wang Liming,Zang Mengya,et al.,The relationship between CCL20-CCR6-Th17 axis and vascular invasion and metastasis of hepatocellular carcinoma[J].Chinese Journal of Cancer,2015,37(1):5-10.[畅秀丽,王黎明,臧梦雅,等.CCL20-CCR6-Th17轴与肝细胞癌血管浸润转移的关系[J].中华肿瘤杂志,2015,37(1):5-10.]
[23]Fujii H,Itoh Y,Yamaguchi K,et al.Chemokine CCL20 enhances the growth of HuH7 cells via phosphorylation of p44/42 MAPK in vitro[J].Biochem Biophys Res Commun,2004,322(3):1052-1058.
[24]Soliman HH,Nagy H,Kotb N,et al.The role of chemokine CC ligand 20 in patients with liver cirrhosis and hepatocellular carcinoma[J].International Journal of Biological Markers,2012,27(2):e125-131.
[25]Du D,Liu Y,Qian H,et al.The effects of the CCR6/CCL20 biological axis on the invasion and metastasis of hepatocellular carcinoma[J].International Journal of Molecular Sciences,2014,15(4):6441-6452.
[26]Hou KZ,Fu ZQ,Gong H.Chemokine ligand 20 enhances progression of hepatocellular carcinoma via epithelial-mesenchymal transition[J].World Journal of Gastroenterology,2015,21(2):475-483.
[27]Ye LY,Chen W,Bai XL,et al.Hypoxia-induced epithelial-to-mesenchymal transition in hepatocellular carcinoma induces an immunosuppressive tumor microenvironment to promote metastasis[J].Cancer Research,2016,76(4):818.
[28]He H,Wu J,Zang M,et al.CCR6+B lymphocytes responding to tumor cell-derived CCL20 support hepatocellular carcinoma progression via enhancing angiogenesis[J].American Journal of Cancer Research,2017,7(5):1151.
[29]Li WM,Liu HR.CCL20-CCR6 cytokine network facilitate treg activity in advanced grades and metastatic variants of hepatocellular carcinoma[J].Scandinavian Journal of Immunology,2016,83(1):33.
[30]Chen KJ,Lin SZ,Zhou L,et al.Selective recruitment of regulatory T cell through CCR6-CCL20 in hepatocellular carcinoma fosters tumor progression and predicts poor prognosis[J].PLo S One,2011,6(9):e24671.
[31]Rubie C,Frick VO,Ghadjar P,et al.CCL20/CCR6 expression profile in pancreatic cancer[J].Journal of Translational Medicine,2010,8(1):45.
[32]Liu B,Jia Y,Ma J,et al.Tumor-associated macrophage-derived CCL20 enhances the growth and metastasis of pancreatic cancer[J].Journal of Biochemistry,2016,48(12):1067-1074.
[33]Geismann C,Grohmann F,Dreher A,et al.Role of CCL20 mediated immune cell recruitment in NF-κB mediated TRAIL resistance of pancreatic cancer[J].Biochimica Biophysi Acta Mol Cell Res,2017,1864(5):782-796.
[34]Nandi B,Pai C,Huang Q,et al.CCR6,the sole receptor for the chemokine CCL20,promotes spontaneous intestinal tumorigenesis[J].PLo S One,2014,9(5):e97566.
[35]Frick VO,Rubie C,K9lsch K,et al.CCR6/CCL20 chemokine expression profile in distinct colorectal malignancies[J].Scandinavian Journal of Immunology,2013,78(3):298.
[36]Hu D,Du C,Xue W,et al.The expression of chemokine receptors CCR6,CXCR2 and CXCR4 is not organ-specific for distant metastasis in colorectal cancer:A comparative study[J].Histopathology,2013,63(2):167-173.
[37]Yang CC,Ogawa H,Dwinell MB,et al.Chemokine receptor CCR6transduces signals that activate p130Cas and alter c AMP-stimulated ion transport in human intestinal epithelial cells[J].Am JPhysiol Cell Physiol,2005,288(2):C321.
[38]Brand S,Olszak TF,Diebold J,et al.Cell differentiation dependent expressed CCR6 mediates ERK-1/2,SAPK/JNK,and Akt signaling resulting in proliferation and migration of colorectal cancer cells[J].Journal of Cellular Biochemistry,2006,97(4):709-723.
[39]Vicinus B,Rubie C,Faust SK,et al.miR-21 functionally interacts with the 3'UTR of chemokine CCL20 and down-regulates CCL20 expression in miR-21 transfected colorectal cancer cells[J].Cancer Letters,2012,316(1):105-112.
[40]Chen J,Chen Z.The effect of immune microenvironment on the progression and prognosis of colorectal cancer[J].Medical Oncology,2014,31(8):1-8.
[41]Liu J,Duan Y,Cheng X,et al.IL-17 is associated with poor prognosis and promotes angiogenesis via stimulating VEGF production of cancer cells in colorectal carcinoma[J].Biochemical&Biophysical Research Communications,2011,407(2):348-354.
[42]Chin CC,Chen CN,Kuo HC,et al.Interleukin-17 induces CCchemokine receptor 6 expression and cell migration in colorectal cancer cells[J].Journal of Cellular Physiology,2015,230(7):1430.
[43]Nandi B,Shapiro M,Samur MK,et al.Stromal CCR6 drives tumor growth in a murine transplantable colon cancer through recruitment of tumor-promoting macrophages[J].Oncoimmunology,2016,5(8):e1189052