SOCS3对结肠癌增殖和侵袭的调控机制
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摘要
目的探讨细胞因子信号抑制子3(SOCS3)对结肠癌增殖与侵袭能力的调控机制。方法收集我院2014年7月～2017年5月进行肿瘤治疗并经确诊的80例结肠癌患者的癌组织(n=80)和癌旁组织标本(n=80)。通过Western blot分析SOCS3在组织中表达情况。复苏结肠癌细胞系SW480,利用lipo3000转染建SOCS3的过表达质粒;利用小干扰RNA(siRNA)技术转染结肠癌细胞株敲低SOCS3表达。应用CCK-8检测SOCS3基因对结肠癌细胞增殖的影响;采用Transwell试验测定SOCS3基因对于SW480侵袭能力的作用。通过去甲基化及IL-6处理SW480观察对于SOCS3表达的影响,并检测处理之后对SW480增殖、侵袭的作用。结果结肠癌组织中SOCS3表达量均低于癌旁组织;过表达SOCS3后抑制SW480细胞增殖和侵袭,而敲减SOCS3后促进其增殖和侵袭;去甲基化处理SW480上调了SOCS3的表达,SW480增殖和侵袭能力受到抑制;IL-6处理SW480后降低了SOCS3的表达,SW480细胞增殖和侵袭能力得以增强。结论 SOCS3参与结肠癌的发生发展,是结肠癌治疗的潜在靶点。在结肠癌患者中,SOCS3低表达可能与甲基化有关。
Objective To investigate the expression of cytokine signal suppressor 3(SOCS3) in colon cancer tissue and the mechanism by which SOCS3 regulates the proliferation and invasion of colon cancer. Methods We collected the specimens of tumor tissues and paired adjacent tissues from 80 patients with colon cancer undergoing radical resection in our hospital between July, 2014 and May, 2017, and the expression of SOCS3 in the tissue samples was analyzed using Western blotting. We also transfected colon cancer cell line SW480 with a SOCS3-overexpressing plasmid or a small interference RNA(siRNA) for SOCS3 knockdown, and the changes in the cell proliferation and invasion capacity were evaluated using CCK-8 assay and Transwell assay, respectively. The effect of demethylation and IL-6 treatment on SOCS3 expression and the proliferation and invasion of SW480 cells were observed. Results Colon cancer tissues showed a lowered expression of SOCS3 compared with the adjacent tissues. Over-expression of SOCS3 significantly inhibited while SOCS3 knockdown obviously promoted the proliferation and invasion of SW480 cells in vitro. Demethylation treatment up-regulated SOCS3 expression and inhibited the proliferation and invasion capacity of SW480 cells; IL-6 treatment of the cells caused the reverse changes. Conclusion SOCS3 participates in the development and progression of colon cancer and serves as a potential target for colon cancer treatment. In patients with colon cancer, the low expression of SOCS3 possibly as a result of methylation may promote the proliferation and invasion of the cancer cells.
Objective To investigate the expression of cytokine signal suppressor 3(SOCS3) in colon cancer tissue and the mechanism by which SOCS3 regulates the proliferation and invasion of colon cancer. Methods We collected the specimens of tumor tissues and paired adjacent tissues from 80 patients with colon cancer undergoing radical resection in our hospital between July, 2014 and May, 2017, and the expression of SOCS3 in the tissue samples was analyzed using Western blotting. We also transfected colon cancer cell line SW480 with a SOCS3-overexpressing plasmid or a small interference RNA(siRNA) for SOCS3 knockdown, and the changes in the cell proliferation and invasion capacity were evaluated using CCK-8 assay and Transwell assay, respectively. The effect of demethylation and IL-6 treatment on SOCS3 expression and the proliferation and invasion of SW480 cells were observed. Results Colon cancer tissues showed a lowered expression of SOCS3 compared with the adjacent tissues. Over-expression of SOCS3 significantly inhibited while SOCS3 knockdown obviously promoted the proliferation and invasion of SW480 cells in vitro. Demethylation treatment up-regulated SOCS3 expression and inhibited the proliferation and invasion capacity of SW480 cells; IL-6 treatment of the cells caused the reverse changes. Conclusion SOCS3 participates in the development and progression of colon cancer and serves as a potential target for colon cancer treatment. In patients with colon cancer, the low expression of SOCS3 possibly as a result of methylation may promote the proliferation and invasion of the cancer cells.
引文
[1]尹慧,王伟,张强,等.MicroRNA-381的表达下降促进结肠癌的增殖与侵袭[J].西南国防医药,2016,26(7):697-700.
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[5]农晰婷,杨光,张昱.siRNA靶向抑制MACC_1对结直肠癌细胞增殖和侵袭能力的影响[J].陕西医学杂志,2016,45(1):9-11.
[6]陈文彬,钟文洲.GPX1在结直肠癌组织中的表达及其对癌细胞增殖、侵袭及迁移的影响[J].中国肿瘤生物治疗杂志,2017,24(9):995-1001.
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[10]权继传,解亦斌,田艳涛.国际抗癌联盟胃癌TNM分期系统第七版解读[J].中华诊断学电子杂志,2014,2(1):72-4.
[11]梁鸿,张辉,田鹏,等.艾迪联合FOLFOX4方案治疗Ⅲ期结肠癌患者术后效果观察[J].中华实用诊断与治疗杂志,2016,30(2):196-8.
[12]Drebert Z,De Vlieghere E,Bridelance J,et al.Glucocorticoids indirectly decrease colon cancer cell proliferation and invasion via effects on cancer-associated fibroblasts[J].Exp Cell Res,2018,362(2):332-42.
[13]李永福,熊亮发,杨昆宪.SOCS3过表达对乳腺癌细胞侵袭能力的影响及作用机制[J].山东医药,2017,57(24):48-50.
[14]Tang X,Zha L,Li H,et al.Upregulation of GNL3 expression promotes colon cancer cell proliferation,migration,invasion and epithelial-mesenchymal transition via the Wnt/beta-catenin signaling pathway[J].Oncol Rep,2017,38(4):2023-32.
[15]王玉琼,丁佳寅,诸娴,等.炎性因子对人胰腺癌PaTu8988细胞NF-κB及Hedgehog通路成员表达的影响[J].中华胰腺病杂志,2015,15(1):18-21.
[16]张沛,董念国,刘金平.SOCS3基因转染对小鼠CD4~+Th细胞分化及炎症细胞因子表达的影响及机制研究[J].重庆医学,2016,45(36):5049-51,5055.
[17]陈志华,林素勇,韩宏景,等.慢病毒转染KISS1基因对人结直肠癌HCT116细胞增殖、侵袭和迁移能力的影响[J].吉林大学学报:医学版,2017,43(3):577-81,670.
[18]Vakil L,Najafipour R,Rakhshani N,et al.Investigation of FIH-1 and SOCS3 expression in KRAS mutant and wild-type patients with colorectal cancer[J].Tumor Biol,2016,37(7):8841-8.
[19]张天明,蔡成,杜金林,等.沉默缺氧诱导因子-1α对结肠癌SW480细胞生长增殖、侵袭迁移能力的影响[J].中华实验外科杂志,2017,34(6):1063.
[20]Zhang B,Fang L,Wu HM,et al.Mer receptor tyrosine kinase negatively regulates lipoteichoic acid-induced inflammatory response via PI3K/Akt and SOCS3[J].Mol Immunol,2016,76:98-107.
[21]Caldow MK,Ham DJ,Chee A,et al.Muscle-specific deletion of SOCS3 does not reduce the anabolic response to leucine in a mouse model of acute inflammation[J].Cytokine,2017,96:274-8.
[22]Lv YE,Song G,Li P.Correlation of SOCS-1 gene with onset and prognosis of breast cancer[J].Oncol Lett,2018,16(1):383-7.
[23]Urbschat A,Stumpf S,Haenze J,et al.Expression of the antiinflammatory suppressor of cytokine signaling 3(SOCS3)in human clear cell renal cell carcinoma[J].Tumor Biol,2016,37(7):9649-56.
[24]Shang AQ,Wu J,Bi F,et al.Relationship between HER2 and JAK/STAT-SOCS3 signaling pathway and clinicopathological features and prognosis of ovarian cancer[J].Cancer Biol Ther,2017,18(5):314-22.
[25]杨意,朱向东,翟艳会,等.痛泻要方对肝郁脾虚型溃疡性结肠炎大鼠结肠组织中gp130,SOCS3表达的影响[J].山东医药,2017,57(34):20-3.
[26]Ishibashi K,Oguro T,Kumagai S,et al.299IL-6 and SOCS3regulates cell proliferation in renal cell carcinoma cells[J].J Urol,2013,189(4):e121-2.
[27]Hackett AR,Lee DH,Dawood A,et al.STAT3 and SOCS3 regulate NG2 cell proliferation and differentiation after contusive spinal cord injury[J].Neurobiol Dis,2016,89:10-22.
[28]Li XD,Li XM,Gu JW,et al.MiR-155 regulates lymphoma cell proliferation and apoptosis through targeting SOCS3/JAK-STAT3signaling pathway[J].Eur Rev Med Pharmacol Sci,2017,21(22):5153-9.
[29]Lindberg K,Ronn SG,Tornehave D,et al.Regulation of pancreatic beta-cell mass and proliferation by SOCS-3[J].J Mol Endocrinol,2005,35(2):231-43.
[30]刘春来,李永文,董云龙,等.H2228细胞和EML4-ALK阳性肺癌组织中SOCS3基因启动子区甲基化状态的研究[J].中国肺癌杂志,2016,19(9):565-70.
[31]Chu QJ,Shen D,He L,et al.Prognostic significance of SOCS3 and its biological function in colorectal cancer[J].Gene,2017,627:114-22.
[32]Li T,Wu SY,Li S,et al.SOCS3 participates in cholinergic pathway regulation of synovitis in rheumatoid arthritis[J].Connect Tissue Res,2018,59(3):287-94.
[33]Jiang YD,Pagadala J,Miller D,et al.Reduced insulin receptor signaling in retinal Muller cells cultured in high glucose[J].Mol Vis,2013,19:804-11.
[34]Handle F,Erb HH,Luef B,et al.SOCS3 modulates the response to enzalutamide and is regulated by androgen receptor signaling and CpG methylation in prostate cancer cells[J].Mol Cancer Res,2016,14(6):574-85.
[2]Rui Q,Xu ZP,Yang P,et al.Long noncoding RNA expression patterns in lymph node metastasis in colorectal cancer by microarray[J].Biomed Pharmacother,2015,75:12-8.
[3]Ji Q,Zhang L,Liu X,et al.Long non-coding RNA MALAT1promotes tumour growth and metastasis in colorectal cancer through binding to SFPQ and releasing oncogene PTBP2 from SFPQ/PTBP2complex[J].Br J Cancer,2014,111(4):736-48.
[4]何靖炀,刘秋英,魏玲,等.BORIS通过表观修饰对人肝癌细胞SOCS3表达的调控[J].四川大学学报:医学版,2018,49(1):1-7.
[5]农晰婷,杨光,张昱.siRNA靶向抑制MACC_1对结直肠癌细胞增殖和侵袭能力的影响[J].陕西医学杂志,2016,45(1):9-11.
[6]陈文彬,钟文洲.GPX1在结直肠癌组织中的表达及其对癌细胞增殖、侵袭及迁移的影响[J].中国肿瘤生物治疗杂志,2017,24(9):995-1001.
[7]Rigby RJ,Simmons JG,Greenhalgh CJ,et al.Suppressor of cytokine signaling 3(SOCS3)limits damage-induced crypt hyper-proliferation and inflammation-associated tumorigenesis in the colon[J].Oncogene,2007,26(33):4833-41.
[8]Rigby,J R,Greenhalgh,et al.Suppressor of cytokine signaling 3(SOCS3)limits damage-induced crypt hyperproliferation and tumor formation in the colon[J].Inflamm Bowel Dis,2006,12(38):387-98.
[9]Singh S,Chouhan S,Mohammad N,et al.Resistin causes G1 arrest in colon cancer cells through upregulation of SOCS3[J].FEBS Lett,2017,591(10):1371-82.
[10]权继传,解亦斌,田艳涛.国际抗癌联盟胃癌TNM分期系统第七版解读[J].中华诊断学电子杂志,2014,2(1):72-4.
[11]梁鸿,张辉,田鹏,等.艾迪联合FOLFOX4方案治疗Ⅲ期结肠癌患者术后效果观察[J].中华实用诊断与治疗杂志,2016,30(2):196-8.
[12]Drebert Z,De Vlieghere E,Bridelance J,et al.Glucocorticoids indirectly decrease colon cancer cell proliferation and invasion via effects on cancer-associated fibroblasts[J].Exp Cell Res,2018,362(2):332-42.
[13]李永福,熊亮发,杨昆宪.SOCS3过表达对乳腺癌细胞侵袭能力的影响及作用机制[J].山东医药,2017,57(24):48-50.
[14]Tang X,Zha L,Li H,et al.Upregulation of GNL3 expression promotes colon cancer cell proliferation,migration,invasion and epithelial-mesenchymal transition via the Wnt/beta-catenin signaling pathway[J].Oncol Rep,2017,38(4):2023-32.
[15]王玉琼,丁佳寅,诸娴,等.炎性因子对人胰腺癌PaTu8988细胞NF-κB及Hedgehog通路成员表达的影响[J].中华胰腺病杂志,2015,15(1):18-21.
[16]张沛,董念国,刘金平.SOCS3基因转染对小鼠CD4~+Th细胞分化及炎症细胞因子表达的影响及机制研究[J].重庆医学,2016,45(36):5049-51,5055.
[17]陈志华,林素勇,韩宏景,等.慢病毒转染KISS1基因对人结直肠癌HCT116细胞增殖、侵袭和迁移能力的影响[J].吉林大学学报:医学版,2017,43(3):577-81,670.
[18]Vakil L,Najafipour R,Rakhshani N,et al.Investigation of FIH-1 and SOCS3 expression in KRAS mutant and wild-type patients with colorectal cancer[J].Tumor Biol,2016,37(7):8841-8.
[19]张天明,蔡成,杜金林,等.沉默缺氧诱导因子-1α对结肠癌SW480细胞生长增殖、侵袭迁移能力的影响[J].中华实验外科杂志,2017,34(6):1063.
[20]Zhang B,Fang L,Wu HM,et al.Mer receptor tyrosine kinase negatively regulates lipoteichoic acid-induced inflammatory response via PI3K/Akt and SOCS3[J].Mol Immunol,2016,76:98-107.
[21]Caldow MK,Ham DJ,Chee A,et al.Muscle-specific deletion of SOCS3 does not reduce the anabolic response to leucine in a mouse model of acute inflammation[J].Cytokine,2017,96:274-8.
[22]Lv YE,Song G,Li P.Correlation of SOCS-1 gene with onset and prognosis of breast cancer[J].Oncol Lett,2018,16(1):383-7.
[23]Urbschat A,Stumpf S,Haenze J,et al.Expression of the antiinflammatory suppressor of cytokine signaling 3(SOCS3)in human clear cell renal cell carcinoma[J].Tumor Biol,2016,37(7):9649-56.
[24]Shang AQ,Wu J,Bi F,et al.Relationship between HER2 and JAK/STAT-SOCS3 signaling pathway and clinicopathological features and prognosis of ovarian cancer[J].Cancer Biol Ther,2017,18(5):314-22.
[25]杨意,朱向东,翟艳会,等.痛泻要方对肝郁脾虚型溃疡性结肠炎大鼠结肠组织中gp130,SOCS3表达的影响[J].山东医药,2017,57(34):20-3.
[26]Ishibashi K,Oguro T,Kumagai S,et al.299IL-6 and SOCS3regulates cell proliferation in renal cell carcinoma cells[J].J Urol,2013,189(4):e121-2.
[27]Hackett AR,Lee DH,Dawood A,et al.STAT3 and SOCS3 regulate NG2 cell proliferation and differentiation after contusive spinal cord injury[J].Neurobiol Dis,2016,89:10-22.
[28]Li XD,Li XM,Gu JW,et al.MiR-155 regulates lymphoma cell proliferation and apoptosis through targeting SOCS3/JAK-STAT3signaling pathway[J].Eur Rev Med Pharmacol Sci,2017,21(22):5153-9.
[29]Lindberg K,Ronn SG,Tornehave D,et al.Regulation of pancreatic beta-cell mass and proliferation by SOCS-3[J].J Mol Endocrinol,2005,35(2):231-43.
[30]刘春来,李永文,董云龙,等.H2228细胞和EML4-ALK阳性肺癌组织中SOCS3基因启动子区甲基化状态的研究[J].中国肺癌杂志,2016,19(9):565-70.
[31]Chu QJ,Shen D,He L,et al.Prognostic significance of SOCS3 and its biological function in colorectal cancer[J].Gene,2017,627:114-22.
[32]Li T,Wu SY,Li S,et al.SOCS3 participates in cholinergic pathway regulation of synovitis in rheumatoid arthritis[J].Connect Tissue Res,2018,59(3):287-94.
[33]Jiang YD,Pagadala J,Miller D,et al.Reduced insulin receptor signaling in retinal Muller cells cultured in high glucose[J].Mol Vis,2013,19:804-11.
[34]Handle F,Erb HH,Luef B,et al.SOCS3 modulates the response to enzalutamide and is regulated by androgen receptor signaling and CpG methylation in prostate cancer cells[J].Mol Cancer Res,2016,14(6):574-85.