摘要
目的:
研究表明IL-11、IL-11R与多种恶性肿瘤的生长、分化、进展密切相关。本实验采用Western blot法检测IL-11、IL-11R在原发性肝癌中的表达,探讨二者的表达与肝癌及相关临床和病理指标间的关系。
方法:
收集30例原发性肝癌手术患者的新鲜肿瘤组织、邻近的非癌肝组织标本及其临床、病理资料。采用Western blot法检测IL-11、IL-11R在肝癌组织、邻近的非癌肝组织中的表达。分别测定IL-11、IL-11R及β-actin带的积分光密度(IOD)值,以目的蛋白与相应β-actin的IOD值比值(A值)来表示目的蛋白的表达水平。
结果:
(1)IL-11在肝癌组织中表达水平(A值)(0.71±0.19),显著高于癌旁肝组织(0.34±0.27 P<0.01),二者差异有显著性,而IL-11的表达与患者性别、诊断年龄、肿瘤大小、有无肝硬化、有无淋巴结转移均无相关性(P>0.05),根据Edmondson病理分级分组,Ⅳ级肿瘤表达A值(0.83±0.13),明显高于Ⅰ+Ⅱ+Ⅲ级肿瘤表达A值(0.60±0.18 P<0.05),在包膜受侵犯组肝癌中表达A值(0.89±0.10)明显高与包膜未受侵犯组(0.64±0.18 P<0.05);在有门静脉癌栓组肝癌组中表达A值(0.83±0.13)亦明显高于无门静脉癌栓组(0.62±0.19 P<0.05)。
(2)IL-11R的肝癌组织中表达水平(A值)(0.56±0.19),显著高于癌旁肝组织(0.41±0.25 P<0.01),二者差异有显著性,IL-11R的表达与患者性别、诊断年龄、肿瘤大小、有无肝硬化、肿瘤的分化程度均无相关性(P>0.05),肿瘤伴有淋巴结转移组A值为(0.70±0.09),明显高于不伴淋巴结转移组(0.50±0.19 P<0.05)。在包膜受侵犯组肝癌中表达A值(0.72±0.09)明显高与包膜未受侵犯组(0.48±0.17 P<0.05);在有门静脉癌栓组中表达A值(0.67±0.15)亦明显高于无门静脉癌栓组(0.49±0.16 P<0.05)。
结论:
(1)IL-11和IL-11R在肝癌组织及癌旁肝组织均有表达。肝癌组织中表达明显高于癌旁肝组织。提示IL-11/IL-11R可能与参与肝癌的发生。
(2)IL-11的表达在分化程度低、包膜受侵犯、门静脉有癌栓组肝癌组织标本表达水平高;IL-11R的表达在有淋巴结转移、包膜受侵犯、门静脉有癌栓组肝组织标本表达水平高。表明IL-11/IL-11R可能参与肝癌的分化、侵袭及转移过程。
Objectives:
Previous investigations have shown that interleukin-11(IL-11)and interleukin-11 receptor(IL-11R)have been correlated with the regulation of tumor progression,cellular growth and differentiation in several malignant tumors.The objectives of this study were to clarify the role of IL-11 and IL-11R in human hepatocelluar carcinoma.
Methods:
30 PHC tissues,their pericarcinomatous liver tissues and their clinicopathological factors were obtained in the current study.Expression levers of IL-11 and IL-11R proteins in samples of pericarcinomatous liver and tumor tissue were analyzed by Western blot.The IOD of IL-11、IL-11R andβ-actin was quantitatively analysised by Analysis software.The expression level of IL-11 and IL-11R was denoted by the ratio of IOD,which was called value A.
Results:
(1)The value A of IL-11 in PHC tissue is 0.71±0.19,which sharply higher than that in pericarcinomatous liver tissue(0.34±0.27 P<0.01),The expression of IL-11 has nothing to do with gender,age,size of tumor,corrhosis and lymph node metastasis.There is significance difference between the expression of IL-11 in gradeⅣ(0.83±0.13)and gradeⅠ+Ⅱ+Ⅲ(0.60±0.18)according to Edmondson's grad(P<0.05).Also the expression of IL-11 is significantly related to capsule invasion(capsule invasion 0.89±0.10 non-capsule invasion 0.64±0.18 P<0.05)and tumor's thrombus in portal vein(tumor's thrombus in portal vein 0.83±0.13 No tumor's thrombus in portal vein 0.62±0.19 P<0.05)
(2)The value A.of IL-11R in PHC tissue is 0.56±0.19,which remarkable higher than that in pericacinomatous liver tissue(0.41±0.25 P<0.01).The expression of IL-11R have no relationship with gender,age,size of tumor,cirrhosis and differentiation grade of tumor.But there is statistical difference between the expression of IL-11R in tumor with lymph node metastasis(0.70±0.09)and tumor without lymph node metastasis(0.50±0.19 P<0.05).Also the expression of IL-11R is significantly related to capsule invasion(capsule invasion 0.72±0.09 non- capsule invasion 0.48±0.17 P<0.05)and tumor's thrombus in portal vein(tumor's thrombus in portal vein 0.67±0.15 No tumor's thrombus in portal vein 0.49±0.16 P<0.05)
Conclusion:
(1)The expression of IL-11 and IL-11R is upregulated obviously in PHC tissue,which indicate that IL-11/IL-11R may be concerned with the occurrence of PHC.
(2)IL-11's expression is markly higher in Edmonson gradingⅣ, capsule invasion,tumor's thrombus in portal vein group than that in Edmonson gradingⅠ+Ⅱ+Ⅲ,non-capsule invasion,No tumor's thrombus in portal vein group.IL-11R's expression is obviously higher in lymph node metastasis,capsule invasion,tumor's thrombus in portal vein group than that in non-metastasis non-capsule invasion,No tumor's thrombus in portal vein group.These findings suggest that IL-11/IL-11R pathway may play important role in the differentiation,invasion and transfer of PHC.
引文
[1]Tominaga S,Kuroishi T,Aoki K,et al.Cancer mortality statistics in 33countries 1953-1992.International Union Against Cancer,1998,1:50-69.
[2]Mizukami Y,Li J,Zhang X,et al.Hypoxia inducible factor-1 independent regulation of vascular endothelial growth factor by hypoxia in colon cancer.Cancer Res,2004,64:1765-1772.
[3]Moon WS,Rhyu KH,Kang MJ,et al.Over expression of VEGF and angiopoietin 2:a key to high vascularity of hepatocellular carcinoma? Mod Pathol,2003,16:552-557.
[4]Hanavadi S,Martin TA,Watkins G,et al.Expression of interleukin 11 and its receptor and their prognostic value in human breast cancer.Ann Surg Oncol,2006,13:802-808.
[5]Du XX,Williams DA.Interleukin-11.Review of molecular.Cell biology and clinical use.Blood,1997,89:3897-3908.
[6]Ayumi Yoshizaki,Toshiyuki Nakayama,Kazuyuki Yamazumi,et al.Expression of interleukin(IL)-11 and IL-11 receptor in human colorectal adenocarcinoma:IL-11 up-regulates of the invasive and proliferative activity of human colorectal carcinoma cells.International journal of oncology 2007,29:869-876.
[7]Okuda K.Hepatocellular carcinoma.J Hepatol,2000,32:225-237.
[8]Stewart BW,Kleihues P.World Cancer Report.Lyon:IARC Press for IARC/WHC,2003,11:203-207.
[9]吴孟超.原发性肝癌.见:吴阶平主编,黄家驷外科学 第六版.北京:人民卫生出版社,2001:1223-1233.
[10]Castellani R,Visscher DW,Wykes S,et al.Interaction of transforming growth factor 2 alpha and epidemal growth factor receptor in breast carcinoma.Cancer,1994,73:344-349.
[11]Du XX,Williams DA.Interleukin-11:A multifunctional growth factor derived from the hemopoietic microenvironment.Blood,1994,83:2030-2037.
[12]于宝华 周晓燕.PI3K/Akt/mTOR的信号传导通路在恶性肿瘤中的研究进展.中华病理学杂志,2005,34:13-16.
[13]Du X,Williams DA.Update on development of interleukin-11.Current Opinion Hematology,1995,3:182-188.
[14]Leonard WL Lin JX.Cytokine receptor signaling pathways.J Allergy Clin Immunol,2000, 105: 877-888.
[15]Robb L,Hilton DJ,Brook PT,et al. Identification of a second murine interleukin-11 receptor a chain gene (IL-11Ra) with a restricted pattern of expression. Genomics, 1997:387-389.
[16]Romas E,Udagawa N,Zhou H,et al. The role of gp130-mediated signals in osteoclast development: regulation of interleukin 11 production by osteoblasts and distribution of its receptor in bone marrow cultures.J Exp Med,1996,183:2581-2591.
[17]Trepicchio WL, Dorner AJ.Interleukin-ll:A gpl30 cytokine.Ann N Y Acad Sci, 1998,856:12-21.
[18]Toshiyuki Nakayama,Ayumi Yoshizaki,Seiya Izumida,et al. Expression of interleukin-11(IL-11) and IL-11 receptor a in human gastric carcinoma and EL-11 upregulates the invasive activity of human gastric carcinoma cells.International journal of oncology,2007,30:825-833.
[19]Greenwood Van,Meerveld B,Venkova K,et al.Recombinant human interleukin-11 restores smooth muscle function in the jejunum and colon of human leukocyte antigen-B27 rats With intestinal inflammation. J Pharmacol Exp Ther,2001,299:58-66.
[20]Soda H, Raymond E,Sharma S,et al.Recombinant human interleukin-11 is unlikely to stimulate the growth of the most common solid tumors. Anticancer Drugs, 1999, 10: 97-101.
[21]Stahl N,Farrugella TJ,Boulton TG,et al.Choice of STATs and other substrates specified by modular tyrosine-based motifs in cytokine receptors. Science, 1995, 267: 1349-1353.
[22]Gerhartz C,Heesel B,Sasse J,et al.Differential activation of acute phase response factor/STAT3 and STAT1 via the cytoplasmic domain of the interleukin-6 signal transducer gp130.J Biol Chem, 1996,271:12991-12998.
[23]Du X,Williams DA. Interleukin 11: review of molecular, cell biology,and clinical use. Blood,1997,89:3897-3908.
[24]Sotiriou C,Lacroix M, Lespagnard L,et al. Interleukins-6 and IL-11 expression in primary breast cancer and subsequent development of bone metastases.Cancer Lett, 2001,169:87-95.
[25]Campbell CL,Guardiani R, Ollari C,et al. Interleukin-11 receptor expression in primary ovarian carcinomas. Gynecol Oncol,2001, 80: 121-127.
[26]Campbell CL, Jiang Z,Savarese DM,et al. Increased expression of the interleukin- [11]receptor and evidence of STAT3 activation in prostate carcinoma. Am J Pathol,2001, 158:25-32.
[27]Satheesha Hanavadi,Tracey A, Martin, et al. Expression of interleukin 11 and its receptor and their prognostic value in human breast cancer. Ann Surg Oncol, 2006, 13: 802-808.
[28]Tsimanis A,Shvidel L,Klepfish A,et al. Over-expression of the functional interleukin-11 alpha receptor in the development of B-cell chronic lymphocytic leukemia.Leuk Lymphoma, 2001, 42: 195-205.
[29]Bromberg JF MH, Wrzeszczynska G, Devgan,et al.STAT3 as an oncogene. Cell, 1999,98:295-303.
[30]Yang YC, Yin T. Interleukin-11 and its receptor. Biofactors, 1992,4:15-21.
[31]Fang JY, Richardson BC. The MAPK signaling pathways and colorectal cancer. Lancet Oncol,2005,6:322-327.
[1]Kawashimal I,Takigucki Y.Interleukin-11:a novel stroma-derived cytokine.Prog Growth Factor Res,1992,4:191-206.
[2]Morris JC,Neben S,Bennett F,et al.Molecular cloning and characterization of murine interleukin-11.Exp Hematol,1996,24:1369-1376.
[3]Czupryn M,Bennett F,Dube J,et al.Alanine-scanning mutagenesis of human interleukin-11:identification of regions important for biological activity.J Ann NY Acad Sci,1995,762:152-164.
[4]李元,陈松森,王渭池等.基因工程药物,北京:化工出版社,2002,1,1291-1295.
[5]Karow J,Hudson KR,Hall MA,et al.Mediation of interleukin-11 dependent biological responses by a soluble form of the interleukin-11 receptor.Biochem J,1996,318:489-495.
[6]Baumann H,Wang Y,Morella KK,et al.Complex of the soluble IL-11 receptor and IL-11 acts as IL-6-type cytokine in hepatic and nonhepatic cells.J Immunol,1996,157:284-290.
[7]Romas E,Udagawa N,Zhou H,et al.The role of gp130-mediated signals in osteoclast development:regulation of interleukin 11 production by osteoblasts and distribution of its receptor in bone marrow cultures.J Exp Med,1996,183:2581-2591.
[8]Dahmen H,Horsten U,Kuster A,et al.Activation of the signal transducer gp130by interleukin-11 and interleukin-6 is mediated by similar molecular interactions.Biochem J,1998,331:695-702.
[9]Nandurkar HH,Hilton DJ,Nathan P,et al.The human IL-11 receptor requires gp130 for signalling:Demonstration by molecular cloning of the receptor.Oncogene,1996,12:585-587.
[10]Stahl N,Farrugella TJ,Boulton TG,et al.Choice of STATs and other substrates specified by modular tyrosine-based motifs in cytokine receptors.Science,1995,267:1349-1353.
[11]Gerhartz C,Heesel B,Sasse J,et al.Differential activation of acute phase response factor/Stat3 and Stat1 via the cytoplasmic domain of the interleukin 6 signal transducer gp130.Ⅱ.Src homology SH2 domains define the specificity of stat factor activation.J Biol Chem,1996,271:12999-13007.
[12]Schwertschlag US,Trepicchio WL,Dykstra KH,et al.Hematopoietic, immunodulatory and epithelial effect of interleukin-11.Leukemia,1999,13:1307-1315.
[13]Du XX,Williams DA.Interleukin-11:a multifunctional growth factor derived from the hematopoietic microenvironment.Blood,1994,8:2023-2030.
[14]Bruno E,Briddell RA,Cooper RJ,et al.Further examination of the effects of recombinant cytokines on the proliferation of human megakarycoytes progenitor cells.Blood,1991,77:2339-2346.
[15]Ballen KK,Becker PS,Yeap BY,et al.Autologous stem-cell transplantation can be performed safely without the use of blood-product support.J Clin Oncol,2004,22:4087-4094.
[16]Du XX,Liu Q,Schindel DT,et al.Trophic effects of interleukin-11 in rats with experimental short bowel syndrome.J Pediatr Surg,1996,31:1047-1050.
[17]Ault P,Kantarjian H,Welch MA,et al.Interleukin 11 may improve thrombocytopenia associated with imatinib mesylate therapy.Leukemia Research,2004,28:613-618.
[18]阎昭,蒋惠留,张媛.白介素-11对血小板生成影响的研究进展.中国医院用药评价与分析,2001,1:1741-1745.
[19]刘健,陈强,陈亦贵等.国产重组人白介素-11生物治疗化疗引起血小板减少的临床研究.临床肿瘤学杂志,2004,9,152-153.
[20]王秀美,吕静.重组人白介素-11防治化疗所致血小板减少.国外医学肿瘤学分册,2003,30:439-442.
[21]陈涛.白介素-11与慢性阻塞性肺疾病.国外医学内科学分册,2002,29:200-202.
[22]Fujimoto K,Momose T,Okubo Y,et al.A case of chronic eosinophilic pneumonia involving IL-5 and GM-CSF.Nihon Kyobu Shikkan Gakkai Zasshi,1995,33:310-313.
[23]Rodriguez MH,Amaud S,Blanchet JP.IL-11 directly stimulates murine and human erythroid burst formation in semisolid cultures.Exp Hematol,1995,23:545-550.
[24]王自力,梁国栋.IL-11的生物学活性及其应用研究进展.国外医学免疫学分册,2000,23:179-181.
[25]Tsuchida M,Brown SA,Tutt LM,et al.A model of human anti-T-cell monoclonal antibody therapy in SCID mice engrafted with human peripheral blood lymphocytes.Clin Transplant.1997,11:522-528.
[26]Peterson RL,Bozza MM,Domer AJ.Interleukin-11 induces intestinal epithelial cell growth arrest through effects on retinoblastoma protein phosphorylation.Am J Pathol,1996,149:895-902.
[27]Greenwood Van,Meerveld B,Venkova K,et al.Recombinant human interleukin-11 restores smooth muscle function in the jejunum and colon of human leukocyte antigen-B27 rats With intestinal inflammation.J Pharmacol Exp Ther,2001,299:58-66.
[28]Weich NS,Fitzgerald M,Wang A,et al.Recombinant human interleukin-11synergizes with steel factor and interleukin-3 to promote directly the early stages of routine megakaryocyte development in vitro.Blood,2000,95:503-509.
[29]Booth C,Potten CS.Effects of IL-11 on the growth of intestinal epithelial cells in vitro.Cell Prolif,1995,28:581-594
[30]Du XX,Doerschuk CM,Orazi A,et al.A bone marrow stromal-derived growth factor,intedeukin-11,stimulates recovery of small intestinal mucosal cells after cytoablative therapy.Blood,1994,83:33-37.
[31]Cotreau MM,Stonis I,Strahs A,et al.A multiple-dose,safety,tolerability,pharmacokmetics and pharmacodvnamic study of oral recombinant human interleukin-11.Biopharm Drug Dispos,2004,25:291-296.
[32]Ito Y,Yamamoto M,Li M,et al.Temporal expression of mRNA for neuropoietic cytokines,interleukin-11(IL-11),oncostatain M(OSM),cardiotrophin-1(CT-1)and their receptors(IL-11 Ralpha and OSM R beta)in peripheral nerve injury.Neurochem Res,2000,25:1113-1118.
[33]Hermann JA,Hall MA,Maini RN,et al.Important immunoregulatory role of interleukin-11 in the inflammatory process in rheumatoid arthritis.Arthritis Rheum,1998,41:1388-1397.
[34]Dorner AJ,Goldman SJ,Keith JC Jr.Interleukin-11.BioDrugs,1997,8:418-429.
[35]Maeshima K,Takahashi T,Nakahira K,et al.A protective role of interleukin 11on hepatic injury in acute endotoxemia.Shock,2004,21:134-138.
[36]Toshiyuki Nakayama,Ayumi Yoshizaki,Seiya Izumida,et al.Expression of interleukin-11(IL-11)and IL-11 receptor a in human gastric carcinoma and IL-11upregulates the invasive activity of human gastric carcinoma cells.International journal of oncology,2007,30:825-833.
[37]Ayumi Yoshizaki,Toshiyuki Nakayama,Kazuyuki Yamazumi,et al.Expression of intedeukin-11(IL-11)and IL-11 receptor a in human colorectal adenocarcinoma:IL-11 up-regulates the invasive and proliferative activity of human colorectal carcinoma cells.International journal of oncology,2007,29:869-876.
[38]Cara L.Campbell,Zhong Jiang,et al.Increased Expression of the Interleukin-11Receptor and Evidence of STAT3 Activation in Prostate Carcinoma.The American joural of Pathlogy,2001,158:25-32.
[39]Cara L.Campbell,Rachel Guardiani,et al.Interleukin-11 Receptor Expression in Primary Ovarian Carcinomas.Gynecologic Oncology,2001,80:121-127.