人皮肤鳞状细胞癌内IGFBP7的表达及其意义
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摘要
目的:研究IGFBP7在人皮肤鳞状细胞癌(简称鳞癌)组织及细胞中的表达情况探讨IGFBP7与上皮细胞间质转型(epithelial-mesenchymal transition, EMT)的上皮标记蛋白细胞角蛋白(cytokeratin,CK)在鳞癌中的表达及两者之间的相关性。
方法:采用免疫组织化学亲和素-生物素-过氧化物酶(Avidin-Biotin-Peroxidase Complex,SABC)法检测50例皮肤鳞状细胞癌皮损和14例正常对照皮肤组织中IGFBP7表达;同时用实时荧光定量PCR(Real time-PCR)和免疫印迹(western-blot)方法检测人永生化角质形成细胞系HaCaT和皮肤鳞癌细胞系A431中IGFBP7各自的表达情况。
结果: IGFBP7在正常皮肤组织中的阳性率为100%,而皮肤鳞状细胞癌组织中表达的阳性率为58.0%,两者表达有显著性差异(P<0.01);IGFBP7在高分化和低分化SCC中均低表达,但在低分化的SCC中的表达更少(P<0.01);IGFBP7和CK在皮肤鳞状细胞癌中的表达具有相关性(r=0.812,P<0.01);永生化角质形成细胞系HaCaT中IGFBP7的mRNA和蛋白表达水平均高于人皮肤鳞癌细胞系A431。
结论: IGFBP7在人皮肤鳞癌组织及细胞中低表达,IGFBP7与肿瘤的病理学分级有关,且和CK表达呈正相关;IGFBP7的表达缺失可能在皮肤鳞状细胞癌的发生发展中起到重要作用,为皮肤鳞癌的诊断及治疗研究提供实验基础。
Objectives : To study the expression of IGFBP7,a recently described member of insulin-like growth factor binding protein(IGFBP) family, in the cutaneous squamous cell carcinoma(SCC) and human SCC cell line and analyse the correlation between the expression of IGFBP7 and cytokeratin, which is considered to be a distinctive indicator of epithelial-mesenchymal transition (EMT).
Methods : immunohistological staining method was applied to analyze the location of IGFBP7 expressions in 50 human squmaous cell carcinoma and 14 normal skin tissues.In addition, The expression of IGFBP7 messenger ribonucleic acid (mRNA) and protein was evaluated in the HaCaT cell line and A431 cell line by Real-time PCR and western-blot seperately.
Results :The express rate of IGFBP7 is 58.0% in SCC specimens and 100% in the normol skin, There was significant differences between squamous cell carcinoma and normal skin tissues(P<0.01).The percentage of IGFBP7-positive cells in well - differentiated SCC specimens was also substantially higer than that in poorly -differentiated SCC specimens (P < 0.01). Furthermore, the expression of IGFBP7 was positively associated with the expression of cytokeratin (r=0.812,P<0.01). The lower mRNA and protein expression of IGFBP7 was seen in A431,shown by Real-time PCR and Western blotting(P<0.01).
Conclusions: IGFBP7 is expressed constitutively and more intensely in normal tissues and cell line than that in SCC.The loss of IGFBP7 may play an important role in the pathogenesis and the development of skin squamous cell carcinoma .
方法:采用免疫组织化学亲和素-生物素-过氧化物酶(Avidin-Biotin-Peroxidase Complex,SABC)法检测50例皮肤鳞状细胞癌皮损和14例正常对照皮肤组织中IGFBP7表达;同时用实时荧光定量PCR(Real time-PCR)和免疫印迹(western-blot)方法检测人永生化角质形成细胞系HaCaT和皮肤鳞癌细胞系A431中IGFBP7各自的表达情况。
结果: IGFBP7在正常皮肤组织中的阳性率为100%,而皮肤鳞状细胞癌组织中表达的阳性率为58.0%,两者表达有显著性差异(P<0.01);IGFBP7在高分化和低分化SCC中均低表达,但在低分化的SCC中的表达更少(P<0.01);IGFBP7和CK在皮肤鳞状细胞癌中的表达具有相关性(r=0.812,P<0.01);永生化角质形成细胞系HaCaT中IGFBP7的mRNA和蛋白表达水平均高于人皮肤鳞癌细胞系A431。
结论: IGFBP7在人皮肤鳞癌组织及细胞中低表达,IGFBP7与肿瘤的病理学分级有关,且和CK表达呈正相关;IGFBP7的表达缺失可能在皮肤鳞状细胞癌的发生发展中起到重要作用,为皮肤鳞癌的诊断及治疗研究提供实验基础。
Objectives : To study the expression of IGFBP7,a recently described member of insulin-like growth factor binding protein(IGFBP) family, in the cutaneous squamous cell carcinoma(SCC) and human SCC cell line and analyse the correlation between the expression of IGFBP7 and cytokeratin, which is considered to be a distinctive indicator of epithelial-mesenchymal transition (EMT).
Methods : immunohistological staining method was applied to analyze the location of IGFBP7 expressions in 50 human squmaous cell carcinoma and 14 normal skin tissues.In addition, The expression of IGFBP7 messenger ribonucleic acid (mRNA) and protein was evaluated in the HaCaT cell line and A431 cell line by Real-time PCR and western-blot seperately.
Results :The express rate of IGFBP7 is 58.0% in SCC specimens and 100% in the normol skin, There was significant differences between squamous cell carcinoma and normal skin tissues(P<0.01).The percentage of IGFBP7-positive cells in well - differentiated SCC specimens was also substantially higer than that in poorly -differentiated SCC specimens (P < 0.01). Furthermore, the expression of IGFBP7 was positively associated with the expression of cytokeratin (r=0.812,P<0.01). The lower mRNA and protein expression of IGFBP7 was seen in A431,shown by Real-time PCR and Western blotting(P<0.01).
Conclusions: IGFBP7 is expressed constitutively and more intensely in normal tissues and cell line than that in SCC.The loss of IGFBP7 may play an important role in the pathogenesis and the development of skin squamous cell carcinoma .
引文
[1]赵辨.中国临床皮肤病学.第一版.南京:江苏科学技术出版社2010 ; 1527-1529.
[2] Leethanakul C,Patel V,Gillespie J,et a1.Gene expression profiles in squamous cell carcinomas of the oral cavity:use of laser capture Microdissection for the construction and analysis of stage-specific cDNA libraries.Oral Oncology,2000,36:474.
[3]华积德.肿瘤外科学[M].北京:人民军医出版社,1995,970-975.
[4] Marks R.Epide miology of non-melanoma skin cancer and solarkeratoses in Australia:a tale of self-immolation in Elysian fields.Australas J Dermatol, 1997, 38 (1):26.
[5] Alam M,Ratner D.Cutaneous squamous-cell carcinoma.N Engl Med,2001 ,334(13):975.
[6] Bustin SA, Jenkins PJ. The growth hormone-insulin-like growth factor-I axis andcolorectal cancer. Trends Mol Med, 2001,7(10):447-454.
[7] Chen RY, Chen HX, Jian P, et al. Intratumoral injection of pcDNA3.1-IGFBP7 inhibits malignant melanoma growth in C57BL/6J mice by inducing apoptosis and down-regulating VEGF expression. Oncol Rep, 23(4):981-988.
[8] Tamura K, Hashimoto K, Suzuki K, et al. Insulin-like growth factor binding protein-7 (IGFBP7) blocks vascular endothelial cell growth factor (VEGF)-induced angiogenesis in human vascular endothelial cells. Eur J Pharmacol, 2009,610(1-3):61-67.
[9] Kanemitsu N, Kato MV, Miki T, et al. Characterization of the promoter of the murine mac25 gene. Biochem Biophys Res Commun, 2000,279(1):251-257.
[10] Wajapeyee N, Serra RW, Zhu X, et al. Oncogenic BRAF induces senescence and apoptosis through pathways mediated by the secreted protein IGFBP7. Cell, 2008,132(3):363-374.
[11] Sprenger CC, Damon SE, Hwa V, et al. Insulin-like growth factor binding protein-related protein 1 (IGFBP-rP1) is a potential tumor suppressor protein for prostate cancer. Cancer Res, 1999,59(10):2370-2375.
[12] Haugk KL, Wilson HM, Swisshelm K, et al. Insulin-like growth factor (IGF)-binding protein-related protein-1: an autocrine/paracrine factor that inhibits skeletal myoblast differentiation but permits proliferation in response to IGF. Endocrinology, 2000,141(1):100-110.
[13] Wilson HM, Birnbaum RS, Poot M, et al. Insulin-like growth factor binding protein-related protein 1 inhibits proliferation of MCF-7 breast cancer cells via a senescence-like mechanism. Cell Growth Differ, 2002,13(5):205-213.
[14] Ruan W, Wang Y, Ma Y et al. HSP60, a protein downregulated by IGFBP7 in colorectal carcinoma. J Exp Clin Cancer Res 2010; 29: 41.
[15] Smirnov DA, Foulk BW, Doyle GV, Connelly MC, Terstappen LW, O'Hara SM. Global gene expression profiling of circulating endothelial cells in patients with metastatic carcinomas. Cancer Res 2006; 66: 2918.
[16] Sprenger CC, Damon SE, Hwa V, et al. Insulin-like growth factor binding protein-related protein 1 (IGFBP-rP1) is a potential tumor suppressor protein for prostate cancer. Cancer Res, 1999,59(10):2370-2375.
[17] Chen RY, Chen HX, Lin JX et al. In-vivo transfection of pcDNA3.1-IGFBP7 inhibits melanoma growth in mice through apoptosis induction and VEGF downexpression. J Exp Clin Cancer Res 2010; 29: 13.
[18] Masterson J,O’DeaS.Posttranslational truncation of E—cadherin and significance for tumour progression [J] .Ceils Tissues Organs,2007,185(1-3):175—179.
[19] ShibataT , Hirohashi S. E-cadherin cell adhesion system in human cancer[J].Seikagaku,2006.78(7):647-656.
[20] Vizioli MG, Sensi M, Miranda C et al. IGFBP7: an oncosuppressor gene in thyroid carcinogenesis. Oncogene 2010; 29: 3835-44. Lin J, Lai M, Huang Q, Ruan W, Ma Y, Cui J. Reactivation of IGFBP7 by DNA demethylation inhibits human colon cancer cell growth in vitro. Cancer Biol Ther 2008; 7: 1896.
[21] Christiansen JJ, Rajasekaran AK. Reassessing epithelial to to mesenchymal transition as a prerequisite for carcinoma invasion and metastasis. Cancer Res 2006; 66: 8319.
[22] Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition. J Clin Invest 2009; 119: 1420.
[23] Klymkowsky MW, Savagner P. Epithelial-mesenchymal transition: a cancer researcher’s conceptual friend and foe. Am J Pathol 2009; 174: 1588.
[24] Yang J, Weinberg RA. Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Dev Cell 2008; 14: 818.
[25] Tarin D, Thompson EW, Newgreen DF. The fallacy of epithelial mesenchymal transition in neoplasia. Cancer Res 2005; 65: 5996.
[26] Murphy JF, Fitzgerald DJ. Vascular endothelial growth factor induces cyclooxygenase-dependent proliferation of endothelial cells via the VEGF-2 receptor. Faseb J, 2001,15(9):1667-1669.
[27] Ruan WJ, Lin J, Xu EP, et al. IGFBP7 plays a potential tumor suppressor role against colorectal carcinogenesis with its expression associated with DNA hypomethylation of exon 1. J Zhejiang Univ Sci B, 2006,7(11):929-932.
[1] Kanemitsu N, Kato MV, Miki T, et al. Characterization of the promoter of the murine mac25 gene. Biochem Biophys Res Commun, 2000,279(1):251-257.
[2] Hwa V, Oh Y, Rosenfeld RG. The insulin-like growth factor-binding protein (IGFBP) superfamily. Endocr Rev, 1999,20(6):761-787.
[3] Sato Y, Chen Z, Miyazaki K. Strong suppression of tumor growth by insulin-like growth factor-binding protein-related protein 1/tumor-derived cell adhesion factor/mac25. Cancer Sci, 2007,98(7):1055-1063.
[4] Komatsu S, Okazaki Y, Tateno M, et al. Methylation and downregulated expression of mac25/insulin-like growth factor binding protein-7 is associated with liver tumorigenesis in SV40T/t antigen transgenic mice, screened by restriction landmark genomic scanning for methylation (RLGS-M). Biochem Biophys Res Commun, 2000,267(1):109-117.
[5] Oh Y. IGFBPs and neoplastic models. New concepts for roles of IGFBPs in regulation of cancer cell growth. Endocrine, 1997,7(1):111-113.
[6] Usui T, Murai T, Tanaka T, et al. Characterization of mac25/angiomodulin expression by high endothelial venule cells in lymphoid tissues and its identification as an inducible marker for activated endothelial cells. Int Immunol, 2002,14(11):1273-1282.
[7] Murphy JF, Fitzgerald DJ. Vascular endothelial growth factor induces cyclooxygenase-dependent proliferation of endothelial cells via the VEGF-2 receptor. Faseb J, 2001,15(9):1667-1669.
[8] Ruan WJ, Lin J, Xu EP, et al. IGFBP7 plays a potential tumor suppressor role against colorectal carcinogenesis with its expression associated with DNA hypomethylation of exon 1. J
[9] Ruan W, Wang Y, Ma Y et al. HSP60, a protein downregulated by IGFBP7 in colorectal carcinoma. J Exp Clin Cancer Res 2010; 29: 41.
[10] Smirnov DA, Foulk BW, Doyle GV, Connelly MC, Terstappen LW, O'Hara SM. Global gene expression profiling of circulating endothelial cells in patients with metastatic carcinomas. Cancer Res 2006; 66: 2918. Zhejiang Univ Sci B, 2006,7(11):929-932.
[11] Chen RY, Chen HX, Jian P, et al. Intratumoral injection of pcDNA3.1-IGFBP7 inhibits malignant melanoma growth in C57BL/6J mice by inducing apoptosis and down-regulating VEGF expression. Oncol Rep, 23(4):981-988.
[12] Chen RY, Chen HX, Lin JX et al. In-vivo transfection of pcDNA3.1-IGFBP7 inhibits melanoma growth in mice through apoptosis induction and VEGF downexpression. J Exp Clin Cancer Res 2010; 29: 13.
[13] Vizioli MG, Sensi M, Miranda C et al. IGFBP7: an oncosuppressor gene in thyroid carcinogenesis. Oncogene 2010; 29: 3835-44. Lin J, Lai M, Huang Q, Ruan W, Ma Y, Cui J. Reactivation of IGFBP7 by DNA demethylation inhibits human colon cancer cell growth in vitro. Cancer Biol Ther 2008; 7: 1896.
[14] Christiansen JJ, Rajasekaran AK. Reassessing epithelial to to mesenchymal transition as a prerequisite for carcinoma invasion and metastasis. Cancer Res 2006; 66: 8319.
[15] ShibataT , Hirohashi S. E-cadherin cell adhesion system in human cancer[J].Seikagaku,2006.78(7):647-656.
[16] Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition. J Clin Invest 2009; 119: 1420.
[17] Klymkowsky MW, Savagner P. Epithelial-mesenchymal transition: a cancer researcher’s conceptual friend and foe. Am J Pathol 2009; 174: 1588.
[18] Yang J, Weinberg RA. Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Dev Cell 2008; 14: 818.
[19] Tarin D, Thompson EW, Newgreen DF. The fallacy of epithelial mesenchymal transition in neoplasia. Cancer Res 2005; 65: 5996.
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[26] Ruan W, Wang Y, Ma Y et al. HSP60, a protein downregulated by IGFBP7 in colorectal carcinoma. J Exp Clin Cancer Res 2010; 29: 41.
[27] Smirnov DA, Foulk BW, Doyle GV, Connelly MC, Terstappen LW, O'Hara SM. Global gene expression profiling of circulating endothelial cells in patients with metastatic carcinomas. Cancer Res 2006; 66: 2918.
[2] Leethanakul C,Patel V,Gillespie J,et a1.Gene expression profiles in squamous cell carcinomas of the oral cavity:use of laser capture Microdissection for the construction and analysis of stage-specific cDNA libraries.Oral Oncology,2000,36:474.
[3]华积德.肿瘤外科学[M].北京:人民军医出版社,1995,970-975.
[4] Marks R.Epide miology of non-melanoma skin cancer and solarkeratoses in Australia:a tale of self-immolation in Elysian fields.Australas J Dermatol, 1997, 38 (1):26.
[5] Alam M,Ratner D.Cutaneous squamous-cell carcinoma.N Engl Med,2001 ,334(13):975.
[6] Bustin SA, Jenkins PJ. The growth hormone-insulin-like growth factor-I axis andcolorectal cancer. Trends Mol Med, 2001,7(10):447-454.
[7] Chen RY, Chen HX, Jian P, et al. Intratumoral injection of pcDNA3.1-IGFBP7 inhibits malignant melanoma growth in C57BL/6J mice by inducing apoptosis and down-regulating VEGF expression. Oncol Rep, 23(4):981-988.
[8] Tamura K, Hashimoto K, Suzuki K, et al. Insulin-like growth factor binding protein-7 (IGFBP7) blocks vascular endothelial cell growth factor (VEGF)-induced angiogenesis in human vascular endothelial cells. Eur J Pharmacol, 2009,610(1-3):61-67.
[9] Kanemitsu N, Kato MV, Miki T, et al. Characterization of the promoter of the murine mac25 gene. Biochem Biophys Res Commun, 2000,279(1):251-257.
[10] Wajapeyee N, Serra RW, Zhu X, et al. Oncogenic BRAF induces senescence and apoptosis through pathways mediated by the secreted protein IGFBP7. Cell, 2008,132(3):363-374.
[11] Sprenger CC, Damon SE, Hwa V, et al. Insulin-like growth factor binding protein-related protein 1 (IGFBP-rP1) is a potential tumor suppressor protein for prostate cancer. Cancer Res, 1999,59(10):2370-2375.
[12] Haugk KL, Wilson HM, Swisshelm K, et al. Insulin-like growth factor (IGF)-binding protein-related protein-1: an autocrine/paracrine factor that inhibits skeletal myoblast differentiation but permits proliferation in response to IGF. Endocrinology, 2000,141(1):100-110.
[13] Wilson HM, Birnbaum RS, Poot M, et al. Insulin-like growth factor binding protein-related protein 1 inhibits proliferation of MCF-7 breast cancer cells via a senescence-like mechanism. Cell Growth Differ, 2002,13(5):205-213.
[14] Ruan W, Wang Y, Ma Y et al. HSP60, a protein downregulated by IGFBP7 in colorectal carcinoma. J Exp Clin Cancer Res 2010; 29: 41.
[15] Smirnov DA, Foulk BW, Doyle GV, Connelly MC, Terstappen LW, O'Hara SM. Global gene expression profiling of circulating endothelial cells in patients with metastatic carcinomas. Cancer Res 2006; 66: 2918.
[16] Sprenger CC, Damon SE, Hwa V, et al. Insulin-like growth factor binding protein-related protein 1 (IGFBP-rP1) is a potential tumor suppressor protein for prostate cancer. Cancer Res, 1999,59(10):2370-2375.
[17] Chen RY, Chen HX, Lin JX et al. In-vivo transfection of pcDNA3.1-IGFBP7 inhibits melanoma growth in mice through apoptosis induction and VEGF downexpression. J Exp Clin Cancer Res 2010; 29: 13.
[18] Masterson J,O’DeaS.Posttranslational truncation of E—cadherin and significance for tumour progression [J] .Ceils Tissues Organs,2007,185(1-3):175—179.
[19] ShibataT , Hirohashi S. E-cadherin cell adhesion system in human cancer[J].Seikagaku,2006.78(7):647-656.
[20] Vizioli MG, Sensi M, Miranda C et al. IGFBP7: an oncosuppressor gene in thyroid carcinogenesis. Oncogene 2010; 29: 3835-44. Lin J, Lai M, Huang Q, Ruan W, Ma Y, Cui J. Reactivation of IGFBP7 by DNA demethylation inhibits human colon cancer cell growth in vitro. Cancer Biol Ther 2008; 7: 1896.
[21] Christiansen JJ, Rajasekaran AK. Reassessing epithelial to to mesenchymal transition as a prerequisite for carcinoma invasion and metastasis. Cancer Res 2006; 66: 8319.
[22] Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition. J Clin Invest 2009; 119: 1420.
[23] Klymkowsky MW, Savagner P. Epithelial-mesenchymal transition: a cancer researcher’s conceptual friend and foe. Am J Pathol 2009; 174: 1588.
[24] Yang J, Weinberg RA. Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Dev Cell 2008; 14: 818.
[25] Tarin D, Thompson EW, Newgreen DF. The fallacy of epithelial mesenchymal transition in neoplasia. Cancer Res 2005; 65: 5996.
[26] Murphy JF, Fitzgerald DJ. Vascular endothelial growth factor induces cyclooxygenase-dependent proliferation of endothelial cells via the VEGF-2 receptor. Faseb J, 2001,15(9):1667-1669.
[27] Ruan WJ, Lin J, Xu EP, et al. IGFBP7 plays a potential tumor suppressor role against colorectal carcinogenesis with its expression associated with DNA hypomethylation of exon 1. J Zhejiang Univ Sci B, 2006,7(11):929-932.
[1] Kanemitsu N, Kato MV, Miki T, et al. Characterization of the promoter of the murine mac25 gene. Biochem Biophys Res Commun, 2000,279(1):251-257.
[2] Hwa V, Oh Y, Rosenfeld RG. The insulin-like growth factor-binding protein (IGFBP) superfamily. Endocr Rev, 1999,20(6):761-787.
[3] Sato Y, Chen Z, Miyazaki K. Strong suppression of tumor growth by insulin-like growth factor-binding protein-related protein 1/tumor-derived cell adhesion factor/mac25. Cancer Sci, 2007,98(7):1055-1063.
[4] Komatsu S, Okazaki Y, Tateno M, et al. Methylation and downregulated expression of mac25/insulin-like growth factor binding protein-7 is associated with liver tumorigenesis in SV40T/t antigen transgenic mice, screened by restriction landmark genomic scanning for methylation (RLGS-M). Biochem Biophys Res Commun, 2000,267(1):109-117.
[5] Oh Y. IGFBPs and neoplastic models. New concepts for roles of IGFBPs in regulation of cancer cell growth. Endocrine, 1997,7(1):111-113.
[6] Usui T, Murai T, Tanaka T, et al. Characterization of mac25/angiomodulin expression by high endothelial venule cells in lymphoid tissues and its identification as an inducible marker for activated endothelial cells. Int Immunol, 2002,14(11):1273-1282.
[7] Murphy JF, Fitzgerald DJ. Vascular endothelial growth factor induces cyclooxygenase-dependent proliferation of endothelial cells via the VEGF-2 receptor. Faseb J, 2001,15(9):1667-1669.
[8] Ruan WJ, Lin J, Xu EP, et al. IGFBP7 plays a potential tumor suppressor role against colorectal carcinogenesis with its expression associated with DNA hypomethylation of exon 1. J
[9] Ruan W, Wang Y, Ma Y et al. HSP60, a protein downregulated by IGFBP7 in colorectal carcinoma. J Exp Clin Cancer Res 2010; 29: 41.
[10] Smirnov DA, Foulk BW, Doyle GV, Connelly MC, Terstappen LW, O'Hara SM. Global gene expression profiling of circulating endothelial cells in patients with metastatic carcinomas. Cancer Res 2006; 66: 2918. Zhejiang Univ Sci B, 2006,7(11):929-932.
[11] Chen RY, Chen HX, Jian P, et al. Intratumoral injection of pcDNA3.1-IGFBP7 inhibits malignant melanoma growth in C57BL/6J mice by inducing apoptosis and down-regulating VEGF expression. Oncol Rep, 23(4):981-988.
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