p57～（kip2）在人体肝癌中杂和性缺失及mRNA和蛋白表达关系研究
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摘要
目的：研究p57~(kip2)基因在人体肝细胞癌(hepatocellular carcinoma，HCC)不同阶段的杂合性缺失(loss of heterozygosity，LOH)及其mRNA和蛋白表达情况，以及三者之间的关系，以探讨HCC发生的分子生物学机制。方法：运用PCR—聚丙烯酰胺凝胶电泳—银染法对30例肝癌组织p57~(kip2)基因位点上2个微卫星位点(TH01和D11S2359)进行LOH的检测，同时运用原位分子杂交和免疫组化技术分别检测30例正常肝组织、30例癌周肝硬化和30例肝癌组织中p57~(kip2)mRNA及P57~(kip2)蛋白的表达情况。结果：1．LOH：30例肝癌组织中有9例至少在1个微卫星位点(30.0％)表现出LOH，其中分化好肝癌组织和分化差肝癌组织的LOH率之间差异有统计学意义，相关分析呈正相关。2．p57~(kip2) mRNA表达：正常肝组织组未见表达，癌周肝硬化组与肝癌组阳性表达率分别为33.33％和16.67％。肝癌组分化好和分化差阳性表达率之间差异有统计学意义，相关分析呈正相关。3．P57~(kip2)蛋白表达：正常肝组织组未见表达；癌周肝硬化组与肝癌组阳性表达率分别为56.67％和63.33％。肝癌组分化好者与分化差者阳性表达率之间差异有统计学意义，相关分析呈正相关。4．肝癌p57~(kip2) LOH与其mRNA表达之间的关系：TH01的LOH与其mRNA表达的缺失有正相关关系；D11S2359的LOH则与其mRNA表达的缺失无相关性；两个位点LOH与mRNA表达之间无相关性。5．肝癌p57~(kip2) LOH与蛋白表达之间的关系：单个位点LOH与蛋白表达的缺失都有正相关关系；两个位点同时LOH与蛋白表达的缺失无相关性。6．肝癌p57~(kip2)mRNA与蛋白表达之间的关系：两者之间无相关性。结论：1．p57~(kip2)
Objective: To study the loss of heterozygosity (LOH) of p57~(kip2) and expressions of p57~(kip2) mRNA & protein in various stages of human hepatocellular carcinoma (HCC) in order to explore the molecular mechanism of hepatocarcinoma.
Methods: LOH of two microsatellite loci (TH01 and D11S2359) were detected in the p57~(kip2) gene site by using PCR-polyacrylamide gel electrophoresis-silver staining method. Immunohistochemistry staining and in situ hybirdization (ISH) were also used to show the expression of p57~(kip2) mRNA and protein in normal liver tissue, pericancerous cirrhosis and HCC.
Results: 1. LOH: LOH was identifided at least in 9 cases out of 30 (30.0%) on one microsatellite loci. The positive rates of LOH in high differentiated HCC tissues and low differentiated HCC tissues were 3.33% and 26.67% respectively, there was significant difference and positive correlation between them. 2.Expression of p57~(kip2) mRNA: There were no expressions in normal liver tissue. Expressions in pericancerous cirrhosis and hepatocellular carcinoma were 33.33% and 16.67% respectively. In group of hepatocellular carcinoma tissues, the expressions in high differentiated HCC tissues and low differentiated HCC tissues were 28.57% and 0 respectively, there was significant difference and positive correlation between them.
Objective: To study the loss of heterozygosity (LOH) of p57~(kip2) and expressions of p57~(kip2) mRNA & protein in various stages of human hepatocellular carcinoma (HCC) in order to explore the molecular mechanism of hepatocarcinoma.
Methods: LOH of two microsatellite loci (TH01 and D11S2359) were detected in the p57~(kip2) gene site by using PCR-polyacrylamide gel electrophoresis-silver staining method. Immunohistochemistry staining and in situ hybirdization (ISH) were also used to show the expression of p57~(kip2) mRNA and protein in normal liver tissue, pericancerous cirrhosis and HCC.
Results: 1. LOH: LOH was identifided at least in 9 cases out of 30 (30.0%) on one microsatellite loci. The positive rates of LOH in high differentiated HCC tissues and low differentiated HCC tissues were 3.33% and 26.67% respectively, there was significant difference and positive correlation between them. 2.Expression of p57~(kip2) mRNA: There were no expressions in normal liver tissue. Expressions in pericancerous cirrhosis and hepatocellular carcinoma were 33.33% and 16.67% respectively. In group of hepatocellular carcinoma tissues, the expressions in high differentiated HCC tissues and low differentiated HCC tissues were 28.57% and 0 respectively, there was significant difference and positive correlation between them.
引文
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[14] Barnes DM, Dublin EA, Fisher CJ, Levison CA, Millis RR. Immunohitochemical detection of p53 protein in mammary carcinoma: an important new independent indicator of prognosis? Hum Pathol 1993; 24: 469-476.
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[1] Matsuoka S, Edwards MC, Bai C, et al. p57~(kip2), a structurally distinct member of the p21~(Cip1) CDK inhibitor family, is a candidate tumor suppressor gene.[J] Genes Dev, 1995, 9(6): 650
[2] Reid LH, Crider Miller SJ, Ande West, et al. Genomic organization of the human p57~(kip2) gene and its analysis in the G401 Wilms' Tumor assay.[J] Cancer Res, 1996, 56(6): 1214
[3] Lee MH, Reynisdottir I, Massague J. Cloning of p57~(kip2), a Cyclin dependent kinase inhibitor with unique domain structure and tissue distribution.[J] Genes Dev, 1995,9(6): 639
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[12] Orlow I, Iavarone A, Crider-Miller SJ, et al. Cyclin-dependent kinase inhibitor p57~(Kip2) in soft tissue sarcomas and Wilms tumors.[J] Cancer Res, 1996,6(6): 1219
[13] Nakai S, Maszki T, Shiratori Y, et al. Expression of p57~(kip2) in hepatocellular carcinoma: relationship between tumor differentiation and patient survival. [J] Int J Oncol, 2002, 20(4): 769
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[17] Bourcigaux N, Gaston V, Logie A etal. High expression of cyclin E and G1 CDK and loss of function of p57KIP2 are involved in proliferation of malignant sporadic adrenocortical tumors. [J]Clin Endocrinol Metab, 2000 Jan;85(1):322
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[1] Grana X, Reddy EP. Cell cycle control in mammlian cells: role of Cyclins, Cyclin dependent kinase (CDKs), growth suppressor and Cyclin dependent kinase inhibitors (CDKs). J Oncogene, 1995, 11(1): 21-26
[2] Matsuoka S, Edwards MC, Bai C, et al. p57kip2, a structurally distinct member of the p21Cip1 CDK inhibitor family, is a candidate tumor suppressor gene. Genes Dev, 1995, 9(6): 650-662
[3] Reid LH, Crider Miller SJ, Ande West, et al. Genomic organization of the human p57kip2 gene and its analysis in the G401 Wilms' Tumor assay. Cancer Res, 1996, 56(6): 1214-1218
[4] Watanabe H,Pan ZQ,Selareiber-Agus N, et al. Suppression of cell transformation by the cyclindependt kinase inhibitor p57kip2 requires binding to proliferating cell nuclearantigen. Bio chemistry,1998,95(4):1392-1397.
[5] Shin JY, Kim HS, Park J, et al. Mechanism for inactivation of the KIP family cyclin dependent kinase inhibitior genes in gastric cancer cell.Cancer Res,2000,60(2):262-265.
[6] Lee MH, Reynisdottir I, Massague J. Cloning of p57kip2, a Cyclin dependent kinase inhibitor with unique domain structure and tissue distribution. Genes Dev, 1995, 9(6): 639-644
[7] Rosenberg E, Rita I. Expression of cell cycle regulators p57kip2, CyclinD1, and CyclinE in epithelial ovarian tumors and survival. Human Pathol, 2001, 32(8): 808-813
[8] Malik R, Brown KW. Epigenetic gene deregulation in cancer. Br J Cancer, 2000, 83(12): 1583-1588
[9] Jones PA, Laird PW. Cancer-epigenetics comes of age. Nature Genetics, 1999, 21(2): 163-167
[10] Matsuki S, Thompson J, Edwards M, et al. Imprinting of the gene encoding a human Cyclin-dependent kinase inhibitor p57Kip2 on chromosome 11p15.5. Proc Natl Acad Sci USA, 1996, 93(8): 3026-3030
[11] Higashimoto K, Soejima H, Saito T,et al. Imprinting disruption of the CDKN1C/KCNQ1OT1 domain: the molecular mechanisms causing Beckwith-Wiedemann syndrome and cancer. Cytogenet Genome Res. 2006;113(1-4):306-12.
[12] Orlow I, Iavarone A, Crider-Miller SJ, et al. Cyclin-dependent kinase inhibitor p57Kip2 in soft tissue sarcomas and Wilms tumors. Cancer Res, 1996, 6(6): 1219-1221
[13] Lee MP, Debaun M, Randhawa G, et al. Low freguency of p57Kip2 mutation in Beckwith-Wiedemann Syndrome. Am J Hum Genet. 1997, 61(2): 304-309
[14] O'Keef D, Dao D, Zhao L, et al. Coding mutations in p57Kip2 are present in some cases of Beckwith-Wiedemann syndrome but are rare of absent in Wilms' tumors. Am J Hum Genet, 1997, 61(2): 295-303
[15] Matsumoto M,Farihata M, Ohtsuki Y, et al. Immunohistochemical characterization of p57kip2 expression in human esophageal squamous cell carcinoma. Anticancer Res, 2000, 20(3B): 1947-1952
[16] Ito Y ,Takeda T, Sakon M, et al. Expression of p57/Kip2 protein in hepatocellular carcinoma. Oncology, 2001;61(3):221-5
[17] Nan KJ, Guo H, Ruan ZP, et al. Expression of p57(kip2) and its relationship with clinicopathology, PCNA and p53 in primary hepatocellular carcinoma. World J Gastroenterol. 2005 Feb 28;ll(8):1237-40.
[18] Nakai S, Maszki T, Shiratori Y, et al. Expression of p57kip2 in hepatocellular carcinoma: relationship between tumor differentiation and patient survival. Int Oncol, 2002, 20(4): 769-775
[19] Shin JY, Kim HS, Lee KS, et al. Mutation and expression of the p27kipl and p57kip2 genes in human gastric cancer. ExpMol Med,, 2000,32(2):79-83.
[20] Nijjar T, Wining D, Tames L, et al. p57kip2expression and loss of heterozy gosity duing immortal conversion of cultured human mammary epithelial cells. Cancer Res, 1999,59(20):5112-5118.
[21] Lai S, Coepfert H, Gillenwater AM, et al. Loss of imprinting and genticalterations of the cyclin dependent kinase inhibitor p57kip2 gene in head and neck squamous cell carcinma .Clin Cancer R ES,2000,6(8):3172-3176.
1．孙江华，章宗籍，申丽娟。p57~(kip2)异常表达与肿瘤。昆明医学院学报，2005，26(1B)：137-140
[2] 张思维，李连弟，鲁风珠，等。中国1990—1992年原发性肝癌死亡调查分析。中华肿瘤杂志，1999，21：245—249。
[3] Sakamoto M, Hirohashi S, Shimosato Y. Early stages of multistep hepatocarcinogenesis: adenomatous hyperplasia and early hepatocellular carcinoma. Hum Pathol, 1991, 22(2): 172-178.
[4] Buetow KH, Murray JC, Israel JL, et al. Loss of heterozygosity suggests tumor suppressor gene responsible for primary hepatocellular carcinoma. Proc Natl Acad Sci USA, 1989, 86(22): 8852-8856.
[5] Barbacid T, Sanuits W, Civin C, et al. P53 gene mRNA expression and chromosome 17p allele loss in hepatocellular carcinomas. Chin Oncol, 1996,14 (8) :2224-2231.
[6] Grana X, Reddy EP. Cell cycle control in mammlian cells: role of Cyclins, Cyclin dependent kinase (CDKs), growth suppressor and Cyclin dependent kinase inhibitors (CDKs). Oncogene, 1995, 11(1): 21-26.
[7] Matsuoka S, Edwards MC, Bai C, et al. p57kip2, a structurally distinct member of the p21Cip1CDK inhibitor family, is a candidate tumor suppressor gene. Genes Dev, 1995, 9(6): 650-662.
[8] Reid LH, Crider Miller SJ, Ande West, et al. Genomic organization of the human p57kip2 gene and its analysis in the G401 Wilms' Tumor assay. Cancer Res, 1996, 56(6): 1214-1218.
[9] Hoffmann MJ, Florl AR, Seifert HH, et al. Multiple mechanisms downregulate CDKN1C in human bladder cancer. Int J Cancer, 2005 Apr 10;114(3):406-413.
[10] Nakai S, Maszki T, Shiratori Y, et al. Expression of p57kip2 in hepatocellular carcinoma: relationship between tumor differentiation and patient survival. Int J Oncol, 2002, 20(4): 769-775.
[11] Edmonson HA, Tumor of the liver and intrahepatic bile ducts. Altas of tumor, Section 7, Fascide 25, Armed Forces Institute of Pathology, Washington DC, 1958.
[12] Syeling Lai, Helmuth Goepfert, Ann M. Gillenwater, et al. Loss of Imprinting and Genetic Alterations of the Cyclin-dependent Kinase Inhibitor p57KIP2 Gene in Head and Neck Squamous Cell Carcinoma. Clinical Cancer Research 2000, 6(8), 3172-3176.
[13] Cong WM, Bakker A, Swalsky PA.et al. Multiple genetic alterations involed in the tumorigenesis of human cholangiocancinoma: a molecular genetic and clinicopathological study. Cancer Res Clin Oncol, 2001,127:187-192.
[14] Barnes DM, Dublin EA, Fisher CJ, Levison CA, Millis RR. Immunohitochemical detection of p53 protein in mammary carcinoma: an important new independent indicator of prognosis? Hum Pathol 1993; 24: 469-476.
[15] Kawamata N, Morosetti R, Miller CW, et al. Molecular analysis of the cyclin-dependent kinase inhibitor gene p27/Kip1 in human malignancies. Cancer Res, 1995,55(11): 2266-2269.
[16] Russo AA, Jeffrey PD, Patten AK, et al. Crystal structure of the p27Kip1 cyclin-dependent-kinase inhibitor bound to the cyclin A-Cdk2 complex. Nature, 1996, 382(6589): 325-331.
[17] Luo Y, Hurwitz J, Massagen J, et al. Cell-cyclin inhibition by independent CDK and PCNA binding domains in p21Cipl. Nature, 1995,375(6527): 159-161.
[18] Rosenberg E, Demopoulos RI, Jacquotte AZ, et al. Expression of cell cycle regulation regulators p57~(kip2), CyclinD_1 and CyclinE in epithelial ovarian tumors and survival. Hum Pathol 2001; 32:808-813.
[19] Matsuka S, Thompson J, Edwards M, et al. Imprinting of the gene encoding a human Cyclin-dependent kinase inhibitor p57~(Kip2) on chromosome 11p15.5.Proc Natl Acad Sci USA, 1996, 93(8): 3026-3030.
[20] Shin JY, Kim HS, Lee KS, et al. Mutation and expression of the p27kip1 and p57kip2 genes in human gastric cancer. ExpMol Med,, 2000,32(2):79-83.
[21] Ito Y, Yoshida H, Nakano K, et al.Expression of p57~(kip2) protein in normal and neoplastic thyroid tissues.Mol Med,2002,9(4):373-376.
[22] Ito Y, Takeda T, Wakasa K, et al.Expression of p57~(kip2) protein in pancreatic adenocarcinoma. Pancreas, 2001,23(3):246-250.
[23] Nijjar T, Wining D, Tames L, et al. p57~(kip2) expression and loss of heterozy gosity duing immortal conversion of cultured human mammary epithelial cells. Cancer Res, 1999,59(20):5112-5118.
[24] Wolfgang Hartmann, Andreas Waha, Arend Koch, et al. p57~(KLP2) Is Not Mutated in Hepatoblastoma but Shows Increased Transcriptional Activity in a Comparative Analysis of the Three Imprinted Genes p57~(KIP2), IGF2, and H19. American Journal of Pathology. 2000;157:1393-1403.
[25] Anderson J, Gordon A, McManus A, et al. Disruption of imprinted genes at chromosome region 11p15.5in paediatric rhabdomyosarcoma. Neoplasia, 1999,1(4):340-348
[26] 孔萌萌。Rb与p57~(kip2)在肝细胞癌发生发展过程中的表达研究：[硕士学位论文]。昆明医学院：基础医学院，2004。
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