转录抑制因子ZHX2在结直肠癌中的表达及其临床病理意义的研究
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摘要
目的：检测转录抑制因子ZHX2(zinc-fingers and homeoboxes2, ZHX2)在结直肠癌(colorectal carcinoma)中的表达情况,分析其与p53和survivin表达的关系,进而探讨ZHX2在结直肠癌发生和发展中的地位。方法：(1)利用免疫组织化学(Immunohistochemistry, IHC)的方法检测73例结直肠癌组织及其对应的癌旁正常黏膜组织中的ZHX2、p53和survivin蛋白的表达情况。(2)分析ZHX2、p53和survivin蛋白表达情况与临床病理参数的关系。(3)分析p53和survivin蛋白的表达情况与ZHX2蛋白表达之间的相关性。结果：(1)73例结直肠癌组织中ZHX2蛋白的阳性率为82.2%(60/73),癌旁正常组织中ZHX2蛋白的阳性率为94.5%(69/73),差异具有统计学意义(P<0.05)。(2)在结肠癌组织中,ZHX2蛋白的阳性表达与肿瘤发生部位及分化程度有关(P<0.05),与性别、年龄、肿瘤大小、浸润深度、淋巴结转移及Dukes分期无关(P>0.05)。对73例结直肠癌病例进行随访生存分析,得出ZHX2(＋)组的中位生存期为55.3个月,ZHX2(-)组的中位生存期为24.7个月,ZHX2(＋)组病例的的生存时间明显长于ZHX2(-)组(P<0.05)。(3)73例结直肠癌组织中p53和survivin蛋白的阳性率分别是72.6%(53/73)、52.1%(38/73),在其对应的癌旁正常组织中p53和survivin蛋白的阳性率分别是38.4%(28/73)、20.5%(15/73)。在结直肠癌中,p53蛋白的阳性表达与淋巴结转移及Dukes分期有关(P<0.05),与性别、年龄、肿瘤直径、部位、分化程度、浸润深度无关(P>0.05)。survivin蛋白的阳性表达与肿瘤的分化程度有关(P<0.05),与性别、年龄、肿瘤直径、部位、浸润深度、淋巴结转移及Dukes分期无关(P>0.05)。(4)在结直肠癌中,ZHX2与p53之间无显著相关(r=0.082,P=0.491>0.05),ZHX2与survivin之间也无显著相关(r=0.123,P=0.300>0.05)。ZHX2(+)组p53和survivin的阳性率分别为73.3%(44/60)、55.0%(33/60,),两者阳性表达率无差别(P>0.05)；ZHX2(-)组p53和survivin的阳性率分别为69.2%(9/13)、38.5%(5/13),两者阳性表达率亦无差别(P>0.05)。结论：(1)ZHX2作为一种转录抑制因子,可能参与结直肠癌的发生、发展,并有助于患者预后的判断。(2)ZHX2、survivin在参与结直肠癌中发生、发展过程中可能存在各自的作用途径。
Objective:To detect the expression of zinc-fingers and homeoboxes2(ZHX2) protein in colorectal carcinoma, and to analysis the relationship the expression of ZHX2protein with p53and survivin in colorectal carcinoma. And then explore the role of ZHX2in the occurrence and development of colorectal cancer. Methods:(1) Immunohistochemistry was used to detect the expressions of ZHX2、p53and survivin protein in73colorectal carcinoma tissues and their corresponding noncarcinoma mucosa tissue.(2) The results about the expressions of ZHX2、p53and survivin protein were analyzed by combination with the clinical and pathological data of the patients.(3) It was performed to analyzed the relationship expression of the p53and survivin protein with ZHX2. Results:(1) The positive rates of ZHX2in colorectal carcinoma samples and noncarcinoma tissue were82.2%(60/73) and 94.5%(69/73), respectively. The difference between the rates was significant(P <0.05).(2) It showed significant correlation with the tumor location and the degree of differentiation(P<0.05). However, no correlation was revealed between ZHX2expression and the gender, age, tumor size, depth of invasion, lymph metastasis and the Dukes stage (P>0.05). Through the follow-up the73colorectal cancer cases, the result of the survival Analysis was that the median survival time of ZHX2(-) group was55.3months and ZHX2(+) was24.7months. The survival time of ZHX2(+) group was longer than the ZHX2(-) group (P<0.05).(3) The positive rates of p53and survivin in colorectal carcinoma samples were72.6%(53/73)、52.1%(38/73), and in noncarcinoma tissue were38.4%(28/73)、20.5%(15/73).About p53expression in colorectal carcinoma, it showed significant correlation with the lymph metastasis and Dukes stage(P<0.05). However, no correlation was revealed between p53expression and the gender, age, tumor size, depth of invasion, tumor location and the degree of differentiation(P>0.05). About survivin expression in colorectal carcinoma, it showed significant correlation with the degree of differentiation(P<0.05). However, no correlation was revealed between survivin expression and the gender, age, tumor size, tumor location,depth of invasion, lymph metastasis and the Dukes stage (P>0.05).(4) In colorectal cancer, There were no significant correlation between ZHX2and P53(r=0.082, P=0.491>0.05), as same as the relationship between ZHX2and Survivin (r=0.123, P=0.300>0.05). the positive rates of p53and survivin in the ZHX2(+) group were73.3%(44/60)、55.0%(33/60),the difference between the rates was no significant(P>0.05); and in the ZHX2(-) group were69.2%(9/13).38.5%(5/13), the difference between the rates was no significant(P>0.05). Conclusion:(1) As a transcription inhibitor, ZHX2may be involved in tumorgenesis and progression of colorectal carcinoma which contribute to the prognosis of patients.(2) Respectively, ZHX2, p53and Survivin may had their possible pathways during the occurrence and development of colorectal cancer.
Objective:To detect the expression of zinc-fingers and homeoboxes2(ZHX2) protein in colorectal carcinoma, and to analysis the relationship the expression of ZHX2protein with p53and survivin in colorectal carcinoma. And then explore the role of ZHX2in the occurrence and development of colorectal cancer. Methods:(1) Immunohistochemistry was used to detect the expressions of ZHX2、p53and survivin protein in73colorectal carcinoma tissues and their corresponding noncarcinoma mucosa tissue.(2) The results about the expressions of ZHX2、p53and survivin protein were analyzed by combination with the clinical and pathological data of the patients.(3) It was performed to analyzed the relationship expression of the p53and survivin protein with ZHX2. Results:(1) The positive rates of ZHX2in colorectal carcinoma samples and noncarcinoma tissue were82.2%(60/73) and 94.5%(69/73), respectively. The difference between the rates was significant(P <0.05).(2) It showed significant correlation with the tumor location and the degree of differentiation(P<0.05). However, no correlation was revealed between ZHX2expression and the gender, age, tumor size, depth of invasion, lymph metastasis and the Dukes stage (P>0.05). Through the follow-up the73colorectal cancer cases, the result of the survival Analysis was that the median survival time of ZHX2(-) group was55.3months and ZHX2(+) was24.7months. The survival time of ZHX2(+) group was longer than the ZHX2(-) group (P<0.05).(3) The positive rates of p53and survivin in colorectal carcinoma samples were72.6%(53/73)、52.1%(38/73), and in noncarcinoma tissue were38.4%(28/73)、20.5%(15/73).About p53expression in colorectal carcinoma, it showed significant correlation with the lymph metastasis and Dukes stage(P<0.05). However, no correlation was revealed between p53expression and the gender, age, tumor size, depth of invasion, tumor location and the degree of differentiation(P>0.05). About survivin expression in colorectal carcinoma, it showed significant correlation with the degree of differentiation(P<0.05). However, no correlation was revealed between survivin expression and the gender, age, tumor size, tumor location,depth of invasion, lymph metastasis and the Dukes stage (P>0.05).(4) In colorectal cancer, There were no significant correlation between ZHX2and P53(r=0.082, P=0.491>0.05), as same as the relationship between ZHX2and Survivin (r=0.123, P=0.300>0.05). the positive rates of p53and survivin in the ZHX2(+) group were73.3%(44/60)、55.0%(33/60),the difference between the rates was no significant(P>0.05); and in the ZHX2(-) group were69.2%(9/13).38.5%(5/13), the difference between the rates was no significant(P>0.05). Conclusion:(1) As a transcription inhibitor, ZHX2may be involved in tumorgenesis and progression of colorectal carcinoma which contribute to the prognosis of patients.(2) Respectively, ZHX2, p53and Survivin may had their possible pathways during the occurrence and development of colorectal cancer.
引文
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[1]Kawata H, Yamada K, Shou Z, et al. Zinc-fingers and homeoboxes(ZHX) 2,a novel member of the ZHX family, functions as a transcriptional repressor[J]. The Biochemical journal,2003,373(3):747-757.
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[11]田晓丰,赵红蕾,孙月芳,等.肝癌组织中ZHX2基因启动子甲基化及其临床病理特征的关系[J].中国老年学杂志,2011,31(9)：3444-3446.
[12]Yamada K, Ogata-Kawata H, Matsuura K, et al. ZHX2 and ZHX3 repress cancer markers in normal hepatocytes[J]. Front Biosci,2009,14:3724-3732.
[13]Armellini A, Sarasquete ME, Garcia-Sanz R, et al. Low expression of ZHX2, but not RCBTB2 or RAN, is associated with poor outcome in multiple myeloma[J]. Br J Haematology,2008,141(2):212-215.
[14]Legartova S, Harnivarova-Horakova A, Bartova E, et al. Expression of RNA, ZHX-2,and CHC1L genes in multiple myeloma patients and in myeloma cell lines treated with HDAC and Dnmts inhibitors[J]. Neoplasma, 2010,57(5):482-487.
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[19]Gargalovic PS, Ebilgin A, Kohannim O, et al. Quantitative trait locus mapping and identification of Zhx2 as a novel regulator of plasma lipid metabolism [J]. Circ Cardiovasc Genet.2010; 3(1):60-67.
[20]Wu C, Qiu R, Wang J, et al. ZHX2 interacts with Ephrin-B and regulates neural progenitor maintenance in the developing cerebral cortex[J]. J Neurosci, 2009; 29(23):7404-7412.
[2]Mueller J, Gazzoli I, Bandipalliam P, et al. Comperhensive molecular analysis of mismatch repair gene defects in suspected lynch syndrome (hereditary nonpolyposis colorectal cancer)cases[J]. Cancer Res,2009, 69:7053-7061.
[3]Hamicarova A, Kozubek SKIC, Pachemik J, et al. Distinct nuclear arrangement of active and inactive and inactive c-myc genes in control and differentiatied colon carcinoma cells[J]. Exp Cell Res,2006,312(20): 4019-4035.
[4]Molinari F, Martin V, Saletti P, et al. Differing deregulation of EGFR and downstream proteins in primary colorectial cancer and related metastatic sites may be clinically relevant[J]. Br J Cancer,2009,100(7):1087-1094.
[5]Pancione M, Forte N, Fucci A, et al. Prognostic role of beta-catenin and p53 expression in the metastatic progression of sporadic colorectal cancer[J]. Hum Pathol,2010,41(6):867-876.
[6]Wettergren Y, Odin E, Nilsson G, et al. p16INK4a gene promoter hypeimethylation in mucosa as a prognostic factor for patients with colorectal cancer[J]. Mol Med,2008,14(7/8):412-421.
[7]Martin M, Simon-Assmann P, Kedinger M, et al. DCC regulates cell adhesion in human colon cancer derived HT-29 cells and associates with ezrin[J]. Eur J Cell Biol,2006,85(8):769-783.
[8]King-Yin Lam A, Ong K, Ho YH. Colorectal mucinous adenocarcinoma:the clinicopathologic features and signficiance of p16 and p53 expression [J]. Dis Colon Rectum,2006,49:1275-1283.
[9]Kawata H, Yamada K, Shou Z, et al. The mouse zinc-fingers and homoboxes (ZHX) family;ZHX2 forms a heterodimer with ZHX3[J]. Gene,2003, 323:133-140.
[10]Kawata H, Yamada K, Shou Z, et al. Zinc-fingers and homeoboxes(ZHX) 2,a novel member of the ZHX family, functions as a transcriptional repressor[J]. The Biochemical journal,2003,373(3):747-757.
[11]Bayarsaihan D, Enkhmandakh B, Makeyev A, et al. Homez,a homeobox leucine zipper gene specific to the vertebrate lineage[J]. Proc Natl Acad Sci USA,2003,100(18):10358-10363.
[12]Munishi A, Dadheech S, Jain S, et al. Lack of association of G779A ZHX-2 gene variant with HbF levels inβ-thalassemia major[J]. Eur J Haematol,2011, 86(6):502-506.
[13]Liu G, Clement C, Kanwar Y S, et al. ZHX2 proteins regulate podocyte gene expression during the development of nephritic syndrome[J]. J Biol Chem, 2006,281(51):39681-39692.
[14]Wu C, Qiu R, Wang J, er al. ZHX2 interacts with Ephrin-B and regulates neural progenitor maintenance in the develping cerebral cortex[J]. J Neurosci, 2009,29(23):7404-7412.
[15]Yamada K, Ogata-Kawata H, Matsuura K, et al. ZHX2 and ZHX3 repress cancer markers in normal hepatocytes[J]. Front Biosci,2009,14:3724-3732.
[16]Gargalovic PS, Erbilgin A, Kohannim O, et al. Quantitative trait locus mapping and identification of zhx2 as a novel regulator of plasma lipid metabolism [J]. Circ Cardiovasc Genet,2010,3(1):60-67.
[17]Lv Z, Zhang M, Bi J, et al. Promoter hypermethylation of a novel gene, ZHX2, in hepatocellular carcinoma[J]. Am J Clin Pathol,2006,125(5):740-746.
[18]陈伟露,吕自力.肝细胞癌中ZHX2 mRNA的表达及其临床意义的研究[J].中国临床新医学杂志,2011,04(5)：404-406.
[19]Hystad ME, Myklebust JH, Sivertsen EA, et al. Characterization of early stages of human B cell development by gene expression profiling[J]. J Immunology,2007; 179(6):3662-3671.
[20]Nagel S, Schneider B, Rosenwald A, et al. t(4;8)(q27;q24) in hodgkin lymphoma cells targets phosphodiesterase PDE5A and homeobox gene ZHX2[J].Genes, chromosomes & cancer,2011,50(12):996-1009.
[21]Sood AK, Fletcher MS, Gruman LM, et al. The paradoxical expression of maspin in ovarian carcinoma[J]. Clinincal Cancer Research,2002, 8(9):2924-2932.
[22]Armellini A, Sarasquete ME, Garcia-Sanz R, et al. Low expression of ZHX2, but not RCBTB2 or RNA, is associated with poor outcome in multiple myeloma[J]. Br J Haematology,2008,141(2):212-215.
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