HOXA10在卵巢透明细胞癌中的表达及对其增殖和侵袭的影响
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摘要
同源框基因HOXA10属同源异型盒家族HOXA族。研究显示,HOXA10参与女性苗勒氏管发育并在正常女性子宫、阴道上皮组织中表达。近年有资料显示,HOXA10不仅在孕早期子宫内膜上皮分化和间质蜕膜化中起重要作用,还可能参与调控源于异位子宫内膜的卵巢癌的发生。
卵巢透明细胞癌(ovarian clear cell adenocarcinoma,OCCA)的细胞组织结构及免疫表型与子宫内膜及阴道的透明细胞癌极其相似,故目前多数学者认为卵巢透明细胞癌起源于苗勒氏管。由于卵巢透明细胞癌患者合并子宫内膜异位症(endometriosis,EMs)有高达25%—55%,一些学者提出卵巢透明细胞癌很可能来源于异位子宫内膜的恶变,非典型子宫内膜异位症(atypical endometriosis,AEMs)可能是癌前病变,是介于典型子宫内膜异位症与恶变的中间步骤。但是HOXA10在异位子宫内膜恶变和卵巢透明细胞癌形成过程中具有怎样的生物学影响至今尚未见文献报道。
本研究分两部分:(1)观察同源框基因HOXA10在卵巢透明细胞癌和异位子宫内膜中的表达及其与临床预后的相关性分析;(2)应用脂质体转染技术观察HOXA10的表达对卵巢透明细胞癌ES-2细胞增殖、运动和侵袭的影响。
第一部分HOXA10在卵巢透明细胞癌组织中的表达
目的检测HOXA10在卵巢透明细胞癌、正常卵巢、正常在位内膜、卵巢内膜样囊肿及其对应的在位内膜组织中mRNA和蛋白水平的表达,比较它们的表达差异,并分析其与临床预后的相关性。
方法应用RT-PCR法检测卵巢透明细胞癌、正常在位内膜、卵巢内膜样囊肿及其相应在位内膜组织中HOXA10基因的表达;应用免疫组织化学法检测卵巢透明细胞癌、正常卵巢、正常在位内膜、卵巢内膜样囊肿及其相应在位内膜石蜡组织中HOXA10蛋白表达。
结果(1)卵巢透明细胞癌组织中可以检测到明显的HOXA10表达。卵巢内膜样囊肿上皮中未检测到HOXA10的表达,其相对应的在位内膜,随月经周期的不同有不同程度的表达,其中表达阳性的患者,月经周期多处于围排卵期,病理学检查证实均为分泌期子宫内膜;未合并内膜异位症患者的在位内膜与合并内膜异位症患者的在位内膜的HOXA10表达相似。(2) HOXA10蛋白的阳性表达与卵巢透明细胞癌患者的年龄及临床分期无关,但与患者的术后5年生存率呈负相关(R=-0.442,P=0.043)。
结论HOXA10在卵巢透明细胞癌中的异常表达与患者的术后5年生存率密切相关,提示HOXA10基因可能参与卵巢透明细胞癌恶性进展。
第二部分HOXA10基因对卵巢透明细胞癌ES-2细胞增殖、运动和侵袭的影响
目的研究人同源框基因HOXA10对卵巢透明细胞癌ES-2细胞增殖、迁移和侵袭的影响。
方法以脂质体稳定转染建立HOXA10表达的卵巢透明细胞癌ES-2细胞,并筛选高表达阳性克隆,应用Western blot方法检测转染效果。将ES-2细胞分为两组,转染空质粒pcDNA3组和转染质粒HOXA10-pcDNA3组,SRB法分别检测各组细胞HOXA10表达对ES-2细胞增殖的影响;采用细胞划痕试验、Transwell小室检测细胞迁移及侵袭的能力。
结果(1)卵巢透明细胞癌ES-2细胞HOXA10转染效率检测,当质粒与脂质体的比例为1:2.5时可以得到较好的转染效率。(2) SRB法检测细胞增殖显示:HOXA10转染组与空载体组A值分别为0.446±0.0024和0.281±0.002(P＜0.01)。(3)细胞划痕5小时后,HOXA10转染组与空载体组的迁移距离分别为0.47±0.07mm和0.25±0.03mm(P＜0.05)。(4)Transwell小室检测HOXA10转染组和空载体转染组24小时跨膜细胞数分别为446±14个和227±12个(P＜0.01)。
结论HOXA10N以通过促进细胞增殖,增加细胞的运动、侵袭能力参与卵巢透明细胞癌的恶性进展。
以上两部分研究结果显示:(1)同源异型盒转录因子HOXA10在卵巢透明细胞癌组织中的异常表达与预后呈负相关;(2) HOXA10在卵巢透明细胞癌中的表达可以通过促进细胞增殖,增加细胞的运动、侵袭能力参与卵巢透明细胞癌的恶性进展。
Homeobox gene HOXA10 belongs to HOXA cluster of homebox family. HOXA10 was reported to participat in the development of female gential tract and was found to express in normal endometrium and vagina muliebris. Recently,it has been found that HOXA10 may be involved in the carcinogenesis of ovarian carcinoma generating from endometriosis(EMs) besides its effect on endometrium epithelial differentiation and stroma decidualization.
The cellular structure and immunophenotype of ovarian clear cell adenocarcinoma(OCCA) is very similar with those of endometrium and vagina clear cell adenocarcinoma.Most scholars considered OCCA came from the Muller's duct.According to the high percentage(25%—55%) of EMs found in the OCCA patients,a part of OCCA was considered to come from the malignant EMs and atypical endometriosis(AEMs) which could be a kind of precancerous lesion.But little is known about the relationship between HOXA10 in malignant EMs and ovarian carcinogenesis.
Our experiments are divided into two parts as follows:(1) observeing the expression of homebox gene HOXA10 in ovarian clear cell adenocarcinoma and endometriotic tissues and its correlative analysis of clinical prognosis.(2) Establishing HOXA10 expression ES-2 cell line,an ovarian clear cell adenocarcinoma cell line,and investigating the effects of HOXA10 on proliferation,motility and invasion.
SectionⅠExpression of HOXA10 in ovarian clear cell adenocarcinoma
Objective To examine the expression of HOXA10 in ovarian clear cell adenocarcinoma,normal ovarian,normal endometrial,ovarian endometriotic and corresponding endometrial tissues in mRNA and protein level.The relationships between expression of HOXA10 and its correlative clinical prognosis were analyzed.
Methods RT-PCR was used to detect mRNA expression level of HOXA10 in ovarian clear cell adenocarcinoma,normal endometrial,ovarian endometriotic and corresponding endometrial tissues. Immunohistochemistry staining was used to investigate the expression of HOXA10 protein in ovarian clear cell adenocarcinoma,normal ovarian, normal endometrial,ovarian endometriotic and corresponding endometrial tissues.
Results(1) The expression of HOXA10 gene was found in ovarian clear cell adenocarcinoma tissues but not in ovarian endometriosis.Different expression of HOXA10 was found in corresponding normal endometrium in different menstrual cycle.The menstrual cycle of positive expression patients were most in ovulation period and were confirmed to be in secretory phase by pathematology detection.HOXA10 expression of endometrium in patients without endometriosis was the same as that in patients with endometriosis.(2) HOXA10 gene expression level was positively correlated with the stage and grade of ovarian cancers(P＜0.05),but was negatively correlatated with five year survival rate (R=-0.442,P=0.043).
Conclusions Overexpression of HOXA10 may be related to the tumorigenesis of epithelial ovarian cancer and canceration of EMs.
SectionⅡThe effects of HOXA10 on proliferation,motility and invasion of ovarian clear cell adenocarcinoma ES-2
Objective To evaluate the effects of HOXA10 on proliferation,motility and invasion of human ovarian clear-cell carcinoma ES-2.
Methods A stable HOXA10-expressed ES-2 cell line was established and the high positive expression clone was screening out.Enhancement of HOXA10 expression was confirmed by Western blot.ES-2 cells were divided into two groups:HOXA10-ES-2 and pcDNA-ES-2.Cell proliferation of each group were evaluated by Sulforhodamine B assay.The motility and invasion of two groups were evaluated by Wound assay and transwell.
Results(1) The stable HOXA10 expression clones of ES-2 cells were established by Lipofectamine transfection.The transfection efficiency was satisfactory when ratio between plasmid and Lipofectaminewas 1:2.5.(2) The difference of cell proliferation rates between HOXA10 transfected groups and negative control groups cell was significant(0.446±0.0024 vs 0.281±0.002,P＜0.01) by SRB assay.(3) Using wound healing assays,cell motility for HOXA10 transfection groups were faster than that of empty groups at the fifth hour after scratch.(0.47±0.07mm vs 0.25±0.03 mm,P＜0.05).(4) The invasion activity of HOXA10 transfection cells were significantly higher compared with those of control cells(446±14 vs 227±12,P＜0.01) by transwell.
Conclusions HOXA10 could stimulate the carcinogenesis of ovarian clear cell adenocarcinoma by up-regulation proliferation,motility and invasion of cells.
The present study has shown that(1) Homebox gene HOXA10 is over-expressed in ovarian clear cell adenocarcinoma.A reverse correlation between prognosis and HOXA10 expression exists in ovarian clear cell carcinoma.(2) HOXA10 could stimulate the carcinogenesis of ovarian clear cell adenocarcinoma by induce the proliferation,motility and invasion of cells.
卵巢透明细胞癌(ovarian clear cell adenocarcinoma,OCCA)的细胞组织结构及免疫表型与子宫内膜及阴道的透明细胞癌极其相似,故目前多数学者认为卵巢透明细胞癌起源于苗勒氏管。由于卵巢透明细胞癌患者合并子宫内膜异位症(endometriosis,EMs)有高达25%—55%,一些学者提出卵巢透明细胞癌很可能来源于异位子宫内膜的恶变,非典型子宫内膜异位症(atypical endometriosis,AEMs)可能是癌前病变,是介于典型子宫内膜异位症与恶变的中间步骤。但是HOXA10在异位子宫内膜恶变和卵巢透明细胞癌形成过程中具有怎样的生物学影响至今尚未见文献报道。
本研究分两部分:(1)观察同源框基因HOXA10在卵巢透明细胞癌和异位子宫内膜中的表达及其与临床预后的相关性分析;(2)应用脂质体转染技术观察HOXA10的表达对卵巢透明细胞癌ES-2细胞增殖、运动和侵袭的影响。
第一部分HOXA10在卵巢透明细胞癌组织中的表达
目的检测HOXA10在卵巢透明细胞癌、正常卵巢、正常在位内膜、卵巢内膜样囊肿及其对应的在位内膜组织中mRNA和蛋白水平的表达,比较它们的表达差异,并分析其与临床预后的相关性。
方法应用RT-PCR法检测卵巢透明细胞癌、正常在位内膜、卵巢内膜样囊肿及其相应在位内膜组织中HOXA10基因的表达;应用免疫组织化学法检测卵巢透明细胞癌、正常卵巢、正常在位内膜、卵巢内膜样囊肿及其相应在位内膜石蜡组织中HOXA10蛋白表达。
结果(1)卵巢透明细胞癌组织中可以检测到明显的HOXA10表达。卵巢内膜样囊肿上皮中未检测到HOXA10的表达,其相对应的在位内膜,随月经周期的不同有不同程度的表达,其中表达阳性的患者,月经周期多处于围排卵期,病理学检查证实均为分泌期子宫内膜;未合并内膜异位症患者的在位内膜与合并内膜异位症患者的在位内膜的HOXA10表达相似。(2) HOXA10蛋白的阳性表达与卵巢透明细胞癌患者的年龄及临床分期无关,但与患者的术后5年生存率呈负相关(R=-0.442,P=0.043)。
结论HOXA10在卵巢透明细胞癌中的异常表达与患者的术后5年生存率密切相关,提示HOXA10基因可能参与卵巢透明细胞癌恶性进展。
第二部分HOXA10基因对卵巢透明细胞癌ES-2细胞增殖、运动和侵袭的影响
目的研究人同源框基因HOXA10对卵巢透明细胞癌ES-2细胞增殖、迁移和侵袭的影响。
方法以脂质体稳定转染建立HOXA10表达的卵巢透明细胞癌ES-2细胞,并筛选高表达阳性克隆,应用Western blot方法检测转染效果。将ES-2细胞分为两组,转染空质粒pcDNA3组和转染质粒HOXA10-pcDNA3组,SRB法分别检测各组细胞HOXA10表达对ES-2细胞增殖的影响;采用细胞划痕试验、Transwell小室检测细胞迁移及侵袭的能力。
结果(1)卵巢透明细胞癌ES-2细胞HOXA10转染效率检测,当质粒与脂质体的比例为1:2.5时可以得到较好的转染效率。(2) SRB法检测细胞增殖显示:HOXA10转染组与空载体组A值分别为0.446±0.0024和0.281±0.002(P＜0.01)。(3)细胞划痕5小时后,HOXA10转染组与空载体组的迁移距离分别为0.47±0.07mm和0.25±0.03mm(P＜0.05)。(4)Transwell小室检测HOXA10转染组和空载体转染组24小时跨膜细胞数分别为446±14个和227±12个(P＜0.01)。
结论HOXA10N以通过促进细胞增殖,增加细胞的运动、侵袭能力参与卵巢透明细胞癌的恶性进展。
以上两部分研究结果显示:(1)同源异型盒转录因子HOXA10在卵巢透明细胞癌组织中的异常表达与预后呈负相关;(2) HOXA10在卵巢透明细胞癌中的表达可以通过促进细胞增殖,增加细胞的运动、侵袭能力参与卵巢透明细胞癌的恶性进展。
Homeobox gene HOXA10 belongs to HOXA cluster of homebox family. HOXA10 was reported to participat in the development of female gential tract and was found to express in normal endometrium and vagina muliebris. Recently,it has been found that HOXA10 may be involved in the carcinogenesis of ovarian carcinoma generating from endometriosis(EMs) besides its effect on endometrium epithelial differentiation and stroma decidualization.
The cellular structure and immunophenotype of ovarian clear cell adenocarcinoma(OCCA) is very similar with those of endometrium and vagina clear cell adenocarcinoma.Most scholars considered OCCA came from the Muller's duct.According to the high percentage(25%—55%) of EMs found in the OCCA patients,a part of OCCA was considered to come from the malignant EMs and atypical endometriosis(AEMs) which could be a kind of precancerous lesion.But little is known about the relationship between HOXA10 in malignant EMs and ovarian carcinogenesis.
Our experiments are divided into two parts as follows:(1) observeing the expression of homebox gene HOXA10 in ovarian clear cell adenocarcinoma and endometriotic tissues and its correlative analysis of clinical prognosis.(2) Establishing HOXA10 expression ES-2 cell line,an ovarian clear cell adenocarcinoma cell line,and investigating the effects of HOXA10 on proliferation,motility and invasion.
SectionⅠExpression of HOXA10 in ovarian clear cell adenocarcinoma
Objective To examine the expression of HOXA10 in ovarian clear cell adenocarcinoma,normal ovarian,normal endometrial,ovarian endometriotic and corresponding endometrial tissues in mRNA and protein level.The relationships between expression of HOXA10 and its correlative clinical prognosis were analyzed.
Methods RT-PCR was used to detect mRNA expression level of HOXA10 in ovarian clear cell adenocarcinoma,normal endometrial,ovarian endometriotic and corresponding endometrial tissues. Immunohistochemistry staining was used to investigate the expression of HOXA10 protein in ovarian clear cell adenocarcinoma,normal ovarian, normal endometrial,ovarian endometriotic and corresponding endometrial tissues.
Results(1) The expression of HOXA10 gene was found in ovarian clear cell adenocarcinoma tissues but not in ovarian endometriosis.Different expression of HOXA10 was found in corresponding normal endometrium in different menstrual cycle.The menstrual cycle of positive expression patients were most in ovulation period and were confirmed to be in secretory phase by pathematology detection.HOXA10 expression of endometrium in patients without endometriosis was the same as that in patients with endometriosis.(2) HOXA10 gene expression level was positively correlated with the stage and grade of ovarian cancers(P＜0.05),but was negatively correlatated with five year survival rate (R=-0.442,P=0.043).
Conclusions Overexpression of HOXA10 may be related to the tumorigenesis of epithelial ovarian cancer and canceration of EMs.
SectionⅡThe effects of HOXA10 on proliferation,motility and invasion of ovarian clear cell adenocarcinoma ES-2
Objective To evaluate the effects of HOXA10 on proliferation,motility and invasion of human ovarian clear-cell carcinoma ES-2.
Methods A stable HOXA10-expressed ES-2 cell line was established and the high positive expression clone was screening out.Enhancement of HOXA10 expression was confirmed by Western blot.ES-2 cells were divided into two groups:HOXA10-ES-2 and pcDNA-ES-2.Cell proliferation of each group were evaluated by Sulforhodamine B assay.The motility and invasion of two groups were evaluated by Wound assay and transwell.
Results(1) The stable HOXA10 expression clones of ES-2 cells were established by Lipofectamine transfection.The transfection efficiency was satisfactory when ratio between plasmid and Lipofectaminewas 1:2.5.(2) The difference of cell proliferation rates between HOXA10 transfected groups and negative control groups cell was significant(0.446±0.0024 vs 0.281±0.002,P＜0.01) by SRB assay.(3) Using wound healing assays,cell motility for HOXA10 transfection groups were faster than that of empty groups at the fifth hour after scratch.(0.47±0.07mm vs 0.25±0.03 mm,P＜0.05).(4) The invasion activity of HOXA10 transfection cells were significantly higher compared with those of control cells(446±14 vs 227±12,P＜0.01) by transwell.
Conclusions HOXA10 could stimulate the carcinogenesis of ovarian clear cell adenocarcinoma by up-regulation proliferation,motility and invasion of cells.
The present study has shown that(1) Homebox gene HOXA10 is over-expressed in ovarian clear cell adenocarcinoma.A reverse correlation between prognosis and HOXA10 expression exists in ovarian clear cell carcinoma.(2) HOXA10 could stimulate the carcinogenesis of ovarian clear cell adenocarcinoma by induce the proliferation,motility and invasion of cells.
引文
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[31]Schaner ME,Ross DT,Ciaravino G,et al.Gene expression patterns in ovarian carcinomas[J].Mol Biol Cell,2003,14:4376-4386.
[32]Akahane T,Sekizawa A,Okuda T,et al.Disappearance of steroid hormone dependency during malignant transformation of ovarian clear cell cancer[J].Int J Gynecol Pathol,2005,24:369-376.
[33]Kopfstein L,Christofori G.Metastasis:cell-autonomous mechanisms versus contributions by the tumor microenvironment[J].Cell Mol Life Sci 2006,63(4):449-468.
[34]Ludwig T.Local proteolytic activity in tumor cell invasion and metastasis[J].Bioessays,2005,27(11):1181-1191.
[35]Rosette C,Roth RB,Oeth P,et al.Role of ICAM1 in invasion of human breast cancer cells[J].Carcinogenesis,2005,Epub.
[36]Seals DF,Azucena EF Jr,Pass I,et al.The adaptor protein Tks5/Fish is required for podosome formation and function,and for the protease-driven invasion of cancer cells[J].Cancer Cell,2005,7(2):155-165.
[37]Boire A,Covic L,Agarwal A,et al.PAR1 is a matrix metalloprotease-1receptor that promotes invasion and tumorigenesis of breast cancer cells [J].Cell,2005,120(3):303-313.
[38]高进,章静波.癌的侵袭与转移 基础与临床[M].北京:科学出版社,2002:94.
[39]Cillo C,Cantile M,Mortarini R,et al.Differential patterns of HOX gene expression are associated with specific integrin and ICAM profiles in clonal populations isolated from a single human melanoma metastasis [J]. Int J Cancer, 1996, 66(5):692-697.
[40] Sarrio D,MORENO-Bueno G, Sanchez-Estevez C, et al. Expression of cadherins and catenins correlates with distinct histologic types of ovarian carcinomas[J]. Hum Pathol, 2006, 37(8):1042-1049.
[41] Voutilainen KA, Anttila MA, Sillanpaa SM,et al. Prognostic significance of E-cadherin-catenin complex in epithelial ovarian cancer[J]. Clin Pathol, 2006, 59(5):460-467.
[42] Birchmeier W, Behens J. Cadherin expression in carcinomas: role in the formation of cell junctions and the prevention of invasiveness[J].Biochim Biophys Acta, 1994,1198:11-26.
[43] Perl AK, Wilgenbus P, Dahl U, et al. A causal role for E-cadherin in the transition from adenomatocarcinoma[J]. Nature, 1998,3(92): 190-193.
[44] Frixen UH. E-cadherin-mediated cell-cell adhesion prevents invasiveness of human carcinoma cell [J]. Cell Biol, 1991:173-185.
[45] V leminckx K, Vakaet LJ, Mareel M , et al. Genetic manipulation of E-cadherin expression by epithelial. Tumor cell reveals an invasion suppressor role[J]. Cell, 1991,66:107-119.
[46] Miyaki M. Increased cell-substratum adhesion, and decreased secretion and cell growth, induced by E-cadherin transfection of human colon carcinoma cells[J]. Oncogene, 1995,11:2547-2552.
[47] Lorens A. Downregulation of E-cadherin in mouse skin carcinoma cells enhances a migratory and invasive phenotype 1 inked to matrix metal loproteinase-9 gelatinase expression[J]. Lab Invest, 1998, 78:1-12.
[48] Fraggetta F, Pelosi G, Cafici A. CDX2 immunoreactivity in primary and metastatic ovarian mucinous tumours[J]. Virchows Arch, 2003,443(6): 782-786.
[49] Dinulescu, D. M. et al. Role of K-ras and Pten in the development of mouse models of endometriosis and endometrioid ovarian cancer[J]. Nat.Med, 2005(11): 63-70.
[50]Hennessy B.T.,Mills G.B.Ovarian cancer:Homeobox genes,autocrine/paracrine growth,and kinase signaling[J].Elsevier,2006.
[51]Abate-Shen C,Deregulated homeobox gene expression in cancer.Cause or con sequence?[J].Nat Rev Cancer,2002,2(10):777-85.
[52]赵宇清,丰有吉.HOXB7对卵巢透明细胞癌ES-2细胞系侵袭的影响.复旦学报,2007,34(3):346-350.
[53]金鸿雁,丰有吉.反义Snail转录因子抑制卵巢癌转移的实验研究.中华妇产科杂志,2005,40(6):400-403.
[54]Deguchi M,Matsumoto Y,Ishiko O,et al.Angiogenesis in ovarian clear cell carcinoma and its relation to endometriosis[J].Oncol Rep,2000,7(3):651.
[1]Daftary GS,Taylor HS.Implantation in the human:the role of HOX genes [J].Semin Reprod Med,2000,18(3):311-320.
[2]Zao Y,Potter SS.Functional comparison of the HOX a4,HOX a10 and HOX all homeoboxes[J].Dev Biol,2002,244(1):21-36.
[3]Patricia KD,Trent C,Jose T,et al.Enhanced purification and production of M(u|¨)llerian inhibiting substance for therapeutic applications[J].Mol Cellular Endocrin,2003,211:37-41.
[4]William WB,Gall VB,Liang M,et al.Characterization of Hoxa-10/Hoxa-11 Transheterozygotes Reveals Functional Redundancy and Regulatory Interactions[J].Dev Biol,2000,224:373-387.
[5]Svingen, T, Author Svingen T, et al. Hox transcription factors and their elusive mammalian gene targets[J]. Heredity, 2006,97(2): 88-96.
[6] Agnes B, Thomas M, Daniel G, et al. Role of HOXA7 to H0XA13 and PBX1 genes in various forms of MRKH syndrome (congenital absence of uterus and vagina)[J]. Negative Results in Bio Medicine, 2006, 5(4):1-6.
[7] Browne, H, Taylor, H. HOXA10 expression in ectopic endometrial tissue [J]. Endometriosis, 2006, 85(5):1386-1390.
[8] Martin R, Taylor MB, Krikun G, et al. Differential cell-specific modulation of H0XA10 by estrogen and specificity protein 1 response elements[J]. Clin Endocrinol Metab, 2007, 92(5):1920-1926.
[9] Smith, CC, Caroline C. , Taylor, HS, et al. Xenoestrogen exposure imprints expression of genes (HoxalO) required for normal uterine development [J]. Faseb, 2007, 21(1): 239-246.
[10] Akbas GE, Song J, Taylor HS. A H0XA10 estrogen response element (ERE) is differentially regulated by 17-estradiol and diethylstilbestrol (DES)[J]. Mol Biol, 2004, 340(5): 1013-1023.
[11] Suzuki A, Urushitani H, Sato T, et al. Gene expression change in the Mullerian duct of the mouse fetus exposed to diethylstilbestrol in utero. Exp Biol Med, 2007, 232(4):503-514.
[12] Coss D, Thackray VG, Deng CX, et al. Activin regulates luteinizing hormone beta-subunit gene expression through Smad-binding and homeobox elements[J]. Mol Endocrinol, 2005, 19(10):2610-2623.
[13] Yao, MW, Lim, HJ, Schust, DJ, et al. Gene expression profiling reveals progesterone-mediated cell cycle and immunoregulatory roles of Hoxa-10 in the preimplantation uterus[J], Mol Endrcrinol, 2003, 17 (4) :610-627.
[14] Cermik D, Karaca M, Taylor HS. H0XA10 expression is repressed by progesterone in the myometrium: differential tissue-specific regulation of HOX gene expression in the reproductive tract[J]. Clin Endocrinol Metab, 2001,86(7):3387-3392.
[15] Sirbu IO, Gresh L, Barra J, et al. Shifting boundaries of retinoic acid activity control hindbrain segmental gene expression[J].Development, 2005, 132(11):2611-2622.
[16] Cattrall FR, Vollenhoven BJ, Weston GC, et al. Anatomical evidence for in utero androgen exposure in women with polycystic ovary syndrome [J]. Fertil Steril, 2005,84(6):1689-1692.
[17] Cermik D, Selam B, Taylor HS. Regulation of HOXA-10 expression by testosterone in vitro and in the endometrium of patients with polycystic ovary syndrome[J]. Clin Endocrinol Metab, 2003,88(1):238-243.
[18] Jakubowicz DJ, Iuorno MJ, Jakubowicz S, et al. Effects of metformin on early pregnancy loss in the polycystic ovary syndrome[J]. Clin Endocrinol Metab, 2002,87(2):524-529.
[19] Du H, Daftary GS, Lalwani SI, et al. Direct regulation of HOXAIO by 1,25-(OH)_2D_3 in human myelomonocytic cells and human endometrial stromal cells[J]. Mol Endocrinol, 2005, 19(9):2222-2223.
[1]Auersperg N,Wong AS,Choi KC,et al.Ovarian surface epithelium:biology,endocrinology,and pathology[J].Endocr Rev,2001,22(2):255-288
[2]Daftary GS,Taylor HS.Implantation in the human:the role of HOX genes [J].Semin Reprod Med,2000,18(3):311-320.
[3]Zao Y,Potter SS.Functional comparison of the HOX a4,HOX a10 and HOX all homeoboxes[J]. Dev Biol, 2002, 244(1):21-36.
[4] Patricia KD, Trent C, Jose T, et al. Enhanced purification and production of MUllerian inhibiting substance for therapeutic applications[J]. Molecular and Cellular Endocrinology, 2003,211:37-41.
[5] William WB, Gail VB, Liang M, et al. Characterization of Hoxa-10/Hoxa-l1 Transheterozygotes Reveals Functional Redundancy and Regulatory Interactions[J]. Dev Biol, 2000,224:373-387.
[6] Svingen, T, Author Svingen T, et al. Hox transcription factors and their elusive mammalian gene targets[J]. Heredity, 2006,97(2):88-96.
[7] Yamashita T, Tazawa S , Yokohama Y, et al. Suppression of invasive characteristics by antisense introduction of overexpressed HOX genes in ovarian cancer cells[J]. Int J Oncol. 2006,28(4):931-938.
[8] Logani S, Oliva E, Arnell PM, et al. Use of novel immunohisto chemical markers exp ressed in colonic adenocarcinoma to distinguish primary ovarian tumors from metastatic colorectal carcinoma[J]. Mod Pathol,2005, 18(1): 19-25.
[9] Cheng WJ, Liu JS, Yoshida H, et al. Lineage infidelity of epithelial ovarian cancers is controlled by HOX genes that specify regional indentity in the reproductive tract[J]. Nat Med, 2005,11(5): 531-537.
[10] Fraggetta F, Pelosi G, Cafici A. CDX2 immunoreactivity in primary and metastatic ovarian mucinous tumours [J]. Virchows Arch, 2003, 443(6): 782-786.
[11] Dinulescu, D. M. et al. Role of K-ras and Pten in the development of mouse models of endometriosis and endometrioid ovarian cancer[J]. Nat.Med, 2005(11): 63-70.
[12] Ota T, Choi KB, Auersperg N, et al. Cell type- and stage-specific changes in HOXA7 protein expression in human ovarian folliculogenesis: possible role of GDF-9[J]. Differentiation. 2006, 74(1):1-10.
[13] Hennessy B.T., Mills G. B. Ovarian cancer: Homeobox genes, autocrine/paracrine growth,and kinase signaling[J].Elsevier,2006.
[14]Abate-Shen C,Deregulated homeohox gene expression in cancer.Cause or con sequence?[J].Nat Rev Cancer,2002,2(0):777-85.
[2] Nishida M, Watanbe K, Sato N, et al. Malignant transformation of ovarian endometriosis[J]. Gynecol Obstet Invest, 2000,50[Suppl 1] :18-25.
[3] Shimizu M, Ninaido T, Toki T, et al. Clear cell carcinoma has an expression pattem of cell cycle regulatory molecules that is unique among ovarian adenocarcinomas[J]. Cancer, 1999,85(3):699.
[4] Swiersz LM. Role of endometriosis in cancer and tumor development[J].Ann N Y Acad Sci, 2002,955:281-292.
[5] Zanetta GM, Webb MJ, Li H, et al. Hyperestrogenism: a relevant risk factor for the development of cancer from endometriosis [J]. Gynecol Oncol,2000, 79(1): 18-22.
[6] Zao Y, Potter SS. Functional comparison of the HOX a4, HOX alO and HOX all homeoboxes [J]. Dev Biol, 2002,244(1):21-36.
[7] Cheng W, Liu J, Yoshida H, et al. Lineage infidelity of epithelial ovarian cancers is controlled by HOX genes that specify regional identity in the reproductive tract[J]. Nat Med, 2005, 11(5):531-537.
[8] LaneDB, Rutherford TJ, Taylor HS. HOXA10 expression in endometrial adenocarcinoma[J]. Tumour Biol, 2004, 25(5-6):264-269.
[9] Sugiyama T, Kamura T, Kigawa J, et al. Clinical characteristics of clear cell carcinoma of the ovary: a distinct histologic type with poor prognosis and resistance to platinum-based chemotherapy[J]. Cancer, 2000,88(11): 2584-2589.
[10] Sekizawa A, Amemiya S, Otsuka J. Malignant transformation of endometriosis: application of laser microdissection for analysis of genetic alterations according to pathological changes[J]. Med Electron Microsc, 2004,37(2):97-100.
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[18] Deguchi M, MatsumotoY, IshikoO, et al. Angiogenesis in ovarian clear cell carcinoma and its relation to endometriosis[J]. Oncol Rep, 2000,7(3) :651.
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[20] Vider BZ , Zimber A , Chastre E , et al . Deregulated expression of homeobox-containing genes , H0XB6 , B8 , C8 , C9 , and Cdx21, in human colon cancer cell l.ines[J] .Biochem Biophys Res Commun, 2000,272(2):513-518.
[21] Bodey B , Bodey BJ , Siegel SE , et al . Immunocytochemical detection of the homeobox B3 , B4 , and C6 gene products in childhood edulloblastomas/primitive neuroectodermal tumors[J]. Anticancer Res,2000, 20(3A):1769-1780.
[22] Alami Y, Castronovo V , Belotti D , et al . HOXC5 and H0XC8 expression are selectively turned on in human cervical cancer cells compared to normal keratinocytes[J]. Biochem Biophys Res Commun, 1999,257(3): 738-745.
[23] Daftary GS, Taylor HS. Implantation in the human:the role of HOX genes [J]. Semin Reprod Med, 2000,18(3):311-320.
[24] Zao Y, Potter SS. Functional comparison of the HOX a4, HOX alO and HOX all homeoboxes[J]. Dev Biol, 2002, 244(1):21-36.
[25] Patricia KD, Trent C, Jose T, et al. Enhanced purification and production of M(?)llerian inhibiting substance for therapeutic applications[J]. Mol and Cellular Endocrin, 2003,211:37-41.
[26] William WB, Gail VB, Liang M, et al. Characterization of Hoxa-10/Hoxa-11 Transheterozygotes Reveals Functional Redundancy and Regulatory Interactions[J]. Dev Biol, 2000,224:373-387.
[27] Naora H. Lineage infidelity of epithelial ovarian cancers is controlled by HOX genes that specify regional identity in the reproductive tract[J]. Nat Med, 2005,11:531-537.
[28] Russell Broaddus, Wenjun Cheng, Honami Naora, et al. Deregulation of the HOXA10 Homeobox Gene in Endometrial Carcinoma: Role in Epithelial-Mesenchymal Transition[J]. Cancer Res 2006,66:(2):889-897.
[29] Ogawa S, Kaku T, Amada S, et al. Ovarian endometriosis associated with ovarin carcinoma:a clinicopathological and immunohistochemical study[J].Gynecol Oncol,2000,77:298-304.
[30]Fujimura M,Hidaka T,Kataoka K,et al.Absence of estrogen receptor-α expression in human ovarian clear cell adenocarcinoma compared with ovarian serous,endometrioid,and mucinous adenocarcinoma[J].Am J Surg Pathol,2001,25:667-672.
[31]Schaner ME,Ross DT,Ciaravino G,et al.Gene expression patterns in ovarian carcinomas[J].Mol Biol Cell,2003,14:4376-4386.
[32]Akahane T,Sekizawa A,Okuda T,et al.Disappearance of steroid hormone dependency during malignant transformation of ovarian clear cell cancer[J].Int J Gynecol Pathol,2005,24:369-376.
[33]Kopfstein L,Christofori G.Metastasis:cell-autonomous mechanisms versus contributions by the tumor microenvironment[J].Cell Mol Life Sci 2006,63(4):449-468.
[34]Ludwig T.Local proteolytic activity in tumor cell invasion and metastasis[J].Bioessays,2005,27(11):1181-1191.
[35]Rosette C,Roth RB,Oeth P,et al.Role of ICAM1 in invasion of human breast cancer cells[J].Carcinogenesis,2005,Epub.
[36]Seals DF,Azucena EF Jr,Pass I,et al.The adaptor protein Tks5/Fish is required for podosome formation and function,and for the protease-driven invasion of cancer cells[J].Cancer Cell,2005,7(2):155-165.
[37]Boire A,Covic L,Agarwal A,et al.PAR1 is a matrix metalloprotease-1receptor that promotes invasion and tumorigenesis of breast cancer cells [J].Cell,2005,120(3):303-313.
[38]高进,章静波.癌的侵袭与转移 基础与临床[M].北京:科学出版社,2002:94.
[39]Cillo C,Cantile M,Mortarini R,et al.Differential patterns of HOX gene expression are associated with specific integrin and ICAM profiles in clonal populations isolated from a single human melanoma metastasis [J]. Int J Cancer, 1996, 66(5):692-697.
[40] Sarrio D,MORENO-Bueno G, Sanchez-Estevez C, et al. Expression of cadherins and catenins correlates with distinct histologic types of ovarian carcinomas[J]. Hum Pathol, 2006, 37(8):1042-1049.
[41] Voutilainen KA, Anttila MA, Sillanpaa SM,et al. Prognostic significance of E-cadherin-catenin complex in epithelial ovarian cancer[J]. Clin Pathol, 2006, 59(5):460-467.
[42] Birchmeier W, Behens J. Cadherin expression in carcinomas: role in the formation of cell junctions and the prevention of invasiveness[J].Biochim Biophys Acta, 1994,1198:11-26.
[43] Perl AK, Wilgenbus P, Dahl U, et al. A causal role for E-cadherin in the transition from adenomatocarcinoma[J]. Nature, 1998,3(92): 190-193.
[44] Frixen UH. E-cadherin-mediated cell-cell adhesion prevents invasiveness of human carcinoma cell [J]. Cell Biol, 1991:173-185.
[45] V leminckx K, Vakaet LJ, Mareel M , et al. Genetic manipulation of E-cadherin expression by epithelial. Tumor cell reveals an invasion suppressor role[J]. Cell, 1991,66:107-119.
[46] Miyaki M. Increased cell-substratum adhesion, and decreased secretion and cell growth, induced by E-cadherin transfection of human colon carcinoma cells[J]. Oncogene, 1995,11:2547-2552.
[47] Lorens A. Downregulation of E-cadherin in mouse skin carcinoma cells enhances a migratory and invasive phenotype 1 inked to matrix metal loproteinase-9 gelatinase expression[J]. Lab Invest, 1998, 78:1-12.
[48] Fraggetta F, Pelosi G, Cafici A. CDX2 immunoreactivity in primary and metastatic ovarian mucinous tumours[J]. Virchows Arch, 2003,443(6): 782-786.
[49] Dinulescu, D. M. et al. Role of K-ras and Pten in the development of mouse models of endometriosis and endometrioid ovarian cancer[J]. Nat.Med, 2005(11): 63-70.
[50]Hennessy B.T.,Mills G.B.Ovarian cancer:Homeobox genes,autocrine/paracrine growth,and kinase signaling[J].Elsevier,2006.
[51]Abate-Shen C,Deregulated homeobox gene expression in cancer.Cause or con sequence?[J].Nat Rev Cancer,2002,2(10):777-85.
[52]赵宇清,丰有吉.HOXB7对卵巢透明细胞癌ES-2细胞系侵袭的影响.复旦学报,2007,34(3):346-350.
[53]金鸿雁,丰有吉.反义Snail转录因子抑制卵巢癌转移的实验研究.中华妇产科杂志,2005,40(6):400-403.
[54]Deguchi M,Matsumoto Y,Ishiko O,et al.Angiogenesis in ovarian clear cell carcinoma and its relation to endometriosis[J].Oncol Rep,2000,7(3):651.
[1]Daftary GS,Taylor HS.Implantation in the human:the role of HOX genes [J].Semin Reprod Med,2000,18(3):311-320.
[2]Zao Y,Potter SS.Functional comparison of the HOX a4,HOX a10 and HOX all homeoboxes[J].Dev Biol,2002,244(1):21-36.
[3]Patricia KD,Trent C,Jose T,et al.Enhanced purification and production of M(u|¨)llerian inhibiting substance for therapeutic applications[J].Mol Cellular Endocrin,2003,211:37-41.
[4]William WB,Gall VB,Liang M,et al.Characterization of Hoxa-10/Hoxa-11 Transheterozygotes Reveals Functional Redundancy and Regulatory Interactions[J].Dev Biol,2000,224:373-387.
[5]Svingen, T, Author Svingen T, et al. Hox transcription factors and their elusive mammalian gene targets[J]. Heredity, 2006,97(2): 88-96.
[6] Agnes B, Thomas M, Daniel G, et al. Role of HOXA7 to H0XA13 and PBX1 genes in various forms of MRKH syndrome (congenital absence of uterus and vagina)[J]. Negative Results in Bio Medicine, 2006, 5(4):1-6.
[7] Browne, H, Taylor, H. HOXA10 expression in ectopic endometrial tissue [J]. Endometriosis, 2006, 85(5):1386-1390.
[8] Martin R, Taylor MB, Krikun G, et al. Differential cell-specific modulation of H0XA10 by estrogen and specificity protein 1 response elements[J]. Clin Endocrinol Metab, 2007, 92(5):1920-1926.
[9] Smith, CC, Caroline C. , Taylor, HS, et al. Xenoestrogen exposure imprints expression of genes (HoxalO) required for normal uterine development [J]. Faseb, 2007, 21(1): 239-246.
[10] Akbas GE, Song J, Taylor HS. A H0XA10 estrogen response element (ERE) is differentially regulated by 17-estradiol and diethylstilbestrol (DES)[J]. Mol Biol, 2004, 340(5): 1013-1023.
[11] Suzuki A, Urushitani H, Sato T, et al. Gene expression change in the Mullerian duct of the mouse fetus exposed to diethylstilbestrol in utero. Exp Biol Med, 2007, 232(4):503-514.
[12] Coss D, Thackray VG, Deng CX, et al. Activin regulates luteinizing hormone beta-subunit gene expression through Smad-binding and homeobox elements[J]. Mol Endocrinol, 2005, 19(10):2610-2623.
[13] Yao, MW, Lim, HJ, Schust, DJ, et al. Gene expression profiling reveals progesterone-mediated cell cycle and immunoregulatory roles of Hoxa-10 in the preimplantation uterus[J], Mol Endrcrinol, 2003, 17 (4) :610-627.
[14] Cermik D, Karaca M, Taylor HS. H0XA10 expression is repressed by progesterone in the myometrium: differential tissue-specific regulation of HOX gene expression in the reproductive tract[J]. Clin Endocrinol Metab, 2001,86(7):3387-3392.
[15] Sirbu IO, Gresh L, Barra J, et al. Shifting boundaries of retinoic acid activity control hindbrain segmental gene expression[J].Development, 2005, 132(11):2611-2622.
[16] Cattrall FR, Vollenhoven BJ, Weston GC, et al. Anatomical evidence for in utero androgen exposure in women with polycystic ovary syndrome [J]. Fertil Steril, 2005,84(6):1689-1692.
[17] Cermik D, Selam B, Taylor HS. Regulation of HOXA-10 expression by testosterone in vitro and in the endometrium of patients with polycystic ovary syndrome[J]. Clin Endocrinol Metab, 2003,88(1):238-243.
[18] Jakubowicz DJ, Iuorno MJ, Jakubowicz S, et al. Effects of metformin on early pregnancy loss in the polycystic ovary syndrome[J]. Clin Endocrinol Metab, 2002,87(2):524-529.
[19] Du H, Daftary GS, Lalwani SI, et al. Direct regulation of HOXAIO by 1,25-(OH)_2D_3 in human myelomonocytic cells and human endometrial stromal cells[J]. Mol Endocrinol, 2005, 19(9):2222-2223.
[1]Auersperg N,Wong AS,Choi KC,et al.Ovarian surface epithelium:biology,endocrinology,and pathology[J].Endocr Rev,2001,22(2):255-288
[2]Daftary GS,Taylor HS.Implantation in the human:the role of HOX genes [J].Semin Reprod Med,2000,18(3):311-320.
[3]Zao Y,Potter SS.Functional comparison of the HOX a4,HOX a10 and HOX all homeoboxes[J]. Dev Biol, 2002, 244(1):21-36.
[4] Patricia KD, Trent C, Jose T, et al. Enhanced purification and production of MUllerian inhibiting substance for therapeutic applications[J]. Molecular and Cellular Endocrinology, 2003,211:37-41.
[5] William WB, Gail VB, Liang M, et al. Characterization of Hoxa-10/Hoxa-l1 Transheterozygotes Reveals Functional Redundancy and Regulatory Interactions[J]. Dev Biol, 2000,224:373-387.
[6] Svingen, T, Author Svingen T, et al. Hox transcription factors and their elusive mammalian gene targets[J]. Heredity, 2006,97(2):88-96.
[7] Yamashita T, Tazawa S , Yokohama Y, et al. Suppression of invasive characteristics by antisense introduction of overexpressed HOX genes in ovarian cancer cells[J]. Int J Oncol. 2006,28(4):931-938.
[8] Logani S, Oliva E, Arnell PM, et al. Use of novel immunohisto chemical markers exp ressed in colonic adenocarcinoma to distinguish primary ovarian tumors from metastatic colorectal carcinoma[J]. Mod Pathol,2005, 18(1): 19-25.
[9] Cheng WJ, Liu JS, Yoshida H, et al. Lineage infidelity of epithelial ovarian cancers is controlled by HOX genes that specify regional indentity in the reproductive tract[J]. Nat Med, 2005,11(5): 531-537.
[10] Fraggetta F, Pelosi G, Cafici A. CDX2 immunoreactivity in primary and metastatic ovarian mucinous tumours [J]. Virchows Arch, 2003, 443(6): 782-786.
[11] Dinulescu, D. M. et al. Role of K-ras and Pten in the development of mouse models of endometriosis and endometrioid ovarian cancer[J]. Nat.Med, 2005(11): 63-70.
[12] Ota T, Choi KB, Auersperg N, et al. Cell type- and stage-specific changes in HOXA7 protein expression in human ovarian folliculogenesis: possible role of GDF-9[J]. Differentiation. 2006, 74(1):1-10.
[13] Hennessy B.T., Mills G. B. Ovarian cancer: Homeobox genes, autocrine/paracrine growth,and kinase signaling[J].Elsevier,2006.
[14]Abate-Shen C,Deregulated homeohox gene expression in cancer.Cause or con sequence?[J].Nat Rev Cancer,2002,2(0):777-85.