转录因子FOXC1在妇科肿瘤中的表达及临床意义
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摘要
目的转录因子是一类通过对靶基因表达的调控从而起到对机体的发育、分化、代谢等的关键性作用的蛋白质分子。转录因子家族Forkhead Box(FOX家族)是2000年由国际Forkhead/winged helix命名委员会正式统一命名的转录因子家族,其家族成员都可以通过特有DNA结构域结合DNA,近年来研究发现,其功能涉及细胞分化状态的维持、胚胎发育、细胞周期调控、糖类代谢、细胞凋亡等多个生物学过程,其基因突变与发育畸形、肿瘤发生相关。
转录因子FOXC1属FOX家族成员之一。研究发现,其基因突变与动物胚胎发育及人类阿克森费尔德·里格尔综合征(ARS)密切相关,阿克森费尔德·里格尔综合征属于常染色体遗传性发育异常,其临床表现分为视表现型及非视表现型,其中视表现型包括虹膜基质发育低下,小角膜发育低下,前房粘连,角膜混浊及青少年青光眼;非视表现型包括上颌骨发育低下,牙发育不全及脐周皮肤翻转异常。此外,FOXC1可能参与了几种人类生殖道肿瘤发生发展过程,如前列腺癌,子宫内膜癌及卵巢癌等。但迄今,FOXC1基因蛋白在妇科肿瘤组织中的表达及临床意义尚无实验研究报道。本实验研究通过检测FOXC1在浆液性卵巢癌细胞株SKOV-3与HO-8910,良性、交界性及恶性浆液性卵巢肿瘤组织,子宫内膜癌组织及宫颈癌组织中的表达情况,并回顾性研究FOXC1表达与3种恶性妇科肿瘤临床病理特征间的相关性,旨在探讨FOXC1与妇科肿瘤发生、发展间的关系,为进一步深入研究妇科肿瘤的发病机制提供理论依据。
方法体外培养人卵巢癌浆液性囊腺癌SKOV-3及HO-8910细胞株;收集2004年2月~2009年2月间于重庆医科大学附属第二医院病理科经手术切除后存档的石蜡组织标本,其中浆液性卵巢肿瘤(包括良性、交界性及恶性)80例、子宫颈癌54例、子宫内膜癌23例;另收集新鲜卵巢肿瘤标本7例,包括3例散发性浆液性卵巢囊腺癌,2例交界性浆液性囊腺瘤,2例浆液性囊腺瘤及正常卵巢,正常子宫内膜组织做对照,均来自重庆医科大学附属第二医院2008年12月~2009年2月间手术切除的标本。Western-blot及免疫组化法检测2种卵巢癌细胞株中FOXC1蛋白表达。原位杂交法检测卵巢肿瘤中FOXC1mRNA的表达及定位。RT-PCR检测卵巢肿瘤及正常卵巢,子宫内膜组织中FOXC1mRNA表达水平。采用免疫组织化学SP法对2种卵巢癌细胞株、浆液性卵巢肿瘤、宫颈癌、子宫内膜癌石蜡组织中的FOXC1蛋白进行检测;卵巢浆液性囊腺癌患者的血肿瘤相关抗原(CA125)水平均为接受手术前经化学发光法测定;χ2检验或Fisher精确概率法及相关性检验进行统计学分析。
结果⑴FOXC1表达:2株浆液性卵巢囊腺癌中FOXC1蛋白均有表达;FOXC1mRNA在正常卵巢组织及卵巢肿瘤组织中有表达。FOXC1蛋白在46(57.5%)例卵巢肿瘤组织,29(53.7 %)例子宫颈癌组织及FOXC1蛋白在20(87.0 %)例子宫内膜组织有表达。⑵卵巢浆液性囊腺瘤FOXC1蛋白表达阳性率为84%;交界性浆液性肿瘤中FOXC1蛋白表达阳性率为66.7%;浆液性囊腺癌中FOXC1蛋白表达阳性率为37.5%,明显低于浆液性囊腺瘤和交界性浆液性肿瘤组织(P<0.01),且与FIGO手术病理分期及血CA125测定值密切相关(P<0.05),但与年龄、组织学分级及腹水量间无关(P>0.05)。⑶FOXC1阳性表达与宫颈癌组织学分级相关(P<0.05),与宫颈癌的病理分型,FIGO临床分期,宫颈肌层浸润及盆腔淋巴结转移之间无关(P>0.05)。⑷FOXC1蛋白表达与子宫内膜癌病理类型,组织学分级,FIGO手术病理分期,肌层浸润深度,宫颈受累情况及附件受累,盆腔淋巴结转移之间均无关(P>0.05)。
结论⑴浆液性卵巢囊腺瘤及交界性浆液性卵巢囊腺瘤组织中FOXC1蛋白表达水平明显高于浆液性卵巢囊腺癌组织;而在浆液性卵巢囊腺癌中,高中分化囊腺癌的FOXC1蛋白表达水平亦有高于低分化浆液性卵巢囊腺癌的趋势,组织分化程度越低,阳性表达率越低;浆液性囊腺癌中FOXC1蛋白表达阳性率与FIGO手术病理分期呈明显相关及与血CA125测定值水平相关;提示FOXC1蛋白表达可能与卵巢肿瘤细胞的生物学行为有关,并参与了浆液性卵巢癌的发生发展过程。⑵FOXC1阳性表达与宫颈癌的组织学分级相关,FOXC1蛋白可能参与了子宫颈癌的发生及发展过程,提示FOXC1表达降低,是子宫颈癌恶性程度增高的表现。⑶FOXC1可能未参与子宫内膜癌的发生发展过程。
Objective Transcription factors are a group of modular proteins which are involved in a wide variety of biological processes of development, differentiation and metabolism through regulating their target genes. The conserved members of forkhead box(FOX)/winged-helix transcription factor family, whose nomenclature were revised in 2000, have the same basic design in their interaction with DNA through specific DNA-binding forkhead domain. In recent years the function of FOX genes has become better understood in controlling processes, including regulation of maintenance of differentiated cell states, embryogenesis, cell cycle, glycometabolism and cell apoptosis. In addition to their vital roles in normal development processes, a number of mutant FOX genes also participate in development malformation and tumorigenesis.
Transcription factor FOXC1 is a member of FOX family. Studies on animal models have demonstrated the importance of FOXC1 as a developmentally key transcription factor. Mutations of FOXC1 gene in human result in various glaucoma-related phenotypes, e.g. Axenfeld-Rieger syndrome (ARS) is an autosomal dominantly inherited developmental disorder in which patients present with ocular and non-ocular clinical findings. Ocular characteristics include hypoplasia of the anterior iris stroma, microcornea, anterior chamber synechiae, corneal opacity, and juvenile onset glaucoma. Nonocular features typically include maxillary hypoplasia, hypodontia, and failure of involution of the periumbilical skin. Previous study also revealed FOXC1 might be involved in several types of genital tumorigenesis, such as human prostate, endometrial and ovarian cancers.
However, it was unclear whether FOXC1 protein exists in gynecological tumor tissues. In addition, its clinical significance of FOXC1 protein in gynecological tumor remains poorly understood. This study was designed to clarify the problem and explore the association of FOXC1 protein expression with clinicopathologic factors and outcome of the diseases.
Methods Two human serous ovarian cystadenocarcinoma cell lines, SKOV-3 and HO-8910 cells were cultured in vitro. Eighty cases of serous ovarian tumor (including 25 ovarian cystoadenoma, 15 ovarian borderline serous cystoadenoma and 40 serous ovarian cystadenocarcinoma), 54 cervical cancer and 23 endometrial cancer, all paraffin embeded, were retrieved from case files in Department of Pathology of 2nd Affiliated Hospital of Chongqing Medical University between February, 2004 and February, 2009. Seven cases of serous ovarian tumor(including 2 ovarian cystoadenoma, 2 borderline ovarian cystoadenoma, and 3 serous ovarian cystadenocarcinoma), normal ovarian tissues and normal endometrial tissue as positive control, were recruited from gynecological operations of 2nd Affiliated Hospital of Chongqing Medical University between December, 2008 and February, 2009. Western-blot and immunohistochemistry were employed to dectect FOXC1 protein level in 2 ovarian cancer cell lines. In situ hybridization and RT-PCR were used to measure FOXC1 mRNA level in normal endometrium,normal ovarian tissue and ovarian tumors. Immunohistochemistry were employed to determine FOXC1 protein level in paraffin-bedded tumor tissues, including ovarian tumor, cervical cancer and endometrial cancer tissues. The relationships between FOXC1 protein expression of paraffin-bedded tumor tissues and clinicopathologic parameters were examined by Chi-square test or Fisher’s Exact Test and correlation test.
Results⑴FOXC1 mRNA expression was confirmed in normal endometrium and ovarian tumor tissues. FOXC1 protein was revealed in 2 ovarian cancer cell lines, 46(57.5%)cases of ovarian tumor, 29(53.7 %)cervical cancer and 20(87.0 %)endometrial cancer.⑵Positive reactivity was found in 21 (84%) cases of serous ovarian cystoadenoma, in 10 (66.7%) serous ovarian borderline cystoadenoma, and in 15 (37.5%) serous ovarian cystadenocarcinoma. Chi-square test showed a significant correlation between positive FOXC1 immunoreactivity and pathological subtypes of serous ovarian tumor (P<0.01) and FOXC1 protein levels significantly decreased with advancing FIGO stages (Ⅰ~ⅡvsⅢ~Ⅳ) and serum CA125 levels(P<0.05). No significant association was shown between FOXC1 protein expression and clinicopathological factors including age, histological grade and volumes of ascites (P>0.05).⑶Significant correlation in retrospective study was observed between FOXC1 protein expression and histological grades (P<0.05) in cervical cancer. No significant association was shown between FOXC1 protein expression in cervical cancer and clinicopathological factors including pathological types, FIGO stages, lymph node metastasis and etc.⑷No significant association was shown between FOXC1 protein expression in endometrial cancer and clinicopathological factors including pathological types, histological grades, FIGO stages, myometrial invasion and involvement of cervix and adnexa, and lymph node metastasis (P>0.05).
Conclusion⑴Expression levels of FOXC1 protein in paraffin-bedded tissues of serous ovarian cystoadenoma and serous ovarian borderline cystoadenoma were revealed to be significantly higher than in serous ovarian cystadenocarcinoma. There was also a decreasing trend of FOXC1 protein expression with increased histological grades. Positive FOXC1 expression in serous ovarian cystadenocarcinoma was found correlated with FIGO stages, while there was a significantly correlation between FOXC1 expression and serum CA125 levels. Loss of FOXC1 expression may be an early event in serous ovarian tumorigenesis.⑵FOXC1 expression in cervical cancer was revealed correlated with histological grades. Loss of FOXC1 expression may play an important role in genesis and development of cervical cancer.⑶FOXC1 expression may not play a role in genesis and development of endometrial cancer.
转录因子FOXC1属FOX家族成员之一。研究发现,其基因突变与动物胚胎发育及人类阿克森费尔德·里格尔综合征(ARS)密切相关,阿克森费尔德·里格尔综合征属于常染色体遗传性发育异常,其临床表现分为视表现型及非视表现型,其中视表现型包括虹膜基质发育低下,小角膜发育低下,前房粘连,角膜混浊及青少年青光眼;非视表现型包括上颌骨发育低下,牙发育不全及脐周皮肤翻转异常。此外,FOXC1可能参与了几种人类生殖道肿瘤发生发展过程,如前列腺癌,子宫内膜癌及卵巢癌等。但迄今,FOXC1基因蛋白在妇科肿瘤组织中的表达及临床意义尚无实验研究报道。本实验研究通过检测FOXC1在浆液性卵巢癌细胞株SKOV-3与HO-8910,良性、交界性及恶性浆液性卵巢肿瘤组织,子宫内膜癌组织及宫颈癌组织中的表达情况,并回顾性研究FOXC1表达与3种恶性妇科肿瘤临床病理特征间的相关性,旨在探讨FOXC1与妇科肿瘤发生、发展间的关系,为进一步深入研究妇科肿瘤的发病机制提供理论依据。
方法体外培养人卵巢癌浆液性囊腺癌SKOV-3及HO-8910细胞株;收集2004年2月~2009年2月间于重庆医科大学附属第二医院病理科经手术切除后存档的石蜡组织标本,其中浆液性卵巢肿瘤(包括良性、交界性及恶性)80例、子宫颈癌54例、子宫内膜癌23例;另收集新鲜卵巢肿瘤标本7例,包括3例散发性浆液性卵巢囊腺癌,2例交界性浆液性囊腺瘤,2例浆液性囊腺瘤及正常卵巢,正常子宫内膜组织做对照,均来自重庆医科大学附属第二医院2008年12月~2009年2月间手术切除的标本。Western-blot及免疫组化法检测2种卵巢癌细胞株中FOXC1蛋白表达。原位杂交法检测卵巢肿瘤中FOXC1mRNA的表达及定位。RT-PCR检测卵巢肿瘤及正常卵巢,子宫内膜组织中FOXC1mRNA表达水平。采用免疫组织化学SP法对2种卵巢癌细胞株、浆液性卵巢肿瘤、宫颈癌、子宫内膜癌石蜡组织中的FOXC1蛋白进行检测;卵巢浆液性囊腺癌患者的血肿瘤相关抗原(CA125)水平均为接受手术前经化学发光法测定;χ2检验或Fisher精确概率法及相关性检验进行统计学分析。
结果⑴FOXC1表达:2株浆液性卵巢囊腺癌中FOXC1蛋白均有表达;FOXC1mRNA在正常卵巢组织及卵巢肿瘤组织中有表达。FOXC1蛋白在46(57.5%)例卵巢肿瘤组织,29(53.7 %)例子宫颈癌组织及FOXC1蛋白在20(87.0 %)例子宫内膜组织有表达。⑵卵巢浆液性囊腺瘤FOXC1蛋白表达阳性率为84%;交界性浆液性肿瘤中FOXC1蛋白表达阳性率为66.7%;浆液性囊腺癌中FOXC1蛋白表达阳性率为37.5%,明显低于浆液性囊腺瘤和交界性浆液性肿瘤组织(P<0.01),且与FIGO手术病理分期及血CA125测定值密切相关(P<0.05),但与年龄、组织学分级及腹水量间无关(P>0.05)。⑶FOXC1阳性表达与宫颈癌组织学分级相关(P<0.05),与宫颈癌的病理分型,FIGO临床分期,宫颈肌层浸润及盆腔淋巴结转移之间无关(P>0.05)。⑷FOXC1蛋白表达与子宫内膜癌病理类型,组织学分级,FIGO手术病理分期,肌层浸润深度,宫颈受累情况及附件受累,盆腔淋巴结转移之间均无关(P>0.05)。
结论⑴浆液性卵巢囊腺瘤及交界性浆液性卵巢囊腺瘤组织中FOXC1蛋白表达水平明显高于浆液性卵巢囊腺癌组织;而在浆液性卵巢囊腺癌中,高中分化囊腺癌的FOXC1蛋白表达水平亦有高于低分化浆液性卵巢囊腺癌的趋势,组织分化程度越低,阳性表达率越低;浆液性囊腺癌中FOXC1蛋白表达阳性率与FIGO手术病理分期呈明显相关及与血CA125测定值水平相关;提示FOXC1蛋白表达可能与卵巢肿瘤细胞的生物学行为有关,并参与了浆液性卵巢癌的发生发展过程。⑵FOXC1阳性表达与宫颈癌的组织学分级相关,FOXC1蛋白可能参与了子宫颈癌的发生及发展过程,提示FOXC1表达降低,是子宫颈癌恶性程度增高的表现。⑶FOXC1可能未参与子宫内膜癌的发生发展过程。
Objective Transcription factors are a group of modular proteins which are involved in a wide variety of biological processes of development, differentiation and metabolism through regulating their target genes. The conserved members of forkhead box(FOX)/winged-helix transcription factor family, whose nomenclature were revised in 2000, have the same basic design in their interaction with DNA through specific DNA-binding forkhead domain. In recent years the function of FOX genes has become better understood in controlling processes, including regulation of maintenance of differentiated cell states, embryogenesis, cell cycle, glycometabolism and cell apoptosis. In addition to their vital roles in normal development processes, a number of mutant FOX genes also participate in development malformation and tumorigenesis.
Transcription factor FOXC1 is a member of FOX family. Studies on animal models have demonstrated the importance of FOXC1 as a developmentally key transcription factor. Mutations of FOXC1 gene in human result in various glaucoma-related phenotypes, e.g. Axenfeld-Rieger syndrome (ARS) is an autosomal dominantly inherited developmental disorder in which patients present with ocular and non-ocular clinical findings. Ocular characteristics include hypoplasia of the anterior iris stroma, microcornea, anterior chamber synechiae, corneal opacity, and juvenile onset glaucoma. Nonocular features typically include maxillary hypoplasia, hypodontia, and failure of involution of the periumbilical skin. Previous study also revealed FOXC1 might be involved in several types of genital tumorigenesis, such as human prostate, endometrial and ovarian cancers.
However, it was unclear whether FOXC1 protein exists in gynecological tumor tissues. In addition, its clinical significance of FOXC1 protein in gynecological tumor remains poorly understood. This study was designed to clarify the problem and explore the association of FOXC1 protein expression with clinicopathologic factors and outcome of the diseases.
Methods Two human serous ovarian cystadenocarcinoma cell lines, SKOV-3 and HO-8910 cells were cultured in vitro. Eighty cases of serous ovarian tumor (including 25 ovarian cystoadenoma, 15 ovarian borderline serous cystoadenoma and 40 serous ovarian cystadenocarcinoma), 54 cervical cancer and 23 endometrial cancer, all paraffin embeded, were retrieved from case files in Department of Pathology of 2nd Affiliated Hospital of Chongqing Medical University between February, 2004 and February, 2009. Seven cases of serous ovarian tumor(including 2 ovarian cystoadenoma, 2 borderline ovarian cystoadenoma, and 3 serous ovarian cystadenocarcinoma), normal ovarian tissues and normal endometrial tissue as positive control, were recruited from gynecological operations of 2nd Affiliated Hospital of Chongqing Medical University between December, 2008 and February, 2009. Western-blot and immunohistochemistry were employed to dectect FOXC1 protein level in 2 ovarian cancer cell lines. In situ hybridization and RT-PCR were used to measure FOXC1 mRNA level in normal endometrium,normal ovarian tissue and ovarian tumors. Immunohistochemistry were employed to determine FOXC1 protein level in paraffin-bedded tumor tissues, including ovarian tumor, cervical cancer and endometrial cancer tissues. The relationships between FOXC1 protein expression of paraffin-bedded tumor tissues and clinicopathologic parameters were examined by Chi-square test or Fisher’s Exact Test and correlation test.
Results⑴FOXC1 mRNA expression was confirmed in normal endometrium and ovarian tumor tissues. FOXC1 protein was revealed in 2 ovarian cancer cell lines, 46(57.5%)cases of ovarian tumor, 29(53.7 %)cervical cancer and 20(87.0 %)endometrial cancer.⑵Positive reactivity was found in 21 (84%) cases of serous ovarian cystoadenoma, in 10 (66.7%) serous ovarian borderline cystoadenoma, and in 15 (37.5%) serous ovarian cystadenocarcinoma. Chi-square test showed a significant correlation between positive FOXC1 immunoreactivity and pathological subtypes of serous ovarian tumor (P<0.01) and FOXC1 protein levels significantly decreased with advancing FIGO stages (Ⅰ~ⅡvsⅢ~Ⅳ) and serum CA125 levels(P<0.05). No significant association was shown between FOXC1 protein expression and clinicopathological factors including age, histological grade and volumes of ascites (P>0.05).⑶Significant correlation in retrospective study was observed between FOXC1 protein expression and histological grades (P<0.05) in cervical cancer. No significant association was shown between FOXC1 protein expression in cervical cancer and clinicopathological factors including pathological types, FIGO stages, lymph node metastasis and etc.⑷No significant association was shown between FOXC1 protein expression in endometrial cancer and clinicopathological factors including pathological types, histological grades, FIGO stages, myometrial invasion and involvement of cervix and adnexa, and lymph node metastasis (P>0.05).
Conclusion⑴Expression levels of FOXC1 protein in paraffin-bedded tissues of serous ovarian cystoadenoma and serous ovarian borderline cystoadenoma were revealed to be significantly higher than in serous ovarian cystadenocarcinoma. There was also a decreasing trend of FOXC1 protein expression with increased histological grades. Positive FOXC1 expression in serous ovarian cystadenocarcinoma was found correlated with FIGO stages, while there was a significantly correlation between FOXC1 expression and serum CA125 levels. Loss of FOXC1 expression may be an early event in serous ovarian tumorigenesis.⑵FOXC1 expression in cervical cancer was revealed correlated with histological grades. Loss of FOXC1 expression may play an important role in genesis and development of cervical cancer.⑶FOXC1 expression may not play a role in genesis and development of endometrial cancer.
引文
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