CD40分子在人宫颈癌组织中表达的临床意义及CD40信号对宫颈癌细胞株SiHa体外的生物学效应
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摘要
子宫颈癌是常见的妇科恶性肿瘤,发病率在女性恶性肿瘤中居第二位,仅次于乳腺癌。近几年国内外报道宫颈癌的发病率和病死率有年轻化的倾向,35岁以下的妇女宫颈癌发病率明显上升。因此对宫颈癌病因、发病机制的研究,以及寻求更敏感的宫颈癌早期诊断、更有效的治疗方法成为非常必要。
CD40是分子量48KD的细胞表面分子,表达于许多类型细胞中,包括B细胞、树突状细胞、单核细胞、内皮细胞以及一系列肿瘤细胞。CD40属于肿瘤坏死因子受体(TNFR)超家族成员。CD40分子的配体CD40L主要表达于活化的CD4+T辅助(Th)细胞。CD40L/CD40相互作用是特异性免疫应答及其过程中主要的协同刺激信号。大量研究表明,CD40分子可以介导B细胞的增殖、分化、抗体分泌及其类型转换、树突状细胞的激发及分化成熟,内皮细胞粘附分子的改变,炎症因子的释放以及白细胞在炎症部位的聚集等。这表明CD40是免疫反应中的重要分子。
本研究主要探讨CD40及其相关分子在宫颈癌组织上的表达及其临床生物学意义;讨论宫颈癌细胞株SiHah表达CD40及其生物学影响;CD40对用于宫颈癌治疗的化疗药物敏感性的影响。期望寻找宫颈癌肿瘤个性化免疫治疗的新方案。
一、CD40及其相关分子在宫颈癌中的表达及生物学意义
目的:研究宫颈癌组织中CD40分子的表达、并探讨其与宫颈癌侵袭、淋巴结转移等生物学行为的相关性,分析HPV16/18 E6、p16INK4a、VEGF、CD34分子在宫颈癌组织中的表达及其与CD40表达的相关性。方法:采用免疫组织化学方法,对239例宫颈组织标本切片(包括正常子宫颈组织38例,慢性宫颈炎43例,宫颈上皮内瘤变CIN I级36例,CIN II级39例,CIN III级27例,宫颈鳞状上皮癌56例)检测CD40分子的表达;同时检测了HPV16/18 E6、p16INK4a、VEGF、CD34在宫颈组织中的表达。结果:CD40分子在正常宫颈组织、慢性宫颈炎组织和CIN I~II上不表达或弱表达,而CIN III和宫颈癌组织上表达明显增加,阳性率分别达55.55%和67.86%,差异有显著性(p<0.01)。CD40分子在宫颈癌中的表达与宫颈癌的FIGO临床分期(r=0.05, p>0.05)、病理分级(r=-0.12, p>0.05)无相关性,而与肿瘤肌层浸润深度(r=0.44, p<0.01)、有无淋巴转移(r=0.30, p<0.05)有明显的相关性。宫颈癌组织中HPV16/18 E6、p16INK4a、VEGF分子表达均较正常组织高(78.6%、80.36%、87.50%)。CD34 MVD在宫颈癌组织上表达为27.02±10.68,明显较其它各组增高(p<0.001)。HPV16/18-E6阳性表达的宫颈CIN II~III组织中,P16INK4a表达阳性者占90.47%,HPV16/18-E6阳性表达的宫颈癌组织中,P16INK4a表达阳性达97.72%,因此P16INK4a在宫颈CIN II~III及宫颈癌中的表达和HPV16/18-E6的阳性表达有明显的相关性(r=0.362,p<0.05;r=0. 837,p<0.01)。CD40分子的表达和P16INK4a的表达呈正相关(r=0.52,p<0.01);和HPV16/18-E6、VEGF以及CD34 MVD的表达亦有一定的正相关性(r=0.57,p<0.01; r=0.32,p<0.05;r=0.37,p<0.05)。结论:CD40可作为宫颈癌诊断、预后和淋巴结转移评估的客观指标。CD40分子表达与抑癌基因p16INK4a、HPV16/18-E6以及VEGF和CD34 MVD的表达有一定的正相关性,由此提示CD40分子在宫颈癌的发生、发展过程中可能起着非常重要的作用。
二、激发型CD40单抗对宫颈癌细胞株体外增殖和化学药物敏感性的作用
目的:研究CD40分子激发对宫颈癌细胞SiHa化疗敏感性的影响及其机制。
方法:采用流式细胞术检测宫颈癌细胞SiHa上CD40分子的表达,MTT法检测CD40单抗(5C11)联合化疗药物对SiHa细胞的作用,PI染色检测SiHa细胞周期的变化,Annexin V-PI法检测细胞凋亡、Real-time PCR方法分析单抗5C11作用SiHa细胞后凋亡基因表达水平变化。结果:宫颈癌SiHa细胞表面CD40表达率为96.0%,SiHa细胞经5C11作用后出现G2/M期阻滞,5C11和化疗药物盐酸吉西他滨(Gemcitabin)各自抑制细胞生长作用不明显,但两者联合能显著抑制SiHa的生长和促进凋亡。SiHa细胞在和5C11作用24小时后,抗调亡基因BCL-XL的表达明显下调,促调亡基因BAX的上调作用不明显。结论:CD40分子通过介导G2/M期阻滞和调节凋亡基因表达水平增加SiHa细胞对肿瘤化疗药物盐酸吉西他滨敏感性。
Invasive cervical carcinoma is one of the common malignant tumors in woman, ranking the 2nd place among all of female malignant carcinomas, only second to breast cancer. It was reported that incidence and mortality of cervical carcinoma trended to be younger in recent years. The incidence among women of less than 35 has been increasing. So it was important and necessary to investigate the disease etiologically and pathogenesis, in order to explore more sensitive was for diagnosis and more effective therapy of cervical carcinoma.
CD40, a 48KD cell membrane molecule, belongs to the tumor necrosis factor receptor(TNFR) superfamily. CD40 is expressed in many cell types including B cell, dendritic cells, monocytes, endothelial cell, epithelia cell and also many carcinoma cells. CD40 ligand is expressed mainly in activated CD4+T helper cell. Interaction by CD40L-CD40 is a main co-stimulatory signal during antigen-specific immune response and during immune regulation. To date, an increasing number of studies showed that signals mediated by CD40 could contribute to B cell proliferation, Ig secretion and class switching; dendritic cell activation and maturation; adhesion molecules expression on endothelial cell, inflammatory factor secretion, and the accumulation of white cells to the inflammatory sites. These indicated that CD40 is a very important molecule during immune response.
In this study, the expression of CD40 on human cervical carcinoma and their clinical significance were focused. The expression of CD40 on cervical carcinoma cell line SiHa and its biological effects were studied. Moreover we studied the effects of CD40 mAb on the chemosensitivity of human cervical tumor cell line SiHa to Gemcitabin. We hope to find a new method of tumor immunotherapy.
1. the expression and clinical significances of CD40 and related molecules in human cervical carcinoma
Objective: To study the expression of CD40 and associated molecules HPV16/18 E6, P16INK4a, VEGF and CD34 on different types of malignant cervical cancer, and to study their clinical significance. Methods: Surgical biopsy specimens were obtained from 239 patients (includes: 56 cases cervical squamous epithelium cancer, 36 cases of cervical intraepithelial neoplasia (CIN I), CIN II 39 cases of, CIN III 27 of, 43 cases of chronic cervical inflammation and 38 normal controls) . The expression of CD40 and associated molecules HPV, P16INK4a, VEGF and CD34 on different types of malignant cervical cancer were examined by immunohistochemistry. The relation of CD40 and associated molecules and clinical significance were analyzed. Results: The expression of CD40, HPV16/18 E6, P16INK4a, VEGF and CD34 on cervical cancer and CIN III have significant differences from the normal controls, and CIN I~II. The rates of CD40 positive cell in the 56 cases of cancer and in the 27 cases of CIN III were 55.55% and 67.86%, respectively (p<0.01). The positive expression rates of CD40, HPV16/18 E6, P16INK4a and VEGF were 78.6%, 80.36 and 87.50% respectively, and the CD34 MVD was 27.02±10.68. The positive expression rates of P16INK4a were 90.40% and 97.72% in CIN III and cervical cancer respectively. The expression of P16INK4a was significantly associated with HPV16/18 E6 in CIN III and cervical cancer (r=0.362 and r=0. 837, p<0.01 ). CD40 expression had a positive correlation with HPV16/18 E6 (r=0.57, p<0.01), P16INK4a(r=0.52, p<0.01), VEGF(r=0.32, p<0.05) and CD34 MVD(r=0.37, p<0.05). Further more, the expression of CD40 has a close correlation to lymph nodule metastasis(r=0.44, p<0.01) and invasive extent of muscular layer(r=0.30, p<0.05) in cervical cancer. Conclusion: These results suggested that CD40 might be a valuable factor for diagnosis and judgment of prognosis and lymphonudule metastasis in cervical cancer. These data also indicated that CD40 was an important molecule to tumor development.
2. the biological effects of CD40 ligation on human cervical squamous epithelium cancer cell line
Objective: To study the effect of CD40 mAb on the chemosensitivity of human cervical tumor cell line SiHa to Gemcitabin. Methods: Flow cytometric analysis was used to detected expression of CD40 in SiHa. Agonistic anti-human CD40 monoclonal antibody (5C11) was added to the cell culture system. PI staining and Annexin V-PI assay were used to study the biological effects of 5C11 on cervical tumor cell. Cell proliferation was analyzed by MTT assay after treatment with chemotherapeutic drugs. Expression of apoptotic genes mRNA was evaluated by quantitative RT-PCR. Results: The cervical tumor cell line SiHa highly expressed CD40. 5C11 or Gemcitabin could not effectively induced SiHa proliferation arrest, but combination of 5C11 and Gemcitabin could do. CD40 activation can induce arresting the cells at G2/M interphase and down-regulating anti-apoptotic genes BCL-XL expression and up-regulating apoptotic genes BAX expression weakly. Conclusion: CD40 activation could enhance chemosensitivity of human cervical tumor cell to Gemcitabin by inducing arresting the cells at G2/M phase and affecting apoptotic genes expression.
CD40是分子量48KD的细胞表面分子,表达于许多类型细胞中,包括B细胞、树突状细胞、单核细胞、内皮细胞以及一系列肿瘤细胞。CD40属于肿瘤坏死因子受体(TNFR)超家族成员。CD40分子的配体CD40L主要表达于活化的CD4+T辅助(Th)细胞。CD40L/CD40相互作用是特异性免疫应答及其过程中主要的协同刺激信号。大量研究表明,CD40分子可以介导B细胞的增殖、分化、抗体分泌及其类型转换、树突状细胞的激发及分化成熟,内皮细胞粘附分子的改变,炎症因子的释放以及白细胞在炎症部位的聚集等。这表明CD40是免疫反应中的重要分子。
本研究主要探讨CD40及其相关分子在宫颈癌组织上的表达及其临床生物学意义;讨论宫颈癌细胞株SiHah表达CD40及其生物学影响;CD40对用于宫颈癌治疗的化疗药物敏感性的影响。期望寻找宫颈癌肿瘤个性化免疫治疗的新方案。
一、CD40及其相关分子在宫颈癌中的表达及生物学意义
目的:研究宫颈癌组织中CD40分子的表达、并探讨其与宫颈癌侵袭、淋巴结转移等生物学行为的相关性,分析HPV16/18 E6、p16INK4a、VEGF、CD34分子在宫颈癌组织中的表达及其与CD40表达的相关性。方法:采用免疫组织化学方法,对239例宫颈组织标本切片(包括正常子宫颈组织38例,慢性宫颈炎43例,宫颈上皮内瘤变CIN I级36例,CIN II级39例,CIN III级27例,宫颈鳞状上皮癌56例)检测CD40分子的表达;同时检测了HPV16/18 E6、p16INK4a、VEGF、CD34在宫颈组织中的表达。结果:CD40分子在正常宫颈组织、慢性宫颈炎组织和CIN I~II上不表达或弱表达,而CIN III和宫颈癌组织上表达明显增加,阳性率分别达55.55%和67.86%,差异有显著性(p<0.01)。CD40分子在宫颈癌中的表达与宫颈癌的FIGO临床分期(r=0.05, p>0.05)、病理分级(r=-0.12, p>0.05)无相关性,而与肿瘤肌层浸润深度(r=0.44, p<0.01)、有无淋巴转移(r=0.30, p<0.05)有明显的相关性。宫颈癌组织中HPV16/18 E6、p16INK4a、VEGF分子表达均较正常组织高(78.6%、80.36%、87.50%)。CD34 MVD在宫颈癌组织上表达为27.02±10.68,明显较其它各组增高(p<0.001)。HPV16/18-E6阳性表达的宫颈CIN II~III组织中,P16INK4a表达阳性者占90.47%,HPV16/18-E6阳性表达的宫颈癌组织中,P16INK4a表达阳性达97.72%,因此P16INK4a在宫颈CIN II~III及宫颈癌中的表达和HPV16/18-E6的阳性表达有明显的相关性(r=0.362,p<0.05;r=0. 837,p<0.01)。CD40分子的表达和P16INK4a的表达呈正相关(r=0.52,p<0.01);和HPV16/18-E6、VEGF以及CD34 MVD的表达亦有一定的正相关性(r=0.57,p<0.01; r=0.32,p<0.05;r=0.37,p<0.05)。结论:CD40可作为宫颈癌诊断、预后和淋巴结转移评估的客观指标。CD40分子表达与抑癌基因p16INK4a、HPV16/18-E6以及VEGF和CD34 MVD的表达有一定的正相关性,由此提示CD40分子在宫颈癌的发生、发展过程中可能起着非常重要的作用。
二、激发型CD40单抗对宫颈癌细胞株体外增殖和化学药物敏感性的作用
目的:研究CD40分子激发对宫颈癌细胞SiHa化疗敏感性的影响及其机制。
方法:采用流式细胞术检测宫颈癌细胞SiHa上CD40分子的表达,MTT法检测CD40单抗(5C11)联合化疗药物对SiHa细胞的作用,PI染色检测SiHa细胞周期的变化,Annexin V-PI法检测细胞凋亡、Real-time PCR方法分析单抗5C11作用SiHa细胞后凋亡基因表达水平变化。结果:宫颈癌SiHa细胞表面CD40表达率为96.0%,SiHa细胞经5C11作用后出现G2/M期阻滞,5C11和化疗药物盐酸吉西他滨(Gemcitabin)各自抑制细胞生长作用不明显,但两者联合能显著抑制SiHa的生长和促进凋亡。SiHa细胞在和5C11作用24小时后,抗调亡基因BCL-XL的表达明显下调,促调亡基因BAX的上调作用不明显。结论:CD40分子通过介导G2/M期阻滞和调节凋亡基因表达水平增加SiHa细胞对肿瘤化疗药物盐酸吉西他滨敏感性。
Invasive cervical carcinoma is one of the common malignant tumors in woman, ranking the 2nd place among all of female malignant carcinomas, only second to breast cancer. It was reported that incidence and mortality of cervical carcinoma trended to be younger in recent years. The incidence among women of less than 35 has been increasing. So it was important and necessary to investigate the disease etiologically and pathogenesis, in order to explore more sensitive was for diagnosis and more effective therapy of cervical carcinoma.
CD40, a 48KD cell membrane molecule, belongs to the tumor necrosis factor receptor(TNFR) superfamily. CD40 is expressed in many cell types including B cell, dendritic cells, monocytes, endothelial cell, epithelia cell and also many carcinoma cells. CD40 ligand is expressed mainly in activated CD4+T helper cell. Interaction by CD40L-CD40 is a main co-stimulatory signal during antigen-specific immune response and during immune regulation. To date, an increasing number of studies showed that signals mediated by CD40 could contribute to B cell proliferation, Ig secretion and class switching; dendritic cell activation and maturation; adhesion molecules expression on endothelial cell, inflammatory factor secretion, and the accumulation of white cells to the inflammatory sites. These indicated that CD40 is a very important molecule during immune response.
In this study, the expression of CD40 on human cervical carcinoma and their clinical significance were focused. The expression of CD40 on cervical carcinoma cell line SiHa and its biological effects were studied. Moreover we studied the effects of CD40 mAb on the chemosensitivity of human cervical tumor cell line SiHa to Gemcitabin. We hope to find a new method of tumor immunotherapy.
1. the expression and clinical significances of CD40 and related molecules in human cervical carcinoma
Objective: To study the expression of CD40 and associated molecules HPV16/18 E6, P16INK4a, VEGF and CD34 on different types of malignant cervical cancer, and to study their clinical significance. Methods: Surgical biopsy specimens were obtained from 239 patients (includes: 56 cases cervical squamous epithelium cancer, 36 cases of cervical intraepithelial neoplasia (CIN I), CIN II 39 cases of, CIN III 27 of, 43 cases of chronic cervical inflammation and 38 normal controls) . The expression of CD40 and associated molecules HPV, P16INK4a, VEGF and CD34 on different types of malignant cervical cancer were examined by immunohistochemistry. The relation of CD40 and associated molecules and clinical significance were analyzed. Results: The expression of CD40, HPV16/18 E6, P16INK4a, VEGF and CD34 on cervical cancer and CIN III have significant differences from the normal controls, and CIN I~II. The rates of CD40 positive cell in the 56 cases of cancer and in the 27 cases of CIN III were 55.55% and 67.86%, respectively (p<0.01). The positive expression rates of CD40, HPV16/18 E6, P16INK4a and VEGF were 78.6%, 80.36 and 87.50% respectively, and the CD34 MVD was 27.02±10.68. The positive expression rates of P16INK4a were 90.40% and 97.72% in CIN III and cervical cancer respectively. The expression of P16INK4a was significantly associated with HPV16/18 E6 in CIN III and cervical cancer (r=0.362 and r=0. 837, p<0.01 ). CD40 expression had a positive correlation with HPV16/18 E6 (r=0.57, p<0.01), P16INK4a(r=0.52, p<0.01), VEGF(r=0.32, p<0.05) and CD34 MVD(r=0.37, p<0.05). Further more, the expression of CD40 has a close correlation to lymph nodule metastasis(r=0.44, p<0.01) and invasive extent of muscular layer(r=0.30, p<0.05) in cervical cancer. Conclusion: These results suggested that CD40 might be a valuable factor for diagnosis and judgment of prognosis and lymphonudule metastasis in cervical cancer. These data also indicated that CD40 was an important molecule to tumor development.
2. the biological effects of CD40 ligation on human cervical squamous epithelium cancer cell line
Objective: To study the effect of CD40 mAb on the chemosensitivity of human cervical tumor cell line SiHa to Gemcitabin. Methods: Flow cytometric analysis was used to detected expression of CD40 in SiHa. Agonistic anti-human CD40 monoclonal antibody (5C11) was added to the cell culture system. PI staining and Annexin V-PI assay were used to study the biological effects of 5C11 on cervical tumor cell. Cell proliferation was analyzed by MTT assay after treatment with chemotherapeutic drugs. Expression of apoptotic genes mRNA was evaluated by quantitative RT-PCR. Results: The cervical tumor cell line SiHa highly expressed CD40. 5C11 or Gemcitabin could not effectively induced SiHa proliferation arrest, but combination of 5C11 and Gemcitabin could do. CD40 activation can induce arresting the cells at G2/M interphase and down-regulating anti-apoptotic genes BCL-XL expression and up-regulating apoptotic genes BAX expression weakly. Conclusion: CD40 activation could enhance chemosensitivity of human cervical tumor cell to Gemcitabin by inducing arresting the cells at G2/M phase and affecting apoptotic genes expression.
引文
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