COX-2、CCR7促进肿瘤转移机制的研究
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摘要
第一章COX-2、CCR7表达与大肠癌转移的关系
目的探讨COX-2、CCR7表达与大肠癌组织病理分化、浸润深度、淋巴转移等临床病理学参数的关系，并分析COX-2、CCR7表达的相关性。
方法采用免疫组织化学方法对大肠癌组织80例、大肠癌癌旁组织40例石蜡包埋切片进行染色，检测COX-2、CCR7的表达，分析其在大肠癌组织的表达与临床病理学参数的关系，对COX-2、CCR7的表达进行相关性分析。
结果在大肠癌组织，COX-2、CCR7均高表达，表达率分别为72.5％和67.5％，二者表达有相关性(P＜0.05)。COX-2、CCR7的表达均与肿瘤的浸润深度、TNM分期、淋巴转移、肿瘤大小相关(P＜0.05)，与大肠癌患者的诊断年龄、性别等因素无关(P＞0.05)。CCR7的表达与肿瘤的病理分化、肿瘤部位相关，但COX-2的表达与此无关。
结论COX-2、CCR7在大肠癌组织高表达，二者表达有相关性。COX-2、CCR7的表达与大肠癌的浸润深度、TNM分期、淋巴转移、肿瘤大小等临床病理学参数有关。提示临床上联合检测COX-2和CCR7对大肠癌转移的预测可能会有所帮助。
第二章COX-2、CCR7表达与乳腺癌转移的关系
目的探讨COX-2、CCR7表达与乳腺癌组织病理分化、浸润深度、淋巴转移等临床病理学参数的关系，并分析COX-2、CCR7表达的相关性。
方法采用免疫组织化学方法对乳腺癌组织80例、乳腺癌癌旁组织15例石蜡包埋切片进行染色，检测COX-2、CCR7的表达，分析其表达与临床病理学参数的关系，对COX-2、CCR7的表达进行相关性分析。
结果在乳腺癌组织，COX-2、CCR7均高表达，表达率分别为42.5％和38.8％，二者表达有相关性(P＜0.05)。COX-2、CCR7高表达均与肿瘤的病理分化、肿瘤大小、淋巴转移、TNM分期相关(P＜0.05)，与组织学分型、患者年龄无关。
结论COX-2、CCR7在乳腺癌组织高表达，二者表达有相关性。COX-2、CCR7的表达与乳腺癌的病理分化、TNM分期、淋巴转移、肿瘤大小等临床病理学参数有关。提示临床上联合检测COX-2和CCR7对乳腺癌转移的预测可能会有所帮助。
第三章COX-2对肿瘤细胞CCR7表达的调节
目的探讨COX-2对肿瘤细胞CCR7表达的调节及其机制。
方法用NS-398、PGE_2、Con A、EP受体激动／抑制剂作用于肿瘤细胞MDA-MB-231、SW620，RT-PCR、Western blot在mRNA和蛋白水平检测其对肿瘤细胞CCR7表达的影响，Fura-2／AM、趋化小室研究NS-398、PGE_2、Con A等化合物作用于肿瘤细胞MDA-MB-231、SW620后，其对CCL21刺激引起的胞内钙离子内流、趋化细胞和侵袭细胞的影响。
结果在MDA-MB-231和SW620细胞，均可检测到COX-2高表达，CCR7在两者有不同程度的表达，EP_1、EP_2、EP_4受体表达于MDA-MB-231和SW620细胞，EP_3受体仅表达于前者。NS-398(10μmol／L)、AH-23848(10μmol／L)能抑制二者CCR7表达，抑制CCL21刺激的钙离子内流和趋化、侵袭能力，而PGE_2、Con A的作用则与其相反，SC-19220、17-phenyl trinor PGE_2、AH-6809阻断或激动其他EP受体后，没有观察到此变化。说明NS-398(10μmol／L)、AH-23848(10μmol／L)能降低MDA-MB-231、SW620细胞CCR7的功能性表达，抑制肿瘤的转移；PGE_2、Con A则能促进其功能性表达，促进肿瘤的转移。
结论在MDA-MB-231、SW620细胞，抑制COX-2和EP_4受体能下调CCR7的功能性表达，为进一步研究COX-2、CCR7促进肿瘤转移的机制提供了理论基础，也提示COX-2与CCR7表达在肿瘤转移中有协同作用，及他们在肿瘤干预治疗中的潜在应用价值。
第四章siRNA-CCR7对肿瘤细胞转移的影响
目的体外实验探讨siRNA-CCR7对肿瘤转移的影响及其与VEGF-C、VEGF-D、VEGF-A的关系。
方法运用siRNA实验技术，构建抑制CCR7表达的siRNA载体，稳定转染表达CCR7的肿瘤细胞株MDA-MB-231、SW620，在mRNA和蛋白水平检测其对肿瘤细胞CCR7的抑制作用和VEGF-C、VEGF-D、VEGF-A表达的变化；再用钙离子内流、趋化及侵袭实验检测其对肿瘤细胞趋化、侵袭能力的影响。
结果稳定转染siRNA1、siRNA2的MDA-MB-231、SW620细胞，在mRNA、蛋白水平均能有效抑制肿瘤细胞CCR7的表达，并能抑制CCL21刺激的趋化和侵袭能力。在MDA-MB-231细胞，siRNA1、siRNA2能抑制肿瘤细胞CCR7、VEGF-C的表达，不影响MDA-MB-231、SW620细胞VEGF-D、VEGF-A的表达。SW620细胞没有检测到VEGF-C的表达。
结论siRNA-CCR7能有效的抑制乳腺癌和大肠癌细胞的趋化和侵袭，抑制CCR7可下调VEGF-C表达。这一实验结果为我们进一步探讨CCR7在肿瘤转移中的作用及探讨CCR7化学抑制剂或中药成分具有重要启示作用。
Chapter one Correlation between the expression of COX-2 and CCR7in colorectal cancer and tumor metastasis
Objective This study was designed to evaluate the coexpression ofCOX-2 and CCR7 in human colorectal cancer and determine theirrelationships and correlations with lymph node metastasis, tumordifferentiation, invasion depth, lymphatic metastasis and otherclinicopathologic parameters.
Methods Tissue samples of primary tumors from 80 colorectalcancer patients and normal colorectal tissue samples from 40 colorectalcancer patients, undergoing paraffin imbedding slices wereimmunohistochemically examined for COX-2 and CCR7 expressions.
Results COX-2 and CCR7 were highly expressed in colorectalcancer tissues, the positive rate of COX-2 and CCR7 in the primarytumor was 72.5%and 67.5%, respectively. A significant correlation wasfound between the expression scores of COX-2 and CCR7 (P＜0.05), andboth also were correlated with several clinicopathologic parameters,including invasion depth, lymph node metastasis, TNM stage andprimary tumor size, but both were not related to patients' age, sex andother factors (P＞0.05). In addition, only CCR7 expression was associatedwith histology and tumor site (P＜0.05).
Conclusions High expression of COX-2 and CCR7 in humancolorectal cancer was a significantly correlated. COX-2 and CCR7 weresignificantly associated with clinicopathologic parameters, includinginvasion depth, lymph node metastasis, TNM stage and primary tumorsize. This indicate that detection of COX-2 and CCR7 will be helpful topredicting the metastasis of colorectal cancer in clinic.
Chapter 2 Correlation between the expression of COX-2 and CCR7 inbreast cancer and tumor metastasis
Objective This study was designed to assesse the coexpression ofCOX-2 and CCR7 in human breast cancer and analyze their relationships and correlations with lymph node metastasis and tumor differentiation,invasion depth, lymphatic metastasis and other clinicopathologicparameters.
Methods Tissue samples of primary tumors from 80 breast cancerpatients and normal breast tissue samples from 15 breast cancer patients,undergoing paraffin imbedding slice were immunohistochemicallyexamined for COX-2 and CCR7 expressions. Then, we analyzed theirrelationships and correlations with clinicopathologic parameters.
Results COX-2 and CCR7 were over expression in breast cancertissues, the positive rate of COX-2 and CCR7 in the primary tumor was42.5% and 38.8%, respectively. A significant correlation was foundbetween the expression scores of COX-2 and CCR7 (P＜0.05), and bothalso were correlated with several clinicopathologic parameters, includinglymph node metastasis, histology, primary tumor size and TNM stage(P＜0.05), but both were not related to histology type and patients' age(P＞0.05).
Conclusions The over expression of COX-2 and CCR7 in humanbreast cancer were correlated, COX-2 and CCR7 were significantlyassociated with clinicopathologic parameters, including lymph nodemetastasis, histology, primary tumor size, TNM stage. This resultsindicate that detection of COX-2 and CCR7 might be a co-marker ofprediction the metastasis of breast cancer.
Chapter 3 Regulation of CCR7 expression in tumor cells by COX-2
Objective To study the regulation of CCR7 expression by COX-2and its mechanism.
Methods Detected the expression of CCR7 in mRNA and proteinlevels by RT-PCR, immune-histochemicaI and Western blot inMDA-MB-231 and SW620 cells, which incubated with NS-398、PGE_2、Con A、EP receptor agonists or antagonist, then investigated the effect ofthe influx of [ca~(2+)]_i, chemotacfic and invasive responses after the treatedtumor cells stimulated by CCL21, through Fura-2/AM and Chemotacticchamber.
Results COX-2 was over expressed in MDA-MB-231 and SW620cells, CCR7 was expressed in these cells at different levels, EP_1, EP_2, EP_4receptors were expressioned in MDA-MB-231 and SW620 cells, but onlycan be detected the expression of EP_3 in MDA-MB-231 cells. In bothcells could be found the expressed of CCR7, and the calciummobilization, chemotactic and invasive responses activated by CCL21were significantly inhibited when treated with NS-398 (10μmol/L) andAH-23848 (10μmol/L). The negative results could be detected whentreated with PGE_2 (10μmol/L) and Con A (1mg/ml). There were notsignificant differences when treated with SC-19220、17-phenyl trinorPGE_2、AH-6809. These showed that NS-398, AH-23848 could reduce thefunctional expression of CCR7 in MDA-MB-231, SW620 cells, andpromote tumor metastasis, but PGE_2, Con A were the negative.
Conclusions In the MDA-MB-231 and SW620 cells, the inhibitorsof COX-2 and EP_4 receptor can down-regulate the functional expressionof CCR7, will be helpful to further studying the mechanism of COX-2and CCR7 in promoting tumour metastasis, and indicate the synergiceffect of COX-2 and CCR7 in tumour metastasis and the potential role incancer therapy.
Chapter 4 Silencing of CCR7 for Ihibition of tumor metastasis
Objective To study the effect of siRNA-CCR7 in tumor metastasisand its relationship with VEGF-C, VEGF-D, VEGF-A in vitro.
Methods Detected the varied expression of CCR7, VEGF-C,VEGF-D and VEGF-A in mRNA and/or protein levels in MDA-MB-231and SW620 cells stable transfected into siRNAs vectors targeted CCR7,then assessed the effect of the influx of [ca~(2+)]I, chemotactic and invasiveresponses after the stable transfected cells stimulated by CCL21, throughCa~(2+) Mobilization and Matrigel invasion assay.
Results Inhibition of CCR7 expression at the mRNA and proteinlevels could be deteced in MDA-MB-231 and SW620 cells stabletransfected siRNA1, siRNA2 vectors, and the inhibiton of influx of [ca2+]i, chemotactic and invasive responses stimulated by CCL21 also could be found in these cells. In MDA-MB-231 cells, siRNA1, siRNA2 couldinhibit the expression of CCR7, VEGF-C, but not affected the expressionof VEGF-D, VEGF-A in both cells. The expression of VEGF-C inSW620 cells was not detected.
Conclusions Inhibition of CCR7 expression by a siRNA impairschemotactic, invasion and VEGF-C expression of cancer cell lines. It willlay a solid basis for us to further study the role of CCR7 in tumourmetastasis and CCR7 specific inhibitor.
目的探讨COX-2、CCR7表达与大肠癌组织病理分化、浸润深度、淋巴转移等临床病理学参数的关系，并分析COX-2、CCR7表达的相关性。
方法采用免疫组织化学方法对大肠癌组织80例、大肠癌癌旁组织40例石蜡包埋切片进行染色，检测COX-2、CCR7的表达，分析其在大肠癌组织的表达与临床病理学参数的关系，对COX-2、CCR7的表达进行相关性分析。
结果在大肠癌组织，COX-2、CCR7均高表达，表达率分别为72.5％和67.5％，二者表达有相关性(P＜0.05)。COX-2、CCR7的表达均与肿瘤的浸润深度、TNM分期、淋巴转移、肿瘤大小相关(P＜0.05)，与大肠癌患者的诊断年龄、性别等因素无关(P＞0.05)。CCR7的表达与肿瘤的病理分化、肿瘤部位相关，但COX-2的表达与此无关。
结论COX-2、CCR7在大肠癌组织高表达，二者表达有相关性。COX-2、CCR7的表达与大肠癌的浸润深度、TNM分期、淋巴转移、肿瘤大小等临床病理学参数有关。提示临床上联合检测COX-2和CCR7对大肠癌转移的预测可能会有所帮助。
第二章COX-2、CCR7表达与乳腺癌转移的关系
目的探讨COX-2、CCR7表达与乳腺癌组织病理分化、浸润深度、淋巴转移等临床病理学参数的关系，并分析COX-2、CCR7表达的相关性。
方法采用免疫组织化学方法对乳腺癌组织80例、乳腺癌癌旁组织15例石蜡包埋切片进行染色，检测COX-2、CCR7的表达，分析其表达与临床病理学参数的关系，对COX-2、CCR7的表达进行相关性分析。
结果在乳腺癌组织，COX-2、CCR7均高表达，表达率分别为42.5％和38.8％，二者表达有相关性(P＜0.05)。COX-2、CCR7高表达均与肿瘤的病理分化、肿瘤大小、淋巴转移、TNM分期相关(P＜0.05)，与组织学分型、患者年龄无关。
结论COX-2、CCR7在乳腺癌组织高表达，二者表达有相关性。COX-2、CCR7的表达与乳腺癌的病理分化、TNM分期、淋巴转移、肿瘤大小等临床病理学参数有关。提示临床上联合检测COX-2和CCR7对乳腺癌转移的预测可能会有所帮助。
第三章COX-2对肿瘤细胞CCR7表达的调节
目的探讨COX-2对肿瘤细胞CCR7表达的调节及其机制。
方法用NS-398、PGE_2、Con A、EP受体激动／抑制剂作用于肿瘤细胞MDA-MB-231、SW620，RT-PCR、Western blot在mRNA和蛋白水平检测其对肿瘤细胞CCR7表达的影响，Fura-2／AM、趋化小室研究NS-398、PGE_2、Con A等化合物作用于肿瘤细胞MDA-MB-231、SW620后，其对CCL21刺激引起的胞内钙离子内流、趋化细胞和侵袭细胞的影响。
结果在MDA-MB-231和SW620细胞，均可检测到COX-2高表达，CCR7在两者有不同程度的表达，EP_1、EP_2、EP_4受体表达于MDA-MB-231和SW620细胞，EP_3受体仅表达于前者。NS-398(10μmol／L)、AH-23848(10μmol／L)能抑制二者CCR7表达，抑制CCL21刺激的钙离子内流和趋化、侵袭能力，而PGE_2、Con A的作用则与其相反，SC-19220、17-phenyl trinor PGE_2、AH-6809阻断或激动其他EP受体后，没有观察到此变化。说明NS-398(10μmol／L)、AH-23848(10μmol／L)能降低MDA-MB-231、SW620细胞CCR7的功能性表达，抑制肿瘤的转移；PGE_2、Con A则能促进其功能性表达，促进肿瘤的转移。
结论在MDA-MB-231、SW620细胞，抑制COX-2和EP_4受体能下调CCR7的功能性表达，为进一步研究COX-2、CCR7促进肿瘤转移的机制提供了理论基础，也提示COX-2与CCR7表达在肿瘤转移中有协同作用，及他们在肿瘤干预治疗中的潜在应用价值。
第四章siRNA-CCR7对肿瘤细胞转移的影响
目的体外实验探讨siRNA-CCR7对肿瘤转移的影响及其与VEGF-C、VEGF-D、VEGF-A的关系。
方法运用siRNA实验技术，构建抑制CCR7表达的siRNA载体，稳定转染表达CCR7的肿瘤细胞株MDA-MB-231、SW620，在mRNA和蛋白水平检测其对肿瘤细胞CCR7的抑制作用和VEGF-C、VEGF-D、VEGF-A表达的变化；再用钙离子内流、趋化及侵袭实验检测其对肿瘤细胞趋化、侵袭能力的影响。
结果稳定转染siRNA1、siRNA2的MDA-MB-231、SW620细胞，在mRNA、蛋白水平均能有效抑制肿瘤细胞CCR7的表达，并能抑制CCL21刺激的趋化和侵袭能力。在MDA-MB-231细胞，siRNA1、siRNA2能抑制肿瘤细胞CCR7、VEGF-C的表达，不影响MDA-MB-231、SW620细胞VEGF-D、VEGF-A的表达。SW620细胞没有检测到VEGF-C的表达。
结论siRNA-CCR7能有效的抑制乳腺癌和大肠癌细胞的趋化和侵袭，抑制CCR7可下调VEGF-C表达。这一实验结果为我们进一步探讨CCR7在肿瘤转移中的作用及探讨CCR7化学抑制剂或中药成分具有重要启示作用。
Chapter one Correlation between the expression of COX-2 and CCR7in colorectal cancer and tumor metastasis
Objective This study was designed to evaluate the coexpression ofCOX-2 and CCR7 in human colorectal cancer and determine theirrelationships and correlations with lymph node metastasis, tumordifferentiation, invasion depth, lymphatic metastasis and otherclinicopathologic parameters.
Methods Tissue samples of primary tumors from 80 colorectalcancer patients and normal colorectal tissue samples from 40 colorectalcancer patients, undergoing paraffin imbedding slices wereimmunohistochemically examined for COX-2 and CCR7 expressions.
Results COX-2 and CCR7 were highly expressed in colorectalcancer tissues, the positive rate of COX-2 and CCR7 in the primarytumor was 72.5%and 67.5%, respectively. A significant correlation wasfound between the expression scores of COX-2 and CCR7 (P＜0.05), andboth also were correlated with several clinicopathologic parameters,including invasion depth, lymph node metastasis, TNM stage andprimary tumor size, but both were not related to patients' age, sex andother factors (P＞0.05). In addition, only CCR7 expression was associatedwith histology and tumor site (P＜0.05).
Conclusions High expression of COX-2 and CCR7 in humancolorectal cancer was a significantly correlated. COX-2 and CCR7 weresignificantly associated with clinicopathologic parameters, includinginvasion depth, lymph node metastasis, TNM stage and primary tumorsize. This indicate that detection of COX-2 and CCR7 will be helpful topredicting the metastasis of colorectal cancer in clinic.
Chapter 2 Correlation between the expression of COX-2 and CCR7 inbreast cancer and tumor metastasis
Objective This study was designed to assesse the coexpression ofCOX-2 and CCR7 in human breast cancer and analyze their relationships and correlations with lymph node metastasis and tumor differentiation,invasion depth, lymphatic metastasis and other clinicopathologicparameters.
Methods Tissue samples of primary tumors from 80 breast cancerpatients and normal breast tissue samples from 15 breast cancer patients,undergoing paraffin imbedding slice were immunohistochemicallyexamined for COX-2 and CCR7 expressions. Then, we analyzed theirrelationships and correlations with clinicopathologic parameters.
Results COX-2 and CCR7 were over expression in breast cancertissues, the positive rate of COX-2 and CCR7 in the primary tumor was42.5% and 38.8%, respectively. A significant correlation was foundbetween the expression scores of COX-2 and CCR7 (P＜0.05), and bothalso were correlated with several clinicopathologic parameters, includinglymph node metastasis, histology, primary tumor size and TNM stage(P＜0.05), but both were not related to histology type and patients' age(P＞0.05).
Conclusions The over expression of COX-2 and CCR7 in humanbreast cancer were correlated, COX-2 and CCR7 were significantlyassociated with clinicopathologic parameters, including lymph nodemetastasis, histology, primary tumor size, TNM stage. This resultsindicate that detection of COX-2 and CCR7 might be a co-marker ofprediction the metastasis of breast cancer.
Chapter 3 Regulation of CCR7 expression in tumor cells by COX-2
Objective To study the regulation of CCR7 expression by COX-2and its mechanism.
Methods Detected the expression of CCR7 in mRNA and proteinlevels by RT-PCR, immune-histochemicaI and Western blot inMDA-MB-231 and SW620 cells, which incubated with NS-398、PGE_2、Con A、EP receptor agonists or antagonist, then investigated the effect ofthe influx of [ca~(2+)]_i, chemotacfic and invasive responses after the treatedtumor cells stimulated by CCL21, through Fura-2/AM and Chemotacticchamber.
Results COX-2 was over expressed in MDA-MB-231 and SW620cells, CCR7 was expressed in these cells at different levels, EP_1, EP_2, EP_4receptors were expressioned in MDA-MB-231 and SW620 cells, but onlycan be detected the expression of EP_3 in MDA-MB-231 cells. In bothcells could be found the expressed of CCR7, and the calciummobilization, chemotactic and invasive responses activated by CCL21were significantly inhibited when treated with NS-398 (10μmol/L) andAH-23848 (10μmol/L). The negative results could be detected whentreated with PGE_2 (10μmol/L) and Con A (1mg/ml). There were notsignificant differences when treated with SC-19220、17-phenyl trinorPGE_2、AH-6809. These showed that NS-398, AH-23848 could reduce thefunctional expression of CCR7 in MDA-MB-231, SW620 cells, andpromote tumor metastasis, but PGE_2, Con A were the negative.
Conclusions In the MDA-MB-231 and SW620 cells, the inhibitorsof COX-2 and EP_4 receptor can down-regulate the functional expressionof CCR7, will be helpful to further studying the mechanism of COX-2and CCR7 in promoting tumour metastasis, and indicate the synergiceffect of COX-2 and CCR7 in tumour metastasis and the potential role incancer therapy.
Chapter 4 Silencing of CCR7 for Ihibition of tumor metastasis
Objective To study the effect of siRNA-CCR7 in tumor metastasisand its relationship with VEGF-C, VEGF-D, VEGF-A in vitro.
Methods Detected the varied expression of CCR7, VEGF-C,VEGF-D and VEGF-A in mRNA and/or protein levels in MDA-MB-231and SW620 cells stable transfected into siRNAs vectors targeted CCR7,then assessed the effect of the influx of [ca~(2+)]I, chemotactic and invasiveresponses after the stable transfected cells stimulated by CCL21, throughCa~(2+) Mobilization and Matrigel invasion assay.
Results Inhibition of CCR7 expression at the mRNA and proteinlevels could be deteced in MDA-MB-231 and SW620 cells stabletransfected siRNA1, siRNA2 vectors, and the inhibiton of influx of [ca2+]i, chemotactic and invasive responses stimulated by CCL21 also could be found in these cells. In MDA-MB-231 cells, siRNA1, siRNA2 couldinhibit the expression of CCR7, VEGF-C, but not affected the expressionof VEGF-D, VEGF-A in both cells. The expression of VEGF-C inSW620 cells was not detected.
Conclusions Inhibition of CCR7 expression by a siRNA impairschemotactic, invasion and VEGF-C expression of cancer cell lines. It willlay a solid basis for us to further study the role of CCR7 in tumourmetastasis and CCR7 specific inhibitor.
引文
[1] Anggard E, Matschinsky FM, Samuelsson B, et al. Prostaglandins enzymatic analysis. Science, 1969,163: 479-480
[2] Nugteren DH, Van Dorp DA, Bergstrom S, et al. Absolute configuration of the prostaglandins. Nature, 1966; 212: 38-39
[3] Feng L, Wang Z. Chemopreventive effect of celecoxib in oral precancers and cancers. Laryngoscope, 2006, 116(10): 1842-1845
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