KiSS-1、MMP-2和MVD在不同食管病变组织中的表达及其相关性研究
摘要
食管癌是最常见的恶性肿瘤之一,它严重威胁着人类的生命和健康。食管癌的高发地区主要在我国的河南等省份,以往的消化道肿瘤死亡回顾调查显示,每年因食管癌而死亡的人数大约有20万人,位居第4位。引起其死亡的重要原因之一就是浸润和远处转移,因此寻找抑制食管癌浸润转移机制,是目前肿瘤学研究的热点课题之一
肿瘤的发生发展是多步骤、多阶段、多因素和多基因参与的过程。恶性肿瘤增殖失控、侵袭和转移的基础是肿瘤转移相关基因的活化和肿瘤转移抑制基因的失活,KiSS-1及MMPs等的突变和缺失与多数恶性肿瘤的发生密切相关。
KiSS-1是1996年克隆出的一个肿瘤转移抑制基因。研究证明,KiSS-1的表达缺失与多种恶性肿瘤的浸润转移有关。近年来,已有相关文献报道了KiSS-1与多种恶性肿瘤的侵袭和转移密切相关,如乳癌、胃癌、卵巢癌和胰腺癌等。该基因表达的降低与缺失与肿瘤的浸润深度及淋巴结转移密切相关,其作用机制可能与抑制基质金属蛋白酶(matrix metalloproteniases, MMPs)的活性及肿瘤细胞的移行能力有关。
MMPs是一种能降解细胞外基质的所有成分的锌离子依赖性内肽酶,MMPs中降解基底膜最重要的蛋白酶之一是基质金属蛋白酶-2 (matrix metalloproteinase-2, MMP-2),又称明胶酶A,主要消化Ⅳ、Ⅴ、Ⅷ及Ⅹ型胶原和弹性纤维,从而降解细胞外基质及促进肿瘤新生血管的生成。研究表明,MMP-2在胃癌及肺癌等多种恶性肿瘤的浸润转移中扮演着重要角色。KiSS-1和MMP-2可能通过调控肿瘤血管的生成而调节肿瘤生长、侵袭和转移。
新生血管的形成在实体肿瘤的生长转移中起重要作用,研究其血管改变具有重要的临床意义。目前恶性肿瘤血管生成的数量通过测定微血管密度(microvessel density, MVD)进行评估。迄今为止,有关在食管鳞癌中KiSS-1、MMP-2及MVD的表达及其三者与食管鳞癌浸润转移关系的研究,除本课题组前期发表的相关文章外,国内外尚未见其他文献报道。
为深入探讨KiSS-1、MMP-2基因及MVD与食管鳞癌发生发展和浸润转移的关系,寻求检测食管鳞癌发生发展和浸润转移的早期指标,进而寻找可能抑制食管鳞癌发生发展和浸润转移的有效方法。本研究采用免疫组化SP法检测了62例食管鳞癌、31例癌旁不典型增生组织及62例正常食管黏膜组织中KiSS-1及MMP-2蛋白的表达水平并探讨了其临床病理意义；同时用抗CD34抗体检测了62例食管鳞癌组织中的MVD,探讨KiSS-1、MMP-2及MVD的相关性,揭示KiSS-1及MMP-2与食管鳞癌浸润、转移的关系。从而为进一步探讨食管鳞癌发生发展、浸润转移机制及寻找抑制食管鳞癌发生发展的可能途径提供理论基础。
1.采用免疫组织化学SP法检测62例食管鳞癌组织、31例癌旁不典型增生组织及62例正常食管黏膜组织中KiSS-1蛋白的表达情况,并探讨其临床病理学意义。
2.采用免疫组织化学SP法检测62例食管鳞癌组织、31例癌旁不典型增生组织及62例正常食管黏膜组织中MMP-2蛋白的表达情况,并探讨其临床病理学意义；
3.采用免疫组织化学的方法检测62例食管鳞癌组织CD34蛋白表达情况,探讨MVD分布的临床病理学意义。
4.通过检测KiSS-1、MMP-2与CD34蛋白的表达,探讨KiSS-1、MMP-2和MVD分布的相关性及其意义。
5.统计学处理：应用SPSS10.0软件处理,采用x2检验、t检验和方差分析,检验水准α=0.05。
1.正常食管黏膜组织、癌旁不典型增生组织及食管鳞癌组织中KiSS-1蛋白的表达率分别是90.3%(56/62)、67.7%(21/31)及56.5%(35/62),差异有统计学意义(P<0.001)；浸润深度达浅肌层者及深肌层者KiSS-1蛋白的阳性表达率分别为100%(7/7)和50.9%(28/55),组间比较差异有统计学意义(P<0.05)；KiSS-1蛋白在伴淋巴结转移癌组织中的阳性表达率为35.0%(7/20),明显低于无淋巴结转移癌组织66.7%(28/42)；组织学分级为Ⅰ、Ⅱ、Ⅲ级的食管鳞癌组织中KiSS-1蛋白的阳性表达率分别为66.7%(10/15)、56.0%(14/25)、50.0%(11/22),差异无统计学意义(P>0.05)。
2.正常食管黏膜组织、癌旁不典型增生组织及食管鳞癌组织中MMP-2蛋白的表达率分别是22.6%(14/62)、54.8%(17/31)及71.0%(44/62),差异有统计学意义(P<0.05)；组织学分级为Ⅰ、Ⅱ、Ⅲ级的食管鳞癌组织中MMP-2蛋白的阳性表达率分别为46.7%(7/15)、72.0%(18/25)、86.4%(19/22),差异有统计学意义(P<0.05)；浅肌层浸润组及深肌层浸润癌组织中MMP-2蛋白的阳性表达率分别为28.6%(2/7)和76.4%(42/55),且差异有统计学意义(P<0.05)；MMP-2蛋白在伴淋巴结转移癌组织中的阳性表达率为90.0%(18/20),明显高于无淋巴结转移癌组织61.9%(26/42)。
3.62例食管鳞癌组织中平均MVD值为39.4±9.5,其中浸润深度达浅肌层者及深肌层者的MVD值分别为28.1±8.1及40.8±9.1,差异有统计学意义(P<0.05)；组织学分级为Ⅰ、Ⅱ、Ⅲ级的食管鳞癌组织中平均MVD值分别为32.3±4.9、38.6±8.3、45.1±10.6,组间比较差异有统计学意义(P<0.05)；伴淋巴结转移的食管鳞癌组织的MVD值为51.2±6.1,明显高于无淋巴结转移癌组织的MVD值33.8±5.0(P<0.05)。
4.食管鳞癌组织中的KiSS-1及MMP-2蛋白表达呈负相关关系(rs=-0.418,P<0.05)；KiSS-1蛋白表达阴性病例的MVD值为47.8±7.8,比表达阳性病例的MVD值32.9±5.0显著增高(P<0.05)；MMP-2蛋白表达阳性者的MVD值41.0±3.2明显高于MMP-2蛋白表达阴性者的MVD值36.3±3.8。
1. KISS-1蛋白在正常食管黏膜组织、癌旁不典型增生组织及食管鳞癌组织中的阳性表达率依次降低,并与食管鳞癌的浸润深度及淋巴结转移密切相关,提不KiSS-1的表达缺失或降低可能与食管鳞癌的发生发展及浸润转移密切相关。
2.MMP-2蛋白的阳性表达率在正常食管黏膜组织、癌旁不典型增生组织及食管鳞癌组织中显著增高,并与食管鳞癌的分化程度、浸润深度及淋巴结转移密切相关。提示MMP-2可能参与了食管鳞癌的发生发展及浸润转移的过程。
3.食管鳞癌组织中的MVD值与肿瘤的组织学分级、浸润深度及淋巴结转移相关,提示：MVD与肿瘤的生物学行为密切相关,可作为肿瘤预后判断的一项指标,为进一步通过阻断肿瘤微血管生成而治疗肿瘤提供了理论基础。
4.食管鳞癌组织中KiSS-1蛋白表达阴性者MVD值显著高于阳性者,而MMP-2蛋白的表达阳性的MVD值显著高于表达阴性者,且KiSS-1与MMP-2蛋白的表达呈负相关。提示：联合检测KiSS-1、MMP-2及MVD,有望成为判断食管鳞癌患者预后的指标,为进一步研究抑制肿瘤复发转移的可能途径提供了理论依据。
Esophageal carcinoma(EC), one of the most common malignant carcinoma,has been a great threaten to people's lives and health. China, Henan province in particular, is a high incidence area of EC.It ranked 2 in all the reviewed survey of gastrointestinal cancer deaths. It is estimated that nearly 200,000 persons die of EC in all of the world each year. On account of the invasion and metastasis is an important reason leading to death, so discussing the mechanism of invasion and metastasis has become one of the hot topics in EC.
The occurrence and development of tumor is a process of chages involving multi-stage, multi-step, multi-factor and polygene.Tumor metastasis suppressor gene inactivation and tumor metastasis-related gene activation are the material basis of human tumor formation, development and uncontrolled.Previous research found that the mutation and deletion of gene such as KiSS-1 and MMPs most closely related to the occurrence of malignant tumors.
KiSS-1, first cloned in 1996, was an anti-oncogene. It has been proved that the absent expression of KiSS-1 was closely related with the invasion and matastasis of many malignant tumor.In recent years, there are several relevant studies about the close relationship of KiSS-1 and invasion and metastasis in the fields of breast cancer, gastric cancer, pancreatic cancer, lung cancer and so on. The mechanism of KiSS-1 negatively regulated the growth, invasion, metastasis of EC may be through restraining the removal of cells and the activityof MMPs. MMPs is a kind of zinc ion depended endopeptidase, which can divide all components of extracellular matrix. MMP-2 (matrix metalloproteinase-2, MMP-2), also known as gelatin enzyme A,is one of the most important enzymes which dividing the basement membrane among all the MMPs.
It plays a great role in dividing all components of extracellular matrix and regulating tumor vessel formation by digesting IV, V, VII, X type plastic and flexible fiber. A lot of studies had proved that MMP-2 played a key role in invasion and metastasis of many malignant tumors, such as lung cancer, gastric cancer and so on. Furthermore, KiSS-1 and MMP-2 can inhibit the growth, invasion and metastasis of tumor by inhibiting the formation of tumor angiogenesis. There have no other report both in China and abroad so far except the relevant articles pulished by our team before.
To further investigate the correlation between the expression of KiSS-land MMP-2, and explore the effective method of earlier detecting the formation, invasion and metastasis of EC, we detected the expression of KiSS-1 and MMP-2 in 62 normal examples,31 patients with adjacent atypical hyperplasia epithelium and 62 patients with EC by SP method. We also evaluated the MVD in the same 62 patients with EC by CD34 antibody. Besides, the relationship of KiSS-1, MMP-2 protein and MVD in ESCC was evaluated simultaneously. Our research aims to provide the mechanism and theory foundation of how to restrain the formation, development, invasion and metastasis in EC.
1. The KiSS-1 protein expression was detected in 62 cases of normal esophagus mucous membrane tissue,31 cases of adjacent atypical hyperplasia tissue and 62 cases of EC by immunohistochemical SP method, then explored its clinicopathologic significance.
2. The MMP-2 protein expression was also detected in 62 cases of normal esophagus mucous membrane tissue,31 cases of adjacent atypical hyperplasia tissue and 62 cases of EC by immunohistochemical SP method, then explored its clinicopathologic significance.
3. Detected CD34 protein expression in 62 cases of EC by immunohistochemical SP method, then explored its clinicopathologic significance simultaneously.
4. Discussed the relevance and significance of KiSS-1, MMP-2 and MVD by detecting the KiSS-1, MMP-2 and CD34 protein expression.
5. Statistical analysis:Statistics analysis was performed by SPSS 10.0 software, adopt chi-square test, T test and ANOVA, test standard a is 0.05.
1. The KiSS-1 protein expression rate in normal esophagus mucous membrane tissue, adjacent atypical hyperplasia tissue and esophageal squamous cell carcinoma tissue was 90.3%(56/62),67.7%(21/31) and 56.5%(35/62) respectively, and with a significant difference in group comparison (P<0.05); KiSS-1 protein masculine expression rate in infiltration depth of lower muscular layer group and deeper muscular layer group were 100%(7/7) and 50.9%(28/55) respectively, with a significant difference in group comparion (P <0.05); KiSS-1 protein masculine expression rate in lymphatic metastasis group was 35.0%(7/20), significantly lower than those without lymph node metastasis in EC was 66.7%(28/42), and with a significant difference in group comparion (P<0.05). KiSS-1 protein masculine expression in grade ofⅠ,ⅡandⅢwere respectively 66.7%(10/15),56.0%(14/25),50.0%(11/22), and no statistically significant difference (P> 0.05);
2. The MMP-2 protein masculine expression rate in normal esophagus mucous membrane tissue, adjacent atypical hyperplasia tissue and esophageal squamous cell carcinoma tissue were respectively 22.6%(14/62),54.8%(17/31) and 71.0% (44/62), and with a significant difference in group comparison (P<0.05); KiSS-1 protein masculine expression rate in infiltration depth of lower muscular layer group and deeper muscular layer group were 28.6%(2/7) and 76.4%(42/55) respectively, with a significant difference in group comparion (P<0.05);KiSS-1 protein masculine expression rate in lymphatic metastasis group was 90.0% (18/20), significantly higher than those without lymph node metastasis in EC was 61.9%(26/42),and with a significant difference in group comparion (P<0.05); KiSS-1 protein masculine expression in grade ofⅠ,ⅡandⅢwere respectively 46.7%(7/15),72.0%(18/25),86.4%(19/22), the difference was statistically significant (P<0.05).
3. The MVD values infiltrated to shallow muscular layer and those which infiltrated deeper layer were respectively 28.1±8.1 and 40.8±9.1,the difference among groups make statistics sense(P<0.05); The average MVD values in grade ofⅠⅡandⅢwere respectively 32.3±4.9,38.6±8.3, and 45.1±10.6,the difference between two groups was statistically significant (P<0.05); The average MVD values in EC with lymphatic metastasis(51.2±6.1) is signifcantly higher than those which without lymphatic metastasis(33.8±5.0),the difference among groups make statistics sense(P<0.05).
4. The protein expression of KiSS-1 and MMP-2 was negatively correlated (rs=-0.418, P<0.05); The average MVD values in EC which KiSS-1 protein expression is negative was significantly higher than those KiSS-1 protein expression is positive (P<0.05).
1. The KiSS-1 protein expression rate depress by turns in normal esophagus mucous membrane tissue, adjacent atypical hyperplasia tissue and esophagus cancer tissue, and there was a close correlation with the infiltration depth and lymph node metastasis, which suggest that the missing or lower expression of KiSS-1 may be related to the occurrence of EC. It is also closely related to the development, invasion and metastasis of EC.
2. The MMP-2 protein expression rate boost by turns in normal esophagus mucous membrane tissue,adjacent atypical hyperplasia tissue and esophagus cancer tissue,and there was a close correlation with the infiltration depth,differential grade and lymph node metastasis,which suggest that MMP-2 may be involved in the occurrence and development of EC.It is also closely related to the process of invasion and metastasis in EC;
3. The MVD value was closely related with the infiltration depth, differential grade and lymph node metastasis, which suggest that there was a close correlation with tumor biological behavior. MVD may become one of important assistant indexes in the early diagnosis and prognosis of EC, further providing a theoretical basis for gene therapy to block the tumour blood generation;
4. The average MVD value in EC which KiSS-1 protein expression is negative was significantly higher than those KiSS-1 protein expression is positive, while the average MVD value in EC which MMP-2 protein expression is positive was significantly higher than those KiSS-1 protein expression is negative. There was a negative correlation beween the expression of KiSS-1 and MMP-2 protein by immunnohistochemical SP method and by Spearman rank correlation analysis (r,=-0.418, P=0.001).All of these conclusions prompt that joint detection of KiSS-1, MMP-2 and MVD is expected to be an indicator of judging the prognosis of EC, further provide the theoretical basis of inhibiting tumor recurrence and metastasis.
肿瘤的发生发展是多步骤、多阶段、多因素和多基因参与的过程。恶性肿瘤增殖失控、侵袭和转移的基础是肿瘤转移相关基因的活化和肿瘤转移抑制基因的失活,KiSS-1及MMPs等的突变和缺失与多数恶性肿瘤的发生密切相关。
KiSS-1是1996年克隆出的一个肿瘤转移抑制基因。研究证明,KiSS-1的表达缺失与多种恶性肿瘤的浸润转移有关。近年来,已有相关文献报道了KiSS-1与多种恶性肿瘤的侵袭和转移密切相关,如乳癌、胃癌、卵巢癌和胰腺癌等。该基因表达的降低与缺失与肿瘤的浸润深度及淋巴结转移密切相关,其作用机制可能与抑制基质金属蛋白酶(matrix metalloproteniases, MMPs)的活性及肿瘤细胞的移行能力有关。
MMPs是一种能降解细胞外基质的所有成分的锌离子依赖性内肽酶,MMPs中降解基底膜最重要的蛋白酶之一是基质金属蛋白酶-2 (matrix metalloproteinase-2, MMP-2),又称明胶酶A,主要消化Ⅳ、Ⅴ、Ⅷ及Ⅹ型胶原和弹性纤维,从而降解细胞外基质及促进肿瘤新生血管的生成。研究表明,MMP-2在胃癌及肺癌等多种恶性肿瘤的浸润转移中扮演着重要角色。KiSS-1和MMP-2可能通过调控肿瘤血管的生成而调节肿瘤生长、侵袭和转移。
新生血管的形成在实体肿瘤的生长转移中起重要作用,研究其血管改变具有重要的临床意义。目前恶性肿瘤血管生成的数量通过测定微血管密度(microvessel density, MVD)进行评估。迄今为止,有关在食管鳞癌中KiSS-1、MMP-2及MVD的表达及其三者与食管鳞癌浸润转移关系的研究,除本课题组前期发表的相关文章外,国内外尚未见其他文献报道。
为深入探讨KiSS-1、MMP-2基因及MVD与食管鳞癌发生发展和浸润转移的关系,寻求检测食管鳞癌发生发展和浸润转移的早期指标,进而寻找可能抑制食管鳞癌发生发展和浸润转移的有效方法。本研究采用免疫组化SP法检测了62例食管鳞癌、31例癌旁不典型增生组织及62例正常食管黏膜组织中KiSS-1及MMP-2蛋白的表达水平并探讨了其临床病理意义；同时用抗CD34抗体检测了62例食管鳞癌组织中的MVD,探讨KiSS-1、MMP-2及MVD的相关性,揭示KiSS-1及MMP-2与食管鳞癌浸润、转移的关系。从而为进一步探讨食管鳞癌发生发展、浸润转移机制及寻找抑制食管鳞癌发生发展的可能途径提供理论基础。
1.采用免疫组织化学SP法检测62例食管鳞癌组织、31例癌旁不典型增生组织及62例正常食管黏膜组织中KiSS-1蛋白的表达情况,并探讨其临床病理学意义。
2.采用免疫组织化学SP法检测62例食管鳞癌组织、31例癌旁不典型增生组织及62例正常食管黏膜组织中MMP-2蛋白的表达情况,并探讨其临床病理学意义；
3.采用免疫组织化学的方法检测62例食管鳞癌组织CD34蛋白表达情况,探讨MVD分布的临床病理学意义。
4.通过检测KiSS-1、MMP-2与CD34蛋白的表达,探讨KiSS-1、MMP-2和MVD分布的相关性及其意义。
5.统计学处理：应用SPSS10.0软件处理,采用x2检验、t检验和方差分析,检验水准α=0.05。
1.正常食管黏膜组织、癌旁不典型增生组织及食管鳞癌组织中KiSS-1蛋白的表达率分别是90.3%(56/62)、67.7%(21/31)及56.5%(35/62),差异有统计学意义(P<0.001)；浸润深度达浅肌层者及深肌层者KiSS-1蛋白的阳性表达率分别为100%(7/7)和50.9%(28/55),组间比较差异有统计学意义(P<0.05)；KiSS-1蛋白在伴淋巴结转移癌组织中的阳性表达率为35.0%(7/20),明显低于无淋巴结转移癌组织66.7%(28/42)；组织学分级为Ⅰ、Ⅱ、Ⅲ级的食管鳞癌组织中KiSS-1蛋白的阳性表达率分别为66.7%(10/15)、56.0%(14/25)、50.0%(11/22),差异无统计学意义(P>0.05)。
2.正常食管黏膜组织、癌旁不典型增生组织及食管鳞癌组织中MMP-2蛋白的表达率分别是22.6%(14/62)、54.8%(17/31)及71.0%(44/62),差异有统计学意义(P<0.05)；组织学分级为Ⅰ、Ⅱ、Ⅲ级的食管鳞癌组织中MMP-2蛋白的阳性表达率分别为46.7%(7/15)、72.0%(18/25)、86.4%(19/22),差异有统计学意义(P<0.05)；浅肌层浸润组及深肌层浸润癌组织中MMP-2蛋白的阳性表达率分别为28.6%(2/7)和76.4%(42/55),且差异有统计学意义(P<0.05)；MMP-2蛋白在伴淋巴结转移癌组织中的阳性表达率为90.0%(18/20),明显高于无淋巴结转移癌组织61.9%(26/42)。
3.62例食管鳞癌组织中平均MVD值为39.4±9.5,其中浸润深度达浅肌层者及深肌层者的MVD值分别为28.1±8.1及40.8±9.1,差异有统计学意义(P<0.05)；组织学分级为Ⅰ、Ⅱ、Ⅲ级的食管鳞癌组织中平均MVD值分别为32.3±4.9、38.6±8.3、45.1±10.6,组间比较差异有统计学意义(P<0.05)；伴淋巴结转移的食管鳞癌组织的MVD值为51.2±6.1,明显高于无淋巴结转移癌组织的MVD值33.8±5.0(P<0.05)。
4.食管鳞癌组织中的KiSS-1及MMP-2蛋白表达呈负相关关系(rs=-0.418,P<0.05)；KiSS-1蛋白表达阴性病例的MVD值为47.8±7.8,比表达阳性病例的MVD值32.9±5.0显著增高(P<0.05)；MMP-2蛋白表达阳性者的MVD值41.0±3.2明显高于MMP-2蛋白表达阴性者的MVD值36.3±3.8。
1. KISS-1蛋白在正常食管黏膜组织、癌旁不典型增生组织及食管鳞癌组织中的阳性表达率依次降低,并与食管鳞癌的浸润深度及淋巴结转移密切相关,提不KiSS-1的表达缺失或降低可能与食管鳞癌的发生发展及浸润转移密切相关。
2.MMP-2蛋白的阳性表达率在正常食管黏膜组织、癌旁不典型增生组织及食管鳞癌组织中显著增高,并与食管鳞癌的分化程度、浸润深度及淋巴结转移密切相关。提示MMP-2可能参与了食管鳞癌的发生发展及浸润转移的过程。
3.食管鳞癌组织中的MVD值与肿瘤的组织学分级、浸润深度及淋巴结转移相关,提示：MVD与肿瘤的生物学行为密切相关,可作为肿瘤预后判断的一项指标,为进一步通过阻断肿瘤微血管生成而治疗肿瘤提供了理论基础。
4.食管鳞癌组织中KiSS-1蛋白表达阴性者MVD值显著高于阳性者,而MMP-2蛋白的表达阳性的MVD值显著高于表达阴性者,且KiSS-1与MMP-2蛋白的表达呈负相关。提示：联合检测KiSS-1、MMP-2及MVD,有望成为判断食管鳞癌患者预后的指标,为进一步研究抑制肿瘤复发转移的可能途径提供了理论依据。
Esophageal carcinoma(EC), one of the most common malignant carcinoma,has been a great threaten to people's lives and health. China, Henan province in particular, is a high incidence area of EC.It ranked 2 in all the reviewed survey of gastrointestinal cancer deaths. It is estimated that nearly 200,000 persons die of EC in all of the world each year. On account of the invasion and metastasis is an important reason leading to death, so discussing the mechanism of invasion and metastasis has become one of the hot topics in EC.
The occurrence and development of tumor is a process of chages involving multi-stage, multi-step, multi-factor and polygene.Tumor metastasis suppressor gene inactivation and tumor metastasis-related gene activation are the material basis of human tumor formation, development and uncontrolled.Previous research found that the mutation and deletion of gene such as KiSS-1 and MMPs most closely related to the occurrence of malignant tumors.
KiSS-1, first cloned in 1996, was an anti-oncogene. It has been proved that the absent expression of KiSS-1 was closely related with the invasion and matastasis of many malignant tumor.In recent years, there are several relevant studies about the close relationship of KiSS-1 and invasion and metastasis in the fields of breast cancer, gastric cancer, pancreatic cancer, lung cancer and so on. The mechanism of KiSS-1 negatively regulated the growth, invasion, metastasis of EC may be through restraining the removal of cells and the activityof MMPs. MMPs is a kind of zinc ion depended endopeptidase, which can divide all components of extracellular matrix. MMP-2 (matrix metalloproteinase-2, MMP-2), also known as gelatin enzyme A,is one of the most important enzymes which dividing the basement membrane among all the MMPs.
It plays a great role in dividing all components of extracellular matrix and regulating tumor vessel formation by digesting IV, V, VII, X type plastic and flexible fiber. A lot of studies had proved that MMP-2 played a key role in invasion and metastasis of many malignant tumors, such as lung cancer, gastric cancer and so on. Furthermore, KiSS-1 and MMP-2 can inhibit the growth, invasion and metastasis of tumor by inhibiting the formation of tumor angiogenesis. There have no other report both in China and abroad so far except the relevant articles pulished by our team before.
To further investigate the correlation between the expression of KiSS-land MMP-2, and explore the effective method of earlier detecting the formation, invasion and metastasis of EC, we detected the expression of KiSS-1 and MMP-2 in 62 normal examples,31 patients with adjacent atypical hyperplasia epithelium and 62 patients with EC by SP method. We also evaluated the MVD in the same 62 patients with EC by CD34 antibody. Besides, the relationship of KiSS-1, MMP-2 protein and MVD in ESCC was evaluated simultaneously. Our research aims to provide the mechanism and theory foundation of how to restrain the formation, development, invasion and metastasis in EC.
1. The KiSS-1 protein expression was detected in 62 cases of normal esophagus mucous membrane tissue,31 cases of adjacent atypical hyperplasia tissue and 62 cases of EC by immunohistochemical SP method, then explored its clinicopathologic significance.
2. The MMP-2 protein expression was also detected in 62 cases of normal esophagus mucous membrane tissue,31 cases of adjacent atypical hyperplasia tissue and 62 cases of EC by immunohistochemical SP method, then explored its clinicopathologic significance.
3. Detected CD34 protein expression in 62 cases of EC by immunohistochemical SP method, then explored its clinicopathologic significance simultaneously.
4. Discussed the relevance and significance of KiSS-1, MMP-2 and MVD by detecting the KiSS-1, MMP-2 and CD34 protein expression.
5. Statistical analysis:Statistics analysis was performed by SPSS 10.0 software, adopt chi-square test, T test and ANOVA, test standard a is 0.05.
1. The KiSS-1 protein expression rate in normal esophagus mucous membrane tissue, adjacent atypical hyperplasia tissue and esophageal squamous cell carcinoma tissue was 90.3%(56/62),67.7%(21/31) and 56.5%(35/62) respectively, and with a significant difference in group comparison (P<0.05); KiSS-1 protein masculine expression rate in infiltration depth of lower muscular layer group and deeper muscular layer group were 100%(7/7) and 50.9%(28/55) respectively, with a significant difference in group comparion (P <0.05); KiSS-1 protein masculine expression rate in lymphatic metastasis group was 35.0%(7/20), significantly lower than those without lymph node metastasis in EC was 66.7%(28/42), and with a significant difference in group comparion (P<0.05). KiSS-1 protein masculine expression in grade ofⅠ,ⅡandⅢwere respectively 66.7%(10/15),56.0%(14/25),50.0%(11/22), and no statistically significant difference (P> 0.05);
2. The MMP-2 protein masculine expression rate in normal esophagus mucous membrane tissue, adjacent atypical hyperplasia tissue and esophageal squamous cell carcinoma tissue were respectively 22.6%(14/62),54.8%(17/31) and 71.0% (44/62), and with a significant difference in group comparison (P<0.05); KiSS-1 protein masculine expression rate in infiltration depth of lower muscular layer group and deeper muscular layer group were 28.6%(2/7) and 76.4%(42/55) respectively, with a significant difference in group comparion (P<0.05);KiSS-1 protein masculine expression rate in lymphatic metastasis group was 90.0% (18/20), significantly higher than those without lymph node metastasis in EC was 61.9%(26/42),and with a significant difference in group comparion (P<0.05); KiSS-1 protein masculine expression in grade ofⅠ,ⅡandⅢwere respectively 46.7%(7/15),72.0%(18/25),86.4%(19/22), the difference was statistically significant (P<0.05).
3. The MVD values infiltrated to shallow muscular layer and those which infiltrated deeper layer were respectively 28.1±8.1 and 40.8±9.1,the difference among groups make statistics sense(P<0.05); The average MVD values in grade ofⅠⅡandⅢwere respectively 32.3±4.9,38.6±8.3, and 45.1±10.6,the difference between two groups was statistically significant (P<0.05); The average MVD values in EC with lymphatic metastasis(51.2±6.1) is signifcantly higher than those which without lymphatic metastasis(33.8±5.0),the difference among groups make statistics sense(P<0.05).
4. The protein expression of KiSS-1 and MMP-2 was negatively correlated (rs=-0.418, P<0.05); The average MVD values in EC which KiSS-1 protein expression is negative was significantly higher than those KiSS-1 protein expression is positive (P<0.05).
1. The KiSS-1 protein expression rate depress by turns in normal esophagus mucous membrane tissue, adjacent atypical hyperplasia tissue and esophagus cancer tissue, and there was a close correlation with the infiltration depth and lymph node metastasis, which suggest that the missing or lower expression of KiSS-1 may be related to the occurrence of EC. It is also closely related to the development, invasion and metastasis of EC.
2. The MMP-2 protein expression rate boost by turns in normal esophagus mucous membrane tissue,adjacent atypical hyperplasia tissue and esophagus cancer tissue,and there was a close correlation with the infiltration depth,differential grade and lymph node metastasis,which suggest that MMP-2 may be involved in the occurrence and development of EC.It is also closely related to the process of invasion and metastasis in EC;
3. The MVD value was closely related with the infiltration depth, differential grade and lymph node metastasis, which suggest that there was a close correlation with tumor biological behavior. MVD may become one of important assistant indexes in the early diagnosis and prognosis of EC, further providing a theoretical basis for gene therapy to block the tumour blood generation;
4. The average MVD value in EC which KiSS-1 protein expression is negative was significantly higher than those KiSS-1 protein expression is positive, while the average MVD value in EC which MMP-2 protein expression is positive was significantly higher than those KiSS-1 protein expression is negative. There was a negative correlation beween the expression of KiSS-1 and MMP-2 protein by immunnohistochemical SP method and by Spearman rank correlation analysis (r,=-0.418, P=0.001).All of these conclusions prompt that joint detection of KiSS-1, MMP-2 and MVD is expected to be an indicator of judging the prognosis of EC, further provide the theoretical basis of inhibiting tumor recurrence and metastasis.
引文
[1]汤钊猷,朱世熊,曹世龙等.现代肿瘤学.第二版.上海：复旦大学出版社,2003,658.
[2]Hendricks D, Parker MI. Oesophageal cancer in Africa. IUBMB Life,2002,53(4-5):263-68.
[3]Katagiri F, Nagai K,Kida A,et al. Clinical significance of plasma metastin level in pancreatic cancer patients.Oncol Rep,2009,21(3):815-819.
[4]Kostadima L, Pentheroudakis G, Pavlidis N. The missing kiss of life:transcriptional activity of the metastasis supp-ressor gene KiSS-1 in early breast cancer.Anticancer Res, 2007,27(4B):2499-2413.
[5]Yao HL,Yang ZL,Li YG,et al.In situ hybridization study on the expression of KiSS-1 and KAI-1 metastasis suppressor genes in gastric cancer.Zhonghua Wei Chang Wai Ke Za Zhi,2007,10(3):274-247.
[6]Hata K, Dhar DK, Watanabe Y, et al. Expression of metastin and a G-protein-coupled receptor (AXOR12) in epithelial ovarian cancer. Eur J Cancer,2007,43(9):1452-1455.
[7]Liang S, Yang ZL. Expression of KiSS-1 mRNA in pancreatic ductal adenocarcinoma and non-cancerous pancreatic tissues in SD rats, Zhong Nan Da Xue Xue Bao Yi Xue Ban, 2007,32(l):109.
[8]Tokuraku M, Sato H, Murakami S, et al. Activation of the precursor of gelatinase A/72 kDa type IV collagenase/MMP-2 in lung carcinomas correlates with the expression of nembrance-type matrix matalloproeinase and with lymph node metastasis.Int J Cancer, 1995,64(5):355-359.
[9]Sier CF, kubben FJ, Ganesh S,et al.Tissue levei of matrix matalloproteinases MMP-2 and MMP-9 are related to the overall survial of patients with gastric carcinoma.Br J Cancer,1996,74(3):413-417.
[10]Horak E, Leek R, Klenk N, et al. Angiogenesis, assessed by platelet/endothelial cell adhesion molecule antibodies, as indicator of node metastasis and survival in breast cancer. Lancet,1992,34(8828):1120-1124.
[11]Martin L, Holcombe C, Renshaw C, et al. Standarding the counting technique of neovascularization in invasive breast cancer. Breast Cancer Res Treat,1996,37(5):34-46.
[12]Gasparini G. Clinical significance of determination of surrogate markers of angiogenesis in breast cancer.Crit Rev Oncol Hematol.2001,37(2):97-114.
[13]Safwat MD,Habib F,Elayat A,et al. Morphometric and immunohistochemical study of angiogenic marker expressions in invasive ductal carcinoma of human breast.Folia Morphol(Warsz),2009,68(3):144-155.
[14]李钦,陈奎生,张国俊,等.食管鳞癌组织中胰岛素样生长因子-Ⅱ蛋白的表达.郑州大学学报：医学版,2006,41(3)：559-561.
[15]李晟磊,刘宗文,赵秋民等.食管鳞癌组织中RECK mRNA和蛋白的表达及意义.中国肿瘤临床,2007,34(22)：1280-1286.
[16]Weidner N, Folkman J, Pozza F, et al. Tumor angiogenesis:a new significant and independent prognostic indicator in early-stage breast carcinoma. J Natl Cancer Inst,1992, 84(24):1875.
[17]Hendricks D, Parker MI.Oesophageal cancer in Africa.IUBMB Life,2002,53(4-5): 63-268.
[18]Lee JH, Miele ME, Hicks DJ, et al. KiSS-1, a novel human malignant melanoma metastasis-suppressor gene.J Natl Cancer lnst,1996,88(23):1731-1737.
[19]West A, Vojta PJ, Welch DR, et al. Chromosome localization and genomic structure of the KiSS-1 metastasis suppressor-gene (KiSS-1). Genomics,1998,54(1):145-148.
[20]Steven FG, Mary EM, Naohito H, et al. Melanoma metastasis suppression by chromosome: evidence for a pathway regulated-by-CRSP3 and TXNIP. Cancer Res,2003, 63(2):432-440.
[21]Yan C, Wang H, Boyd D. KiSS-1 represses 92-kDa type IV collagenase expression by down-regulating NF-KB binding to the promoter as a consequence of IKB-induced block of P65/P50 nuclear translociation.J Biol Chem,2001,276(2):1164-1172.
[22]Masato k, Michel D, Ann V, et al. The metastasis suppressor gene KiSS-1 encodes KiSS peptins, the natural ligands of the orphan Gprotein couple dreceptor GPR54. J Biol Chem, 2001,276(37):34631-34636.
[23]Muir AI, Chamberlain L, Elshourbagy NA, et al. AXOR12, anovel human G-protein coupled receptor, activated by the peptide KiSS-1.J Biol Chem,2001,276(31):28969-28975.
[24]Stafford LJ, Xia C, Ma W, et al. Identification and characterization of mouse metastasis suppressor KiSS-1 and its G-Protein-coupled receptor.Cancer Res,2002,62(19):399-404.
[25]Lee J. H., Welch D. R. Suppression of metastasis in human breast carcinoma MDA-MB-35 cells after transfection with the metastasis suppressor gene, KiSS-1. Cancer Res.1997, 57(12):2384-2387.
[26]Lee JH., Welch DR. Identification of highly expressed genes in metastasis suppressed chromosome 6/human malignant melanoma hybrid cells using subtractive hybridization and differential display. Int J Cancer,1997,71(6):1035-1044.
[27]Misahide Ikeguchi,Stafford LJ, Li D, et al. Transciptional regulation of KiSS-1 gene expression in metastatic melanoma by specificity protein and its coactivator DR IP-130.Oncogene,2007,26(12):1739-1745.
[28]Shirasaki F,Takata M,Hatta N,et al.Loss of expression of the metastasis suppressor gene KiSS-1 during melanoma progression and its association with LOH of chromosome 6q16.3-q23. Cancer Res,2001,61(20):7422-7425.
[29]Shoji S, Tang XY, Umemura S, et al. Metastin inhibits migration and invasion of renal cell carcinoma with overexpression of metastin receptor.Eur Urol,2009,55(2):441-449.
[30]Shengbing Z, Feng LJ, Bin W, Lingyun G, et al. Expression of KiSS-1 gene and its role in invasion and metastasis of human hepatocellular carcinoma.Anat rec.2009,292(8): 1128-1134.
[31]Ikeguchi M, Hirooka Y, Kaibara N. Quantitative reverse transcriptase polymerase chain reaction analysis for KiSS-1 and orphan G-protein-coupled receptor (hOT7T175) gene expression in hepatocellular carcinoma.J Cancer Res Clin Oncol.2003,129(9):531-535.
[32]Mandai, Konishi I, Kuioda H, et al. Expression of abnomal transcripts of the FHIT (fragile histidine triad) gene in ovarian carcinoma. Eur J Cancer,1998,34(5):745-755.
[33]Liang S, Yang ZL.Expression of KiSS-1mRNA in pancreatic ductal adenocarcinoma and non-cancerous pancreatic tissues in SD rats.Zhong Nan Da Xue Xue Bao Yi Xue Ban,2007, 32(1):109-113.
[34]Masui T, Doi R, Mori T, et al. Metastin and its variant forms suppress migration of pancreatic cancer cells. Biochem Biophys Res Commun,2004,315(1):85-92.
[35]Nagai K,Doi R,Katagiri F,et al.Prognostic value of metastin expression in human pancreatic cancer.J Exp Clin Cancer Res,2009,28:9.
[36]Ringel MD,Hardy E,Bernet VJ,et al.Metastin receptor is overexpressed in papillary thyroid cancer and activates MAP kinase in thyroid cancer cells.J clin Endocrinol Metab,2002,87(5):2399-2402.
[37]Wang ZH,Feng XS,Wang GP,et al.Expression and clinical significance of KiSS-1 and E-cadherin in gastric cardia carcinoma.Zhonghua Wei Chang Wai Ke Za Zhi,2007,10(4): 380-382.
[38]Stark AM, Tongers K, Maass N, et al. Reduced metastasis-suppressor gene mRNA-expression in breast cancer brain metastases.J Cancer Res Clin Oncol,2005,131(3):1191-1198.
[39]Martin TA, Watkins G, Jiang WG, KiSS-1 expression in human breast cancer. Clin Exp Metastasis,2005,22(6):503-511.
[40]Sampieri CL,de la Pena S,Ochoa-Lara M,et al.Expression of matrix metalloproteinases 2 and 9 in human gastric cancer and superficial gastritis.World J Gastroenterol.2010,16(12): 1500-1505.
[41]Kleiner DE, Stetler-Stevenson WG. Matrix metalloproteinases and metastasis. Cancer Chemother Pharmacol,1999,43(Suppl):42-51.
[42]Kawmata H,Kameyama S,Kawai K,et al.Marked acceleration of the metastatic phenotype of a rat bladder carcinoma cell line by the expression of human gelatinase A.Int J Cancer, 1995,63(4):568-575.
[43]Tokuraku M, Sato H, Murakami S, et al. Activation of the precursor of gelatinase A/72 kDa type IV collagenase/MMP-2 in lung carcinomas correlates with the expression of nembrance-type matrix matalloproeinase and with lymph node metastasis.Int J Cancer, 1995,64(5):355-359.
[44]Hansen TF, Sorensen FB, Spindler KL, et al. Microvessel density and the association with single nucleotide polymorphisms of the vascular endothelial growth factor receptor 2 in patients with colorectal cancer.Virchows Arch,2010,456(3):251-260.
[45]Joukov V, Kum ar V, Sorsa T, et al. A recombinant mutant vascular endothelial growth factor that has lost vascular endothelial growth factor receptor-2 binding, activation, and vascular perm eability activies.J Bio Chen,1998,273(12):6599-6602.
[46]Saptefrati L,Climpean AM,Ciornli A,et al.Identification of lymphatic vessels and prognostic value of lymphatic microvessel density in lesions of the uterine cervix.Rom J Morphol Embryol,2009,50(4):589-594.
[47]Man K,Ng KT,Xu A,et al. Suppression of liver tumor growth and metastasis by adiponectin in nude mice through inhibition of tumor angiogenesis and downregulation of Rho kinase/IFN-inducible protein 10/matrix metalloproteinase 9 signaling.Clin Cancer Res,2010,16(3):967-977.
[48]Guo J, Higashi K, Ueda Y, et al. Microvessel density:correlation with 18F-FDG uptake and prognostic impact in lung adenocarcinomas.J Nucl Med,2006,47(3):419-425.
[49]Hata K, Dhar DK, Watanabe Y, et al. Expression of metastin and a G-protein-coupled receptor (AXOR12) in epithelial ovarian cancer. Eur J Cancer,2007,43(9):1452-1459.
[50]Aurrello P, Bellagamba R, Rossi Del Monte S, et al. Apoptosis and microvessel density in gastric cancer:correlation with tumor stage and prognosis.Am Surg,2009,75(12):1183-1188.
[51]Su CH, He YL, Chen ZQ et al. Notch 1 expression in esophageal squamous cell carcinoma and its relation with microvascular angiogenesis.Nan Fang Yi Ke Da Xue Xue Bao.2009, 29(11):2255-2258.
[52]Yoshioka K, OhnoY, Horiguchi Y, et al. Effects of a KiSS-1 peptide, a metastasis suppressor gene, on the invasive ability of renal cell carcinoma cells through a modulation of a matrix metalloproteinase-2 expression.Life Sci.2008,83(9-10):332-338.
[1]Hendricks D, Parker MI. Oesophageal cancer in Africa. IUBMB Life,2002,53(4-5): 263-265.
[2]Folkman J. Clinical applications of research on angiogenesis.N Engl J Med,1995, 333(26):1757-1763.
[3]吴后男,李玉林,张丽红,等.血管内皮因子和E26转录因子在乳腺癌中的表达及意义.中华病理学杂志,2002,31(3)：225-226.
[4]Joukou V, Kumar V, Sorsa T, et al. A recombinant mutant vascular endothelial growth factor-C that has lost vascular andothelial growth factor receptor-2 binding, activation, and vascular permeability activies. J Bio Chen,1998,273(12):6599-6602.
[5]Weidner N,Carroll PR,Flax J,et al. Tumor angiogenesis correlates with metastasis in invasive prostate carcinoma.Am J Pathol,1993,143(2):401-409.
[6]Liotta LA, Saidel MG, Kleinerman J,et al. The significance of hematogenous tumor cell clumps in the metastatic process.Cancere Res,1976,36(3):889-894.
[7]Morris SW, Valentine MB, Kirstein MN, et al. Reassignment of the human ARH9 RAS-related gene to chromosome Ip13-p21. Genomics,1993,15(3):677-679.
[8]Coleman M, Marshall C, Olson MF. RAS and RHO GTPases in G1-phase cell-cycle regulation.Nat Rev Mol Cell Biol,2004,5(5):355-366.
[9]Ohta Y, Fujimura L, Nishio S, et al. A kelch family protein Ndl-L functions as a metastasis suppressor in cancer cells via Rho family proteins mediated mechanism.Int J Oncol,2010, 36(2):427-434.
[10]Surviladze z,Waller A,Wu Y,et al. Identification of a small GTPase inhibitor using a high-throughput flow cytometry bead-based multiplex assay. J Biomol Screen,2010,15(1): 10-20.
[11]DerMardirossian C, Bokoch GM.GDIs:central regulatory molecules in Rho GTPase activation.Trends Cell Biol,2005,15(7):356-363.
[12]Kroot EJ, de-Jong BA, van-Leeuwen MA, et al. The prognostic value of anti-cyclic cit rullinated peptide antibody in patients with recent-onset rheumatoid arthritis. Arthritis Rheum,2000,43(8):1831-1835.
[13]Mediwake R, Isenberg DA, Schellekens GA, et al. Use of anti-citrullinated peptide and anti-RA33 antibodies in distinguishing erosive arthritis in patients with systemic lupus erythematosus and rheumatoid arthritis. Ann Rheum Dis,2001,60(1):67-68.
[14][14]Saptefrati L,Climpean AM,Ciornli A,et al.Identification of lymphatic vessels and prognostic value of lymphatic microvessel density in lesions of the uterine cervix.Rom J Morphol Embryol,2009,50(4):589-594.
[15]Man K,Ng KT,Xu A,et al.Suppression of liver tumor growth and metastasis by adiponectin in nude mice through inhibition of tumor angiogenesis and downregulation of Rho kinase/IFN-inducible protein 10/matrix metalloproteinase 9 signaling.Clin Cancer Res,2010,16(3):967-977.
[16]Guo J, Higashi K, Ueda Y, et al. Microvessel density:correlation with 18F-FDG uptake and prognostic impact in lung adenocarcinomas.J Nucl Med,2006,47(3):419-425.
[17]Hata K, Dhar DK, Watanabe Y, et al. Expression of metastin and a G-protein-coupled receptor (AXOR12) in epithelial ovarian cancer. Eur J Cancer,2007,43(9):1452-1459.
[18]Aurrello P,Bellagamba R,Rossi Del Monte S,et al.Apoptosis and microvessel density in gastric cancer:correlation with tumor stage and prognosis.Am Surg,2009,75(12):1183-1188.
[19]Weidner N, Semple JP, Welch WR, et al. Tumor angiogenesis and metastasis-correlation in invasive breast carcinoma.N Engl J Med,1991,324(3):1-8.
[20]Giatromanolaki A, ivridis E, Koukourakis Ml, et al. Intratumoral angiogenesis:a new Prognostic indicato for stage 1 endometrial adenocarcinomas? Oncology Research,1999, 11(4):205-212.
[21]Ohkawa H, Ohish N, Yagi K. Assay for lipid peroxidesin animal tissue by thiobarbituric acid reaction.Anal Biochem,1979,95(5),351-358.
[22]李志伟,鲁光恩,胡安国,等VEGF的表达及MVD与肝细胞癌侵袭转移和预后的关系.中国现代医学杂志,2003,13(16)：13-17.
[23]Kimura H, NakajimaT, Kagawa K, et al. Angiogenesis in hepatocellar carcinoma as evaluated by CD34 immunohistochemistry.Liver,1998,18(1):14-19.
[24]EI-Assal ON, Yamanoi A, Soda Y, et al. Clinical significance of microvessel density and vascular endothelial growth factor expression in hepatocellar carcimona and surrounding liver:Possible involvement of Vascular endothelial growth factor in the angiogenesis of cirrhotic liver. Hepatology,1998,27(6):1554-1562.
[25]汤钊猷,汤钊猷临床肝癌学,上海科技教育出版社,2000,2：145-146.
[26]Bunsiripaiboon P, Sornmayura P, Wilasrusmee C, et al. The prognostic significance of microvessel density in intrahepatic cholangiocarcinoma. J Med Assoc Thai, 2010,93(1):66-72.
[27]AnticD, Jovanovic MP, Fekete MD, et al. Assessent of Bone Marrow Microvessel Density in Chronic Lymphocytic Leukemia. Appl Immunohistochem Mol Morphol.2010, 15(6),55-58.
[28]Takahashi N, Kawanishi Tabata R, Haba A, et al. Association of seurm endoglin with metastasis in patients with colorectal, breast and other solid tumors, andsuppressive effect of chemotherapy on the serum endoglin. Surgey,2002,131 (suppl):109-113.
[29]Baba M, Konno H, Marni Y, et al. Relationship of p53 and vascular endothelial growth factor in human scirrhous gastric cancer.Eur Surg Res,1998,30(2):130-137.
[30]Maeda K, Cgung YS, Ogawa Y, et al. Prognostic value ofvascular endothelial growth factor expression in gastric carcinoma.Cancer,1996,77(5):858-863.
[31]Takahashi Y, Kitadai Y, Bueana CD, et al. Expression of vascular endothelial growth factor and its receptor,KDR,correlations with vascularity,metastasis and proliferation of human colon cancer.Cancer Res,1995,55(3),964-968.
[32]Tanigawa N,Amaya H,Matsumura M,et al.Correlation between expression of vascular endothelial gastric factor and tumor vascularity and patient outcome in human gastric carcinoma.J Clin Oncol,1997,15(2):826-832.
[33]邵成洁,胡先贵,唐岩,等.胰腺癌的血管生成及临床意义.中国普通外科杂志,2003,12(2)：125-127.
[34][34]Yanase T,Tamura M, Fujita K. Inhibitory effect of angionesis inhibiter TNP2470 on tumor growth and metastasis of human cell lines in vitro and vivo. Cancer Res,1993, 53(2),566-568.
[35]Ellis LM,Takahashi Y,Fenoglio CJ,et al.Vessel counts and vascular endothelial growth factor expression in pancreatic adenocarcinoma.European Journal of Cancer,1998,34(3): 337-340.
[36]Ikeda N,Adaehi M, Taki T, et al. Prognostic significance of angiogenesis in human pancreatic cancer.British Journal of Cancer,1999,79(9-10):1553-1563.
[37]Diekson AJ,Fox SB,Fersad RA,et al.Qunatification of angiogenesis as a independent predictor of prognosis in invasive bladder carcinoma,B J Urol,1994,86(21):1603-1608.
[38]Goddard JC, Sutton CD, Furness PN, et al. Microvessel density at presentation perdicts subsequent muscle invasion in superficial bladder cancer.Clin Cancer Res,2003,9(7): 2583-2586.
[39]Jaeger TM,Weidner N,Chew K, et al.Tumor angiogenesis correlates with lymph node metastases in invasive bladder cancer.J Urol,1995,154(1):69-71.
[40]陈军,史时芳.膀胱移行细胞癌中血管内皮生长因子表达与微血管密度的关系.临床泌尿外科杂志,2002,17(6)：304-306.
[41]Aznar S, Lacal JC. Rho signals to cell growth and apoptosis. Cancer Lett,2001,165(1): 1-10.
[42]Clark EA, Golub TR, Lander ES, et al. Genomic analysis of metastasis reveals an essential role for RhoC.Nature,2000,406(6840):532-535.
[43]Rantapaa-Dahlqvist S,de-Jong BA,Berglin E,et al. Antibodies against cyclic citrullinated peptide and Ig A rheumatoid factor predict the development of rheumatoid arthritis. Arthritis Rheum,2003,48(10):2714-2749.
[44]Okabe H, Satoh S, Kato T, et al. Genome-wide analysis of gene expression in human hepatocellular carcinomas using cDNA microssary:Identification of genes involved in viral Carcinogenesis and tumor progression.Cancer Res,2001,61 (5):2129-2137.
[45]蔡秀军,徐关根,沈波等.RhoC蛋白在原发性肝细胞癌中的表达,浙江大学学报(医学版),2006,35(4),394-396.
[46]刘东明,许月新,韩昱晨,等RhoC及其调节因子RhoGDβI和RhoGDγI在肺癌细胞系中的表达.肿瘤.2009,29(2)：131-134
[47]王萍,杨金凤,张庆,等RhoC基因的过量表达在胃癌中的意义.临床消化病杂志,2007,19(2)：88-90.
[48]石铮,郑岩松,曾金华,等.RhoC基因及蛋白在胃癌肝转移中的表达及意义.中西医结合肝病杂志,2003(Suppl),40-43.
[49]Sokoll KB, Helliwell P. Pharmacologial management of transient synovitis. Expert Opin Pharmacother,2006,7(l):35-46
[50]奈嫚嫚,尹如铁,谢聪,等RhoC和Ki67在宫颈鳞癌中的表达及意义.四川大学学报(医学版).2009,40(2)：236-239.
[51]韩志强,张阿丽,吴明富,等RhoA、RhoC及其效应分子ROCK-1的表达与卵巢癌细胞系恶性行为相关性的体外研究.中华肿瘤杂志,2004；26(7)：385-388.
[52]Horiuchi A, Imai T, Wang C, et al. Up regulation of small GTPases, RhoA and RhoC, is associated with tumor progression in ovarian carcinoma. Laboratory Investigation,2003; 83(6):861-870.
[53]于月成,辛晓燕,吴维光,等.Rho和ROCK蛋白在上皮性卵巢癌中的表达及临床意义.现代肿瘤医学,2006；14(4)：461-464.
[54]李潇,朱丹,潘颖,等RhoC蛋白在卵巢上皮性癌中的表达及临床意义.中国肿瘤临床.2008,35(20),1184-1187.
[55]王海波,刘相萍,杨堃,等RhoA、C干扰载体的构建及其对直肠癌HCT116细胞相应基因表达的影响.山东医药,2008,48(24)：1-3.
[56]陈维荣,刘俐敏,蔡高阳,等.直肠癌RhoC基因表达与临床病理特点的关系.中国普通外科杂志,2004,13(9),691-692.
[57]Fritz G, Just I, Kaina B. Rho GTPases are overexpression in human tumors. Int J Cancer, 1999,81(5):682-687.
[58]van Golen KL, Wu ZF, Qiao XT, et al. RhoC GTPase, a novel transforming oncogene for human mammary epithelial cells that partially recapitulates the inflammatory breast cancer phenotype. Cancer Res,2000,60(20):5832-5838.
[59]Van den Eynden GG, Van der Auwera I, Van Laere S,et al.Validation of a tissue microrray to study differential protein expression in inflammatory and non-inflammatory breast cancer. Breast Cancer Res Treat 2004,85(1):13-22.
[60]邱兴烽,王效民,殷平,等.肝癌组织RhoC蛋白表达与微血管密度的关系.世界华人消化杂志,2006,14(7)：671-675.
[2]Hendricks D, Parker MI. Oesophageal cancer in Africa. IUBMB Life,2002,53(4-5):263-68.
[3]Katagiri F, Nagai K,Kida A,et al. Clinical significance of plasma metastin level in pancreatic cancer patients.Oncol Rep,2009,21(3):815-819.
[4]Kostadima L, Pentheroudakis G, Pavlidis N. The missing kiss of life:transcriptional activity of the metastasis supp-ressor gene KiSS-1 in early breast cancer.Anticancer Res, 2007,27(4B):2499-2413.
[5]Yao HL,Yang ZL,Li YG,et al.In situ hybridization study on the expression of KiSS-1 and KAI-1 metastasis suppressor genes in gastric cancer.Zhonghua Wei Chang Wai Ke Za Zhi,2007,10(3):274-247.
[6]Hata K, Dhar DK, Watanabe Y, et al. Expression of metastin and a G-protein-coupled receptor (AXOR12) in epithelial ovarian cancer. Eur J Cancer,2007,43(9):1452-1455.
[7]Liang S, Yang ZL. Expression of KiSS-1 mRNA in pancreatic ductal adenocarcinoma and non-cancerous pancreatic tissues in SD rats, Zhong Nan Da Xue Xue Bao Yi Xue Ban, 2007,32(l):109.
[8]Tokuraku M, Sato H, Murakami S, et al. Activation of the precursor of gelatinase A/72 kDa type IV collagenase/MMP-2 in lung carcinomas correlates with the expression of nembrance-type matrix matalloproeinase and with lymph node metastasis.Int J Cancer, 1995,64(5):355-359.
[9]Sier CF, kubben FJ, Ganesh S,et al.Tissue levei of matrix matalloproteinases MMP-2 and MMP-9 are related to the overall survial of patients with gastric carcinoma.Br J Cancer,1996,74(3):413-417.
[10]Horak E, Leek R, Klenk N, et al. Angiogenesis, assessed by platelet/endothelial cell adhesion molecule antibodies, as indicator of node metastasis and survival in breast cancer. Lancet,1992,34(8828):1120-1124.
[11]Martin L, Holcombe C, Renshaw C, et al. Standarding the counting technique of neovascularization in invasive breast cancer. Breast Cancer Res Treat,1996,37(5):34-46.
[12]Gasparini G. Clinical significance of determination of surrogate markers of angiogenesis in breast cancer.Crit Rev Oncol Hematol.2001,37(2):97-114.
[13]Safwat MD,Habib F,Elayat A,et al. Morphometric and immunohistochemical study of angiogenic marker expressions in invasive ductal carcinoma of human breast.Folia Morphol(Warsz),2009,68(3):144-155.
[14]李钦,陈奎生,张国俊,等.食管鳞癌组织中胰岛素样生长因子-Ⅱ蛋白的表达.郑州大学学报：医学版,2006,41(3)：559-561.
[15]李晟磊,刘宗文,赵秋民等.食管鳞癌组织中RECK mRNA和蛋白的表达及意义.中国肿瘤临床,2007,34(22)：1280-1286.
[16]Weidner N, Folkman J, Pozza F, et al. Tumor angiogenesis:a new significant and independent prognostic indicator in early-stage breast carcinoma. J Natl Cancer Inst,1992, 84(24):1875.
[17]Hendricks D, Parker MI.Oesophageal cancer in Africa.IUBMB Life,2002,53(4-5): 63-268.
[18]Lee JH, Miele ME, Hicks DJ, et al. KiSS-1, a novel human malignant melanoma metastasis-suppressor gene.J Natl Cancer lnst,1996,88(23):1731-1737.
[19]West A, Vojta PJ, Welch DR, et al. Chromosome localization and genomic structure of the KiSS-1 metastasis suppressor-gene (KiSS-1). Genomics,1998,54(1):145-148.
[20]Steven FG, Mary EM, Naohito H, et al. Melanoma metastasis suppression by chromosome: evidence for a pathway regulated-by-CRSP3 and TXNIP. Cancer Res,2003, 63(2):432-440.
[21]Yan C, Wang H, Boyd D. KiSS-1 represses 92-kDa type IV collagenase expression by down-regulating NF-KB binding to the promoter as a consequence of IKB-induced block of P65/P50 nuclear translociation.J Biol Chem,2001,276(2):1164-1172.
[22]Masato k, Michel D, Ann V, et al. The metastasis suppressor gene KiSS-1 encodes KiSS peptins, the natural ligands of the orphan Gprotein couple dreceptor GPR54. J Biol Chem, 2001,276(37):34631-34636.
[23]Muir AI, Chamberlain L, Elshourbagy NA, et al. AXOR12, anovel human G-protein coupled receptor, activated by the peptide KiSS-1.J Biol Chem,2001,276(31):28969-28975.
[24]Stafford LJ, Xia C, Ma W, et al. Identification and characterization of mouse metastasis suppressor KiSS-1 and its G-Protein-coupled receptor.Cancer Res,2002,62(19):399-404.
[25]Lee J. H., Welch D. R. Suppression of metastasis in human breast carcinoma MDA-MB-35 cells after transfection with the metastasis suppressor gene, KiSS-1. Cancer Res.1997, 57(12):2384-2387.
[26]Lee JH., Welch DR. Identification of highly expressed genes in metastasis suppressed chromosome 6/human malignant melanoma hybrid cells using subtractive hybridization and differential display. Int J Cancer,1997,71(6):1035-1044.
[27]Misahide Ikeguchi,Stafford LJ, Li D, et al. Transciptional regulation of KiSS-1 gene expression in metastatic melanoma by specificity protein and its coactivator DR IP-130.Oncogene,2007,26(12):1739-1745.
[28]Shirasaki F,Takata M,Hatta N,et al.Loss of expression of the metastasis suppressor gene KiSS-1 during melanoma progression and its association with LOH of chromosome 6q16.3-q23. Cancer Res,2001,61(20):7422-7425.
[29]Shoji S, Tang XY, Umemura S, et al. Metastin inhibits migration and invasion of renal cell carcinoma with overexpression of metastin receptor.Eur Urol,2009,55(2):441-449.
[30]Shengbing Z, Feng LJ, Bin W, Lingyun G, et al. Expression of KiSS-1 gene and its role in invasion and metastasis of human hepatocellular carcinoma.Anat rec.2009,292(8): 1128-1134.
[31]Ikeguchi M, Hirooka Y, Kaibara N. Quantitative reverse transcriptase polymerase chain reaction analysis for KiSS-1 and orphan G-protein-coupled receptor (hOT7T175) gene expression in hepatocellular carcinoma.J Cancer Res Clin Oncol.2003,129(9):531-535.
[32]Mandai, Konishi I, Kuioda H, et al. Expression of abnomal transcripts of the FHIT (fragile histidine triad) gene in ovarian carcinoma. Eur J Cancer,1998,34(5):745-755.
[33]Liang S, Yang ZL.Expression of KiSS-1mRNA in pancreatic ductal adenocarcinoma and non-cancerous pancreatic tissues in SD rats.Zhong Nan Da Xue Xue Bao Yi Xue Ban,2007, 32(1):109-113.
[34]Masui T, Doi R, Mori T, et al. Metastin and its variant forms suppress migration of pancreatic cancer cells. Biochem Biophys Res Commun,2004,315(1):85-92.
[35]Nagai K,Doi R,Katagiri F,et al.Prognostic value of metastin expression in human pancreatic cancer.J Exp Clin Cancer Res,2009,28:9.
[36]Ringel MD,Hardy E,Bernet VJ,et al.Metastin receptor is overexpressed in papillary thyroid cancer and activates MAP kinase in thyroid cancer cells.J clin Endocrinol Metab,2002,87(5):2399-2402.
[37]Wang ZH,Feng XS,Wang GP,et al.Expression and clinical significance of KiSS-1 and E-cadherin in gastric cardia carcinoma.Zhonghua Wei Chang Wai Ke Za Zhi,2007,10(4): 380-382.
[38]Stark AM, Tongers K, Maass N, et al. Reduced metastasis-suppressor gene mRNA-expression in breast cancer brain metastases.J Cancer Res Clin Oncol,2005,131(3):1191-1198.
[39]Martin TA, Watkins G, Jiang WG, KiSS-1 expression in human breast cancer. Clin Exp Metastasis,2005,22(6):503-511.
[40]Sampieri CL,de la Pena S,Ochoa-Lara M,et al.Expression of matrix metalloproteinases 2 and 9 in human gastric cancer and superficial gastritis.World J Gastroenterol.2010,16(12): 1500-1505.
[41]Kleiner DE, Stetler-Stevenson WG. Matrix metalloproteinases and metastasis. Cancer Chemother Pharmacol,1999,43(Suppl):42-51.
[42]Kawmata H,Kameyama S,Kawai K,et al.Marked acceleration of the metastatic phenotype of a rat bladder carcinoma cell line by the expression of human gelatinase A.Int J Cancer, 1995,63(4):568-575.
[43]Tokuraku M, Sato H, Murakami S, et al. Activation of the precursor of gelatinase A/72 kDa type IV collagenase/MMP-2 in lung carcinomas correlates with the expression of nembrance-type matrix matalloproeinase and with lymph node metastasis.Int J Cancer, 1995,64(5):355-359.
[44]Hansen TF, Sorensen FB, Spindler KL, et al. Microvessel density and the association with single nucleotide polymorphisms of the vascular endothelial growth factor receptor 2 in patients with colorectal cancer.Virchows Arch,2010,456(3):251-260.
[45]Joukov V, Kum ar V, Sorsa T, et al. A recombinant mutant vascular endothelial growth factor that has lost vascular endothelial growth factor receptor-2 binding, activation, and vascular perm eability activies.J Bio Chen,1998,273(12):6599-6602.
[46]Saptefrati L,Climpean AM,Ciornli A,et al.Identification of lymphatic vessels and prognostic value of lymphatic microvessel density in lesions of the uterine cervix.Rom J Morphol Embryol,2009,50(4):589-594.
[47]Man K,Ng KT,Xu A,et al. Suppression of liver tumor growth and metastasis by adiponectin in nude mice through inhibition of tumor angiogenesis and downregulation of Rho kinase/IFN-inducible protein 10/matrix metalloproteinase 9 signaling.Clin Cancer Res,2010,16(3):967-977.
[48]Guo J, Higashi K, Ueda Y, et al. Microvessel density:correlation with 18F-FDG uptake and prognostic impact in lung adenocarcinomas.J Nucl Med,2006,47(3):419-425.
[49]Hata K, Dhar DK, Watanabe Y, et al. Expression of metastin and a G-protein-coupled receptor (AXOR12) in epithelial ovarian cancer. Eur J Cancer,2007,43(9):1452-1459.
[50]Aurrello P, Bellagamba R, Rossi Del Monte S, et al. Apoptosis and microvessel density in gastric cancer:correlation with tumor stage and prognosis.Am Surg,2009,75(12):1183-1188.
[51]Su CH, He YL, Chen ZQ et al. Notch 1 expression in esophageal squamous cell carcinoma and its relation with microvascular angiogenesis.Nan Fang Yi Ke Da Xue Xue Bao.2009, 29(11):2255-2258.
[52]Yoshioka K, OhnoY, Horiguchi Y, et al. Effects of a KiSS-1 peptide, a metastasis suppressor gene, on the invasive ability of renal cell carcinoma cells through a modulation of a matrix metalloproteinase-2 expression.Life Sci.2008,83(9-10):332-338.
[1]Hendricks D, Parker MI. Oesophageal cancer in Africa. IUBMB Life,2002,53(4-5): 263-265.
[2]Folkman J. Clinical applications of research on angiogenesis.N Engl J Med,1995, 333(26):1757-1763.
[3]吴后男,李玉林,张丽红,等.血管内皮因子和E26转录因子在乳腺癌中的表达及意义.中华病理学杂志,2002,31(3)：225-226.
[4]Joukou V, Kumar V, Sorsa T, et al. A recombinant mutant vascular endothelial growth factor-C that has lost vascular andothelial growth factor receptor-2 binding, activation, and vascular permeability activies. J Bio Chen,1998,273(12):6599-6602.
[5]Weidner N,Carroll PR,Flax J,et al. Tumor angiogenesis correlates with metastasis in invasive prostate carcinoma.Am J Pathol,1993,143(2):401-409.
[6]Liotta LA, Saidel MG, Kleinerman J,et al. The significance of hematogenous tumor cell clumps in the metastatic process.Cancere Res,1976,36(3):889-894.
[7]Morris SW, Valentine MB, Kirstein MN, et al. Reassignment of the human ARH9 RAS-related gene to chromosome Ip13-p21. Genomics,1993,15(3):677-679.
[8]Coleman M, Marshall C, Olson MF. RAS and RHO GTPases in G1-phase cell-cycle regulation.Nat Rev Mol Cell Biol,2004,5(5):355-366.
[9]Ohta Y, Fujimura L, Nishio S, et al. A kelch family protein Ndl-L functions as a metastasis suppressor in cancer cells via Rho family proteins mediated mechanism.Int J Oncol,2010, 36(2):427-434.
[10]Surviladze z,Waller A,Wu Y,et al. Identification of a small GTPase inhibitor using a high-throughput flow cytometry bead-based multiplex assay. J Biomol Screen,2010,15(1): 10-20.
[11]DerMardirossian C, Bokoch GM.GDIs:central regulatory molecules in Rho GTPase activation.Trends Cell Biol,2005,15(7):356-363.
[12]Kroot EJ, de-Jong BA, van-Leeuwen MA, et al. The prognostic value of anti-cyclic cit rullinated peptide antibody in patients with recent-onset rheumatoid arthritis. Arthritis Rheum,2000,43(8):1831-1835.
[13]Mediwake R, Isenberg DA, Schellekens GA, et al. Use of anti-citrullinated peptide and anti-RA33 antibodies in distinguishing erosive arthritis in patients with systemic lupus erythematosus and rheumatoid arthritis. Ann Rheum Dis,2001,60(1):67-68.
[14][14]Saptefrati L,Climpean AM,Ciornli A,et al.Identification of lymphatic vessels and prognostic value of lymphatic microvessel density in lesions of the uterine cervix.Rom J Morphol Embryol,2009,50(4):589-594.
[15]Man K,Ng KT,Xu A,et al.Suppression of liver tumor growth and metastasis by adiponectin in nude mice through inhibition of tumor angiogenesis and downregulation of Rho kinase/IFN-inducible protein 10/matrix metalloproteinase 9 signaling.Clin Cancer Res,2010,16(3):967-977.
[16]Guo J, Higashi K, Ueda Y, et al. Microvessel density:correlation with 18F-FDG uptake and prognostic impact in lung adenocarcinomas.J Nucl Med,2006,47(3):419-425.
[17]Hata K, Dhar DK, Watanabe Y, et al. Expression of metastin and a G-protein-coupled receptor (AXOR12) in epithelial ovarian cancer. Eur J Cancer,2007,43(9):1452-1459.
[18]Aurrello P,Bellagamba R,Rossi Del Monte S,et al.Apoptosis and microvessel density in gastric cancer:correlation with tumor stage and prognosis.Am Surg,2009,75(12):1183-1188.
[19]Weidner N, Semple JP, Welch WR, et al. Tumor angiogenesis and metastasis-correlation in invasive breast carcinoma.N Engl J Med,1991,324(3):1-8.
[20]Giatromanolaki A, ivridis E, Koukourakis Ml, et al. Intratumoral angiogenesis:a new Prognostic indicato for stage 1 endometrial adenocarcinomas? Oncology Research,1999, 11(4):205-212.
[21]Ohkawa H, Ohish N, Yagi K. Assay for lipid peroxidesin animal tissue by thiobarbituric acid reaction.Anal Biochem,1979,95(5),351-358.
[22]李志伟,鲁光恩,胡安国,等VEGF的表达及MVD与肝细胞癌侵袭转移和预后的关系.中国现代医学杂志,2003,13(16)：13-17.
[23]Kimura H, NakajimaT, Kagawa K, et al. Angiogenesis in hepatocellar carcinoma as evaluated by CD34 immunohistochemistry.Liver,1998,18(1):14-19.
[24]EI-Assal ON, Yamanoi A, Soda Y, et al. Clinical significance of microvessel density and vascular endothelial growth factor expression in hepatocellar carcimona and surrounding liver:Possible involvement of Vascular endothelial growth factor in the angiogenesis of cirrhotic liver. Hepatology,1998,27(6):1554-1562.
[25]汤钊猷,汤钊猷临床肝癌学,上海科技教育出版社,2000,2：145-146.
[26]Bunsiripaiboon P, Sornmayura P, Wilasrusmee C, et al. The prognostic significance of microvessel density in intrahepatic cholangiocarcinoma. J Med Assoc Thai, 2010,93(1):66-72.
[27]AnticD, Jovanovic MP, Fekete MD, et al. Assessent of Bone Marrow Microvessel Density in Chronic Lymphocytic Leukemia. Appl Immunohistochem Mol Morphol.2010, 15(6),55-58.
[28]Takahashi N, Kawanishi Tabata R, Haba A, et al. Association of seurm endoglin with metastasis in patients with colorectal, breast and other solid tumors, andsuppressive effect of chemotherapy on the serum endoglin. Surgey,2002,131 (suppl):109-113.
[29]Baba M, Konno H, Marni Y, et al. Relationship of p53 and vascular endothelial growth factor in human scirrhous gastric cancer.Eur Surg Res,1998,30(2):130-137.
[30]Maeda K, Cgung YS, Ogawa Y, et al. Prognostic value ofvascular endothelial growth factor expression in gastric carcinoma.Cancer,1996,77(5):858-863.
[31]Takahashi Y, Kitadai Y, Bueana CD, et al. Expression of vascular endothelial growth factor and its receptor,KDR,correlations with vascularity,metastasis and proliferation of human colon cancer.Cancer Res,1995,55(3),964-968.
[32]Tanigawa N,Amaya H,Matsumura M,et al.Correlation between expression of vascular endothelial gastric factor and tumor vascularity and patient outcome in human gastric carcinoma.J Clin Oncol,1997,15(2):826-832.
[33]邵成洁,胡先贵,唐岩,等.胰腺癌的血管生成及临床意义.中国普通外科杂志,2003,12(2)：125-127.
[34][34]Yanase T,Tamura M, Fujita K. Inhibitory effect of angionesis inhibiter TNP2470 on tumor growth and metastasis of human cell lines in vitro and vivo. Cancer Res,1993, 53(2),566-568.
[35]Ellis LM,Takahashi Y,Fenoglio CJ,et al.Vessel counts and vascular endothelial growth factor expression in pancreatic adenocarcinoma.European Journal of Cancer,1998,34(3): 337-340.
[36]Ikeda N,Adaehi M, Taki T, et al. Prognostic significance of angiogenesis in human pancreatic cancer.British Journal of Cancer,1999,79(9-10):1553-1563.
[37]Diekson AJ,Fox SB,Fersad RA,et al.Qunatification of angiogenesis as a independent predictor of prognosis in invasive bladder carcinoma,B J Urol,1994,86(21):1603-1608.
[38]Goddard JC, Sutton CD, Furness PN, et al. Microvessel density at presentation perdicts subsequent muscle invasion in superficial bladder cancer.Clin Cancer Res,2003,9(7): 2583-2586.
[39]Jaeger TM,Weidner N,Chew K, et al.Tumor angiogenesis correlates with lymph node metastases in invasive bladder cancer.J Urol,1995,154(1):69-71.
[40]陈军,史时芳.膀胱移行细胞癌中血管内皮生长因子表达与微血管密度的关系.临床泌尿外科杂志,2002,17(6)：304-306.
[41]Aznar S, Lacal JC. Rho signals to cell growth and apoptosis. Cancer Lett,2001,165(1): 1-10.
[42]Clark EA, Golub TR, Lander ES, et al. Genomic analysis of metastasis reveals an essential role for RhoC.Nature,2000,406(6840):532-535.
[43]Rantapaa-Dahlqvist S,de-Jong BA,Berglin E,et al. Antibodies against cyclic citrullinated peptide and Ig A rheumatoid factor predict the development of rheumatoid arthritis. Arthritis Rheum,2003,48(10):2714-2749.
[44]Okabe H, Satoh S, Kato T, et al. Genome-wide analysis of gene expression in human hepatocellular carcinomas using cDNA microssary:Identification of genes involved in viral Carcinogenesis and tumor progression.Cancer Res,2001,61 (5):2129-2137.
[45]蔡秀军,徐关根,沈波等.RhoC蛋白在原发性肝细胞癌中的表达,浙江大学学报(医学版),2006,35(4),394-396.
[46]刘东明,许月新,韩昱晨,等RhoC及其调节因子RhoGDβI和RhoGDγI在肺癌细胞系中的表达.肿瘤.2009,29(2)：131-134
[47]王萍,杨金凤,张庆,等RhoC基因的过量表达在胃癌中的意义.临床消化病杂志,2007,19(2)：88-90.
[48]石铮,郑岩松,曾金华,等.RhoC基因及蛋白在胃癌肝转移中的表达及意义.中西医结合肝病杂志,2003(Suppl),40-43.
[49]Sokoll KB, Helliwell P. Pharmacologial management of transient synovitis. Expert Opin Pharmacother,2006,7(l):35-46
[50]奈嫚嫚,尹如铁,谢聪,等RhoC和Ki67在宫颈鳞癌中的表达及意义.四川大学学报(医学版).2009,40(2)：236-239.
[51]韩志强,张阿丽,吴明富,等RhoA、RhoC及其效应分子ROCK-1的表达与卵巢癌细胞系恶性行为相关性的体外研究.中华肿瘤杂志,2004；26(7)：385-388.
[52]Horiuchi A, Imai T, Wang C, et al. Up regulation of small GTPases, RhoA and RhoC, is associated with tumor progression in ovarian carcinoma. Laboratory Investigation,2003; 83(6):861-870.
[53]于月成,辛晓燕,吴维光,等.Rho和ROCK蛋白在上皮性卵巢癌中的表达及临床意义.现代肿瘤医学,2006；14(4)：461-464.
[54]李潇,朱丹,潘颖,等RhoC蛋白在卵巢上皮性癌中的表达及临床意义.中国肿瘤临床.2008,35(20),1184-1187.
[55]王海波,刘相萍,杨堃,等RhoA、C干扰载体的构建及其对直肠癌HCT116细胞相应基因表达的影响.山东医药,2008,48(24)：1-3.
[56]陈维荣,刘俐敏,蔡高阳,等.直肠癌RhoC基因表达与临床病理特点的关系.中国普通外科杂志,2004,13(9),691-692.
[57]Fritz G, Just I, Kaina B. Rho GTPases are overexpression in human tumors. Int J Cancer, 1999,81(5):682-687.
[58]van Golen KL, Wu ZF, Qiao XT, et al. RhoC GTPase, a novel transforming oncogene for human mammary epithelial cells that partially recapitulates the inflammatory breast cancer phenotype. Cancer Res,2000,60(20):5832-5838.
[59]Van den Eynden GG, Van der Auwera I, Van Laere S,et al.Validation of a tissue microrray to study differential protein expression in inflammatory and non-inflammatory breast cancer. Breast Cancer Res Treat 2004,85(1):13-22.
[60]邱兴烽,王效民,殷平,等.肝癌组织RhoC蛋白表达与微血管密度的关系.世界华人消化杂志,2006,14(7)：671-675.
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