食管癌侵袭转移相关基因的研究

英文题名：Studies on Invasion and Metastasis Associated Genes in Esophageal Carcinoma
作者：潘健
论文级别：博士
学科专业名称：免疫学
中文关键词：食管癌 ; 转移 ; 食管癌微血管内皮 ; TFPI-2 ; mir663 ; 有丝分裂灾难
英文关键词：Esophageal carcinoma ; metastasis ; esophageal tumor microvascular endothelial cells ; TFPI-2 ; mir663 ; mitotic catastrophe
学位年度：2010
导师：杨治华 ; 冉宇靓 ; 赵清正
学科代码：100102
学位授予单位：中国协和医科大学
论文提交日期：2010-05-01

摘要

食管癌是人类十大恶性肿瘤之一,尽管食管癌的诊断和治疗取得了较大进展,但食管癌仍然严重威胁着人类的生命和健康。食管癌预后差的主要原因是肿瘤对周围组织的侵袭,以及在肿瘤早期就发生邻近组织和远端组织的转移。目前的研究表明肿瘤微环境中的各种理化因素以及肿瘤间质细胞等都对肿瘤的侵袭转移发挥着重要的调控作用。肿瘤组织中缺氧、酸中毒、大量生长因子、大量蛋白水解酶以及免疫炎性反应等构成了肿瘤组织代谢环境的生物学特征。这种特性不仅对肿瘤的增殖、侵袭、迁移、细胞黏附以及新生血管的形成具有重要影响,同时也对肿瘤组织内的间质细胞产生了广泛的影响。新近的研究表明肿瘤转移依赖于肿瘤细胞与各种基质细胞的协调有效的相互作用。组成肿瘤微环境的基质细胞参与了肿瘤侵袭转移的整个过程。
     本研究针对食管癌侵袭转移与微血管内皮的关系,采用内皮细胞磁珠分选系统从新鲜食管癌组织中分离获得了食管癌微血管内皮,体外成功培养并命名为ECEC。食管癌微血管内皮相对正常内皮具有更强的增殖能力、抗凋亡能力。基因芯片分析发现食管癌内皮高表达趋化因子家族基因以及一些与肿瘤细胞侵袭转移密切相关的基因。将食管癌内皮与食管癌细胞共培养后食管癌细胞的侵袭及运动能力大大增强(P<0.01),并且这种增强作用依赖于肿瘤细胞与内皮细胞的直接接触。将食管癌内皮与食管癌细胞混合接种裸鼠,食管癌内皮可以明显促进移植瘤的生长(4-8倍)、肿瘤的局部侵袭以及远端肺转移的发生(P<0.01)。利用基因芯片分析体外共培养后肿瘤细胞中表达变化的基因,有一系列的侵袭相关基因在肿瘤细胞中上调表达。通过对其中一部分基因如AREG, EREG, MMP1、IL6、MMP3、IL1B、ADM以及Cyr61等的功能验证,其中的AREG和EREG都可以明显促进食管癌细胞的侵袭和迁移,体内移植瘤实验发现AREG和EREG基因都可以明显促进移植瘤的生长(P<0.01),远端肺转移的发生(P<0.01)。并且可以明显缩短实验组裸鼠的存活时间(P<0.01)。这些研究表明食管癌内皮可以促进食管癌细胞体内外的侵袭转移,并且这种作用可能通过食管癌内皮上调食管癌细胞中的一系列侵袭转移基因来实现。我们对其中的基因EREG进行了深入研究,EREG在食管癌细胞系的表达与各细胞系的侵袭能力存在密切关系。分析136例食管癌及配对正常组织中EREG的表达情况发现EREG基因在食管癌及淋巴结转移组织中表达强度明显高于对照正常组织(P<0.01)。分析124例具有完整临床资料的食管癌组织发现EREG的表达与食管癌的原位侵袭(T)和淋巴结转移(N)都密切相关(P分别为0.0001和0.016)。进一步的分析发现EREG高表达的病人生存时间明显短于EREG阴性或低表达病人(P<0.01)。通过COX多因素分析显示EREG是一个独立于肿瘤侵袭以及淋巴结转移的有价值的预后因子。随后我们研究了该基因在食管癌中发挥功能的分子机制。EREG基因可以明显改变食管癌细胞的形态,EREG高表达的细胞呈明显的梭形,相互之间的粘附降低,细胞呈现松散分布。利用EREG的中和抗体进一步明确了EREG对于食管癌细胞侵袭及运动能力的促进作用。细胞免疫荧光显示EREG可以促进肿瘤细胞丝状伪足及片状伪足的形成,并且可以促进应激蛋白c-Jun分子的入核。分子实验表明EREG分子可以活化EGFR信号通路,并激活下游的Src/FAK信号分子,从而影响细胞的骨架蛋白分布以及细胞的运动侵袭能力。这些有关食管癌内皮可以促进肿瘤侵袭转移、食管癌血管内皮特异表达趋化因子等侵袭转移基因、食管癌内皮可以上调肿瘤细胞侵袭转移基因、EREG在食管癌的侵袭转移中发挥重要作用等研究国内外都未见报道。
     利用高侵袭能力的细胞亚克隆EC9706细胞分离获得了一系列食管癌侵袭转移相关基因,其中TFPI-2在很多肿瘤中都提示与肿瘤侵袭转移密切相关。我们的研究提示TFPI-2在食管癌的侵袭转移中发挥重要作用。Western-blot实验提示75%的食管癌标本中TFPI-2下调表达,在大部分食管癌细胞系中也是下调表达。免疫组化显示在肿瘤组织和淋巴结转移灶中TFPI-2均显著下调(P<0.05)。在KYSE450、KYSE510、YES2和EC9706细胞中转染TFPI-2表达质粒,可以显著抑制细胞的侵袭。EC9706细胞中高表达TFPI-2可以显著抑制移植瘤的生长及对邻近组织的侵袭。进一步的研究发现TFPI-2重组蛋白可以显著抑制基质金属蛋白酶的活性以及肿瘤血管的生成。使用TFPI-2的重组蛋白可以显著抑制移植瘤的生长、侵袭以及血管生成(P<0.05)。这些结果提示TFPI-2在食管癌治疗中的潜在应用价值。
     越来越多的证据表明microRNA在肿瘤的发生发展中发挥着广泛的作用。我们使用基因芯片技术筛选获得了一些与食管癌侵袭相关的microRNA,初步的功能实验显示mir10a以及mir663是肿瘤侵袭相关的microRNA。随后的实验发现mir663对胃癌细胞侵袭能力的抑制更明显,而且还可以抑制胃癌细胞的增殖。进一步的RT-PCR显示胃癌细胞系中普遍低表达mir663,将mir663慢病毒感染BGC823及SNU5胃癌细胞,可以引起明显的细胞形态变化及增殖抑制。细胞周期及染色体分析显示mir663可以导致胃癌细胞的有丝分裂灾难,mir663可以导致细胞的G2／M周期阻滞以及扰乱细胞的DNA含量,mir663还可以导致细胞染色体数量出现异常并导致细胞的死亡。Westeren-blot实验显示mir663可以引起胃癌细胞中cyclingB1蛋白的表达上调,cyclinB1作为细胞进入G2／M期的关键蛋白被mir663扰乱可能导致了胃癌细胞的G2／M阻滞。为了进一步研究mir663作为胃癌基因治疗药物的潜力,我们使用mir663的慢病毒表达载体进行了裸鼠移植瘤治疗实验。慢病毒感染胃癌细胞后进行的裸鼠移植瘤实验显示mir663慢病毒可以明显抑制胃癌细胞裸鼠移植瘤的生长,抑制率高达60%,并且mir663慢病毒明显影响胃癌细胞的增殖以及凋亡。以上结果均显示mir663作为胃癌基因治疗药物的潜在应用前景。
Esophageal cancer is one of the ten most common malignancy, although we have developed and made significant progress in the treatment and diagnosis of tumor, it still threatened the health of human. Esophageal cancer is characterized by rapid clinical progression and poor prognosis due to adjacent tissue invasion and distant organs metastasis at a very early stage. Many researches have suggested that tumor microenvironment and interstitial cells play an important role in mediating invasion and metastasis. These malignant tumors always consume a large quantity of oxygen, contain acidosis、growth factor、proteases or proteolytic enzymes and the inflammatory cells. The special microinviroment not only influence the prolifation、invasion、migration、adhesion and angiogenesis of cancer cells but also have profound influence on interstitial cells related with tumor. Recent studies show that metastasis of tumor were determined by the coordination and cooperation between cancer cells and interstitial cells. Interstitial cells participate the whole process of metastasis.
     Our research aimed at realizing the relationship between the metastasis and microvascular endothelial cells of esophageal cancer. Microvascular endothelial cells(ECEC) were separated by MACS system from fresh samples. We found that ECEC can promote the prolifation and have anti-apoptotic ability similar with cancer cells. Analysis of gene expression pattern in ECEC by microarray, there are a lot of genes specially high expressed in ECEC such as chemotatic factor superfamily and some genes related with tumor metastasis. The invasion and migration ability of esophageal cancer cells was significantly improved when these cells co-cultured with ECEC cells (P<0.01) And this improvement depends on the direct contact of tumor cells with ECEC. ECEC can promote the growth、invasion and lung metastasis of xenografts when ECEC and cancer cells were mixed injected into nude mice (P<0.01). Analysis of gene expression pattern in cancer cells when co-cultured with ECEC by microarray, we found that there are so many up-regulated genes related with tumor invasion and metastasis. After function verification of these genes such as AREG、EREG、MMP1、IL6、MMP3、IL1B、ADM and Cyr61, we found that transfection of AREG and EREG can significantly promote the invasion and migration of tumor cells (P<0.01). AREG and EREG gene transfection can also promote the growth of human esophageal cancer cells transplanted subcutaneously into nude mice in vivo (P<0.01). Compared with control, mice of AREG and EREG group showed shorten survival time (P<0.01). In short, ECEC can ptomote the invasion and metastasis of tumor cells in vitro and in vivo. Additionally, ECEC play a critical role in invasion promotion by regulating gene expression of the co-cultured tumor cells. Meanwhile, we put forwards an incisive analysis of the gene EREG. First, we found there was high relationship whit expression of EREG and invasion ability of esophageal cancer cell lines. Immunofluorescence revealed that EREG was over-expressed in esophageal cancer cell lines with high-invasive potential. Immunohistochemical analysis showed EREG was over-expressed in esophageal cancer (P<0.01). The expression of EREG was closely related with local invasion (T) and lymph node metastasis (N). The patients with EREG high expression always show shorten survival time compared with EREG low or negative patients. The over-expressed EREG is a valuable prognostic factor independent of lymph node metastasis or local invasion. The further analysis on the function and molecular mechanisms of EREG indicated that EREG significantly induced changes in cell morphology. EREG high-expressed cells often with a spindle shape and growing loosely. Neutralizing antibody of EREG further confirmed its invasion promotion ability. By immunofluorescence analysis of F-actin and total actin, there was more filopodia and lamellipodia in the cells transfected with EREG. And we also observed that there are more nuclear import of c-Jun protein in EREG transfected cells. Molecular mechanism analysis indicated that treatment of cells with EREG resulted in invasion and redistribution of cytoskeletal proteins of tumor cells and led to a biphasic activation of EGFR and Src/FAK pathway. Based on these programs we can make a conclusion:ECEC can promote the invasion and metastasis of tumor cell in vitro and in vivo, ECEC specially high expressed genes of chemotatic factor superfamily, ECEC cells specially up-regulate a group of metastasis genes when co-cultured with tumor cells, one of the genes EREG which up-regulated by ECEC plays very important roly in the invasion and metastasis of esophageal carcinoma. All of these results have not been reported as yet.
     A highly invasive sub-cell line EC9706-P4 was established, the expression profile of the EC9706-P4 and the parental cell line EC9706 was analyzed by gene microarray analysis. TFPI-2 (Tissue factor pathway inhibitor 2) was identified as a candidate invasion and metastasis inhibitor of esophageal carcinoma cells. TFPI-2 has been implicated as a metastasis-associated gene in many types of tumors. Here we describe the potential involvement of TFPI-2 in the development of esophageal carcinoma. Western blotting revealed that TFPI-2 was down-regulated in 75% of esophageal carcinomas and in most esophageal carcinoma cell (ESCC) lines. Immunohistochemistry revealed that TFPI-2 was significantly down-regulated in tumor tissues and lymph node metastases. Experimental overexpression of TFPI-2 in KYSE450, KYSE510, YES2, and EC9706 cells significantly inhibited their invasive ability. Overexpression of TFPI-2 in EC9706 cells inhibited xenograft tumor growth and invasion into surrounding tissues, as well as reducing lung metastasis. Further studies demonstrated that recombinant TFPI-2 protein significantly inhibited the activity of matrix metalloproteinases and tumor-related angiogenesis. Parenteral treatment with recombinant TFPI-2 protein significantly suppressed xenograft tumor growth and metastasis. Together, these data indicated that TFPI-2 inhibits tumor invasion and angiogenesis both in vitro and in vivo, and suggest a potentially important therapeutic role for recombinant TFPI-2 in the treatment of malignant esophageal carcinomas.
     Accumulating evidence suggests a role for microRNAs in human carcinogenesis as novel types of tumor suppressors or oncogenes. In this study, we aimed to identify microRNAs species involved in the regulation of tumor invasion and growth. Using quantitative RT-PCR analysis, we demonstrated that mir-663 was down-regulated in human gastric cancer cell lines in contrasted to normal cells. Transient introduction of mir-663 lentiviral vector into human gastric cancer cell lines, BGC823 and SNU5, induced the modality changes and proliferation suppression of these cells. In addition, mir-663 disturbed the DNA content and induced mitotic catastrophe phenotype in tumor cells. More over, mir-663 also suppressed in vivo growth of BGC823 and SNU5 cells.Western-blot analyses revealed up-regulation of cyclin B by mir-663 introduction. Our results provided evidence that down-regulation of mir-663 in tumor cells may contribute to aberrant cell hyperplasia, leading to gastric cancer development. Mir-663 might function as a potent suppressor for tumor gene therapy.

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