T淋巴瘤转移诱导因子在胃腺癌中过表达及对预后评估的意义研究

发布时间：2018-05-07 18:10

本文选题：胃腺癌 + T淋巴瘤转移诱导因子　；参考：《延边大学》2016年硕士论文

【摘要】：研究背景：胃癌是源于胃黏膜上皮细胞的恶性肿瘤,主要为胃腺癌。2008年全球新诊断出胃癌近100万例,病死人数74万,是全世界发病率第四、致死率第二的癌症,是临床上常见的恶性肿瘤。虽然胃癌全球总发病率有所下降,但有近三分之二的胃癌病例集中于经济欠发达国家和地区,中国及其他东亚国家高发。在临床上,常用外科手术切除加区域淋巴结清扫及术后放化疗支持,尽管早期胃癌的治疗已经取得了重大进步,但晚期胃癌的长期生存率仍然很低。研究表明,肿瘤的侵袭、转移导致了大部分胃癌患者的死亡并在胃癌的不良预后中扮演了关键角色。胃癌的侵袭、转移是一个多基因调控、多因子参与、多步骤进行的复杂的生物学过程,一般认为癌细胞具有的运动和侵袭能力是产生转移的重要条件。但对于晚期胃癌,其侵袭和转移潜在的分子机制尚不明确。因而寻找可靠的肿瘤预后的标志性因子,以及能够有效抑制肿瘤转移和侵袭的分子靶点,改善肿瘤的预后,是近年来研究的热点,也是肿瘤研究中的一个重点和难点。因此,迫切的需要鉴别胃癌进展期的重要分子,研发新的药物作用靶点,为肿瘤的治疗和患者的预后提供有价值的帮助。T淋巴瘤转移诱导因子(T-cell lymphoma invasion and metastasis-inducing factor, Tiaml)是Habets等于1994年从鼠的T淋巴瘤中分离出来的一种肿瘤转移诱导基因,其产物Tiaml蛋白作为一种鸟苷酸转换因子,特异性激活Rac-1,并通过Tiaml-Rac信号途径,改变肿瘤细胞的形态和功能,调节并诱导肿瘤的侵袭和转移。近年来的研究发现,Tiaml蛋白在多种肿瘤组织和细胞中异常表达,如鼻咽癌、乳腺癌、结直肠癌、视网膜母细胞瘤、原发性肝癌、Ras诱导的皮肤肿瘤等,并与这些肿瘤的早期诊断和不良预后关系密切,但尚未见其异常表达与胃腺癌及其预后之间关系的研究。目的：明确Tiaml蛋白在胃腺癌组织及细胞中的表达和定位,并结合临床病理资料,分析Tiaml过表达与胃腺癌转移、侵袭和不良预后的相关性,为Tiaml作为胃腺癌转移、侵袭和不良预后的分子靶点提供理论和实验依据。方法：采用免疫组化EnVision法检测Tiaml蛋白在102例胃腺癌组织、21例胃异型增生组织和33例癌旁正常组织中的表达及其与胃腺癌临床病理特征之间的关系,采用免疫荧光染色法检测Tiaml在胃腺癌细胞中的定位情况,分析Tiaml在胃癌中过表达以及与胃腺癌患者预后的相关性；通过生存期分析验证Tiaml在胃癌患者预后评估中的标志物作用。结果：(1)Tiaml蛋白在胃腺癌组织和细胞中过表达,主要表达在胞浆中,并有核周聚集现象; (2)胃腺癌组织中Tiaml阳性率为85.3%(87/102),强阳性率为61.8%(63/102),均明显高于胃异型组织和癌旁正常组织(P0.01)。Tiaml蛋白表达水平与胃腺癌分化程度、临床分期、淋巴结转移及浆膜浸润密切相关(P0.05),与患者性别、年龄及肿块大小等均无关。在中、低分化胃腺癌中,Tiaml蛋白强阳性率明显高于高分化的胃腺癌病例(P0.01),表明随着胃腺癌恶性程度的增加,Tiaml蛋白的表达亦显著增强；在Ⅰ～Ⅱ期的胃腺癌中阳性率为51.1%(24/47),在Ⅲ～Ⅳ期的胃腺癌中阳性率为70.9%(39/55),表明Tiaml在进展期胃腺癌中的表达明显高于早期胃腺癌；在发生淋巴结转移的胃腺癌中,Tiaml阳性率高达73.3%(44/60),在发生浆膜浸润的胃腺癌中,Tiaml阳性率高达73.8%(45/61)(3)生存期分析显示,Tiaml高表达的胃癌患者的生存期低于Tiaml低表达患者；单因素分析显示,在发生淋巴结转移的胃腺癌患者中,Tiaml高表达的胃癌患者的生存期低于Tiaml低表达患者；在发生浆膜浸润的胃腺癌患者中,Tiaml高表达的胃癌患者的生存期低于Tiaml低表达患者。结论：(1)Tiaml在胃腺癌组织和细胞中过表达,且主要定位于细胞浆中；(2) Tiaml过表达与胃腺癌的转移、侵袭和不良预后密切相关； (3)Tiaml蛋白过表达有望成为胃腺癌预后不良的有效检测指标及分子治疗靶点。
[Abstract]:Background: gastric cancer is a malignant tumor originate from the epithelial cells of the gastric mucosa. It is mainly the new diagnosis of gastric cancer in the.2008 year of.2008. The death rate is 740 thousand, the incidence of the world is fourth, the mortality rate is second, and it is a common malignant tumor in the clinic. Although the total global incidence of gastric cancer has decreased, it has nearly 2/3 The cases of gastric cancer are concentrated in economically undeveloped countries and regions, in China and in other East Asian countries. In clinic, surgical excision, regional lymph node dissection and postoperative radiotherapy and chemotherapy support are commonly used. Although significant progress has been made in the treatment of early gastric cancer, the long-term survival rate of advanced gastric cancer is still low. Invasion and metastasis lead to the death of most patients with gastric cancer and play a key role in the bad prognosis of gastric cancer. The invasion and metastasis of gastric cancer is a multi gene regulation, multi factor participation and complex biological processes in many steps. It is generally believed that the transport and invasion ability of cancer cells is an important condition for the generation of metastasis. In advanced gastric cancer, the potential molecular mechanisms of invasion and metastasis are not clear. Therefore, it is a hot spot in recent years to find a reliable marker for tumor prognosis, as well as the molecular targets that can effectively inhibit tumor metastasis and invasion, and to improve the prognosis of tumor. Therefore, it is an urgent need. Identifying important molecules in the progression of gastric cancer, developing new drug targets, providing valuable help for.T lymphoma metastasis inducible factor (T-cell lymphoma invasion and metastasis-inducing factor, Tiaml) is a tumor metastasis isolated from T lymphoma of mice in 1994. The inducible gene, the Tiaml protein, as a kind of guanosine conversion factor, specifically activates Rac-1, and changes the morphology and function of tumor cells through the Tiaml-Rac signal pathway to regulate and induce tumor invasion and metastasis. Recent studies have found that Tiaml protein is abnormal expression in various tumor tissues and cells, such as nasopharyngeal carcinoma and mammary gland. Cancer, colorectal cancer, retinoblastoma, primary liver cancer, Ras induced skin tumor and so on, which are closely related to the early diagnosis and poor prognosis of these tumors, but the relationship between abnormal expression and gastric adenocarcinoma and its prognosis has not been seen. Objective: to clarify the expression and localization of Tiaml protein in gastric adenocarcinoma tissue and cells, and to determine the relationship between the expression and localization of gastric adenocarcinoma. The correlation between Tiaml overexpression and metastasis of gastric adenocarcinoma, invasion and poor prognosis was analyzed with clinical and pathological data. The theoretical and experimental basis was provided for Tiaml as a molecular target for metastasis, invasion and poor prognosis of gastric adenocarcinoma. Methods: immunohistochemistry EnVision method was used to detect Tiaml protein in 102 gastric adenocarcinoma tissues, 21 cases of gastric dysplasia and 3 The relationship between the expression of normal paracancerous tissues and the clinicopathological features of gastric adenocarcinoma was observed in 3 cases. The location of Tiaml in gastric adenocarcinoma cells was detected by immunofluorescence staining, and the correlation between the overexpression of Tiaml in gastric cancer and the prognosis of gastric adenocarcinoma patients was analyzed. The prognostic evaluation of Tiaml in gastric cancer patients was verified by the survival time analysis. Results: (1) the expression of Tiaml protein in gastric adenocarcinoma tissue and cells, mainly expressed in the cytoplasm, and the phenomenon of perinuclear aggregation; (2) the positive rate of Tiaml in gastric adenocarcinoma was 85.3% (87/102), and the strong positive rate was 61.8% (63/102), which was significantly higher than the expression level of.Tiaml protein in the gastric anypical tissues and adjacent normal tissues (P0.01). The degree of differentiation, clinical stage, lymph node metastasis and serous infiltration were closely related to gastric adenocarcinoma (P0.05), not related to sex, age and size of the tumor. In low differentiated gastric adenocarcinoma, the strong positive rate of Tiaml protein was significantly higher than that of highly differentiated gastric adenocarcinoma (P0.01), indicating that with the increase of malignancy of gastric adenocarcinoma, the expression of Tiaml protein The positive rate of gastric adenocarcinoma in stage I to stage II was 51.1% (24/47), and the positive rate in gastric adenocarcinoma in stage III to IV was 70.9% (39/55), indicating that the expression of Tiaml in advanced gastric adenocarcinoma was significantly higher than that of early gastric adenocarcinoma, and the positive rate of Tiaml was up to 73.3% (44/60) in the gastric adenocarcinoma which had lymph node metastasis, and was in serous infiltration. In gastric adenocarcinoma, the Tiaml positive rate was up to 73.8% (45/61) (3) (3) survival analysis showed that the survival period of Tiaml high expression of gastric cancer patients was lower than that of Tiaml low expression patients; one factor analysis showed that in the patients with gastric adenocarcinoma with lymph node metastasis, the survival time of the patients with Tiaml high expression of gastric cancer was lower than that of the low expression of Tiaml; in the occurrence of serous dipping In the patients with gastric adenocarcinoma, the survival period of Tiaml high expression of gastric cancer patients was lower than that of Tiaml low expression patients. Conclusion: (1) Tiaml is overexpressed in gastric adenocarcinoma tissue and cells, and mainly located in the cytoplasm; (2) Tiaml overexpression is closely related to metastasis of gastric adenocarcinoma, invasion and bad preconditioning; (3) the overexpression of Tiaml protein is expected to become the stomach. Effective detection targets and molecular therapeutic targets for poor prognosis of adenocarcinoma.

【学位授予单位】：延边大学
【学位级别】：硕士
【学位授予年份】：2016
【分类号】：R735.2

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