PLAC8对肾透明细胞癌细胞生物学行为的影响及作用机制研究

发布时间：2018-03-06 04:15

本文选题：胎盘特异蛋白8　切入点：肾透明细胞癌　出处：《暨南大学》2017年博士论文　论文类型：学位论文

【摘要】：肾细胞癌(RCC)是成人泌尿系统发病率最高的恶性肿瘤之一,发病率稍低于膀胱癌,占所有肾脏全部恶性肿瘤的90%-95%。肾细胞癌主要包括以下三种病理类型,其中透明细胞癌(ccRCC)是发病率最高的病理类型,约占所有报道病例的65%,其次是乳头状肾细胞癌(pRCC)和嫌色肾细胞癌,分别占15%~20%和5%。近年来肾细胞癌发病率呈现逐年上升趋势。超过一半以上的早期肾细胞癌发病时无明显症状,17%以上的肾细胞癌确诊时已经出现远处转移,出现远处转移的肾细胞癌五年生存率小于10%,其中位生存期小于一年。目前手术依然是肾细胞癌最好的的治疗方式,对于已经存在有远处转移的肾细胞癌患者,细胞免疫治疗和肿瘤靶向药物治疗得到越来越多的应用。对于肾透明细胞癌行外科手术治疗后复发的患者目前暂无十分有效的临床治疗方法。因此,对于肾透明细胞癌的具体发生机制的研究具有重大意义,可以提高肾透明细胞癌的诊断与治疗。胎盘特异蛋白8(Placenta specific 8,PLAC8),以前又叫onzin,是一种富含有半胱氨酸的蛋白,首次发现于人类胎盘组织中。PLAC8广泛分布于人体免疫系统及多种组织的上皮细胞中,PLAC8可以参与调节细胞的分裂、分化和细胞凋亡,与人体内多种肿瘤的发生有密切关系。但其在肾细胞癌中的作用尚未见报道。本论文主要目标是研究PLAC8在肾透明细胞癌发生发展中的作用及其可能的作用机制。本论文总共分为四大部分。第一部分通过Real-Time PCR及免疫组化法分析研究PLAC8在肾透明细胞癌及癌旁组织中的表达,发现在肾透明细胞癌组织中,PLAC8蛋白及mRNA表达高于正常肾脏组织。第二部分结合肾透明细胞癌患者临床病例资料,分析研究肾透明细胞癌中PLAC8高表达与患者临床预后之间的关系。得出PLAC8的表达与肾透明细胞癌的疾病进展、预后生存有关,PLAC8表达的高低可以独立作为肾透明细胞患者生存预后的标记物。第三部分主要研究分析PLAC8表达量对肾透明细胞癌细胞生物学行为的影响,肾透明细胞癌细胞中PLAC8表达水平降低后可以降低肾透明细胞癌细胞体外的侵袭和增殖能力,抑制细胞的生存力,并增加肾透明细胞癌对化疗药物(顺铂)的敏感性,增加化疗药物(顺铂)对癌细胞的杀伤性。第四部分主要探讨PLAC8影响肾透明细胞癌细胞生物学行为的可能机制,通过RNA-seq分析我们发现PLAC8下调基因有697个、上调基因有829个;通过Gene Ontology(GO)和KEGG通路富集分析,我们发现PLAC8参与肾透明细胞癌的疾病发生发展最相关的三个通路反应分别是刺激反应,化学物质反应和免疫反应,PLAC8可能在调节肾透明细胞癌炎症微环境中发挥重要作用。
[Abstract]:Renal cell carcinoma (RCC) is one of the most common malignancies in the adult urinary system. The incidence of RCCs is slightly lower than that of bladder cancer, accounting for 90-95 percent of all renal malignancies. RCCs mainly include the following three types of pathology. Clear cell carcinoma (CCCC) is the most common pathological type, accounting for 65% of all reported cases, followed by papillary renal cell carcinoma (pRCC) and chromophobe renal cell carcinoma (RCC). In recent years, the incidence of renal cell carcinoma has been increasing year by year. More than half of the early renal cell carcinoma had no obvious symptoms at the time of onset. More than 17% of renal cell carcinoma had distant metastasis by the time of diagnosis. The 5-year survival rate of renal cell carcinoma with distant metastasis is less than 10 years, of which the survival time is less than one year. Surgery is still the best treatment for renal cell carcinoma. Cellular immunotherapy and tumor targeting drug therapy have been used more and more. There is currently no effective clinical treatment for patients with recurrent renal clear cell carcinoma after surgical treatment. It is of great significance to study the specific mechanism of renal clear cell carcinoma, which can improve the diagnosis and treatment of renal clear cell carcinoma. Placenta specific protein 8 Placenta specific 8 specific PLAC8, formerly called onzin, is a kind of protein rich in cysteine. For the first time, it has been found that PLAC8 is widely distributed in the human immune system and epithelial cells of various tissues in human placenta, and can participate in the regulation of cell division, differentiation and apoptosis. But its role in renal cell carcinoma has not been reported. The main aim of this paper is to study the role of PLAC8 in the development of renal clear cell carcinoma and its possible mechanism. This thesis is divided into four parts. The first part is to study the expression of PLAC8 in renal clear cell carcinoma and adjacent tissues by Real-Time PCR and immunohistochemical method. It was found that the expression of PLAC8 protein and mRNA in renal clear cell carcinoma was higher than that in normal renal tissue. The second part combined with the clinical data of patients with renal clear cell carcinoma. The relationship between the high expression of PLAC8 and the clinical prognosis of renal clear cell carcinoma was analyzed. It was concluded that the expression of PLAC8 and the progression of renal clear cell carcinoma. Prognostic survival related expression of PLAC8 can be used as an independent marker for the survival and prognosis of renal clear cell patients. The third part mainly studies the effect of PLAC8 expression on the biological behavior of renal clear cell carcinoma cells. The decrease of PLAC8 expression in renal clear cell carcinoma cells can reduce the invasion and proliferation of renal clear cell carcinoma cells in vitro, inhibit cell viability, and increase the sensitivity of renal clear cell carcinoma to chemotherapy drugs (cisplatin). In part 4th, the possible mechanism of PLAC8 affecting the biological behavior of renal clear cell carcinoma cells was discussed. By RNA-seq analysis, we found that there were 697 down-regulated genes and 829 up-regulated genes in PLAC8. By means of Gene Ontology and KEGG pathway enrichment analysis, we found that the three most relevant pathway responses of PLAC8 involved in the pathogenesis and development of renal clear cell carcinoma were stimulatory responses. Chemical and immunoreactive PLAC8 may play an important role in regulating the inflammatory microenvironment of renal clear cell carcinoma.
【学位授予单位】：暨南大学
【学位级别】：博士
【学位授予年份】：2017
【分类号】：R737.11

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