The functional analysis and clinical significance of apotosis inducing factor, RCAS1

本研究探讨了肿瘤相关抗原RCAS-1的功能和临床意义。RCAS1是一种II型膜蛋白，可诱导正常外周血淋巴细胞的细胞凋亡。RCAS1基因定位于8q23，其表达受雌激素诱导。在我们以前的研究中，RCAS1在子宫和卵巢癌中有较强的表达，并且RCAS1的表达与子宫癌患者的不良预后显著相关。(1)为了阐明RCAS1在肿瘤行为中的生物学作用，我们用免疫组织化学方法分析了RCAS1的表达与肿瘤间质细胞反应的关系。在肿瘤转移淋巴结中，RCAS1表达阳性的子宫癌患者T淋巴细胞的凋亡指数明显升高。在肿瘤细胞周围的结缔组织中，波形蛋白表达的细胞在RCAS1表达的患者中明显减少。而Fas-L和肿瘤坏死因子-α的表达与载脂蛋白…无关肿瘤间质结缔组织中波形蛋白表达的细胞数和T淋巴细胞的抽动指数增加。根据这些发现，RCAS1的表达通过减少免疫反应和结缔组织反应在肿瘤侵袭性的获得中起关键作用。(2)RCAS1的表达与子宫内膜癌发生发展的关系，腺癌中RCAS1的表达显著高于正常子宫内膜和增生性子宫内膜。RCAS1在子宫内膜腺癌中的表达高于1、2级，提示RCAS1的表达可能与子宫内膜腺癌的恶变和低分化有关。(3)研究了RCAS1和Fas-L在妊娠早期的表达情况。RCAS1和Fas-L表达的降低可能与母体NK细胞的活化和浸润及子宫腺的破坏，导致胎儿排斥反应密切相关。RCAS1和Fas-L在子宫腺和细胞滋养层中的表达可能在下调母体免疫反应，从而维持早期妊娠中起作用。此外，RCAS1可能参与了早期妊娠的维持。需要做的工作有：(1)确定RCAS1的相关分子；(2)阐明RCAS1诱导细胞凋亡的分子机制；(3)明确Fas-L、肿瘤坏死因子和RCAS1之间的不同功能。较少

The functional and clinical significance of tumor-associated antigen, RCAS 1, was investigated in this study. RCAS1, one of type II membrane proteins, induces cell apoptosis in normal peripheral lymphocytes. RCAS1 is chromosomally localized to 8q23 and its expression is induced by estrogen. In our previous study, RCAS1 was strongly expressed in uterine and ovarian cancers and the expression of RCAS1 was strikingly correlated with poorprognosis in uterine cancer patients.(1) In order to clarify a biological role of RCAS1 in tumor behavior, we analyzed an association between RCAS1 expression and tumor stromal cell reaction by immunohistochemistry. In tumor metastatic lymph nodes, the apoptotic index of T lymphocytes significantly increased in uterine cancer patients with RCAS1 expression. In connective tissues surrounded tumor cells, cells with vimentin expression significantly decreased in patients with RCAS1 expression. But the expression of Fas-L or TNF-a was not associated with apoto … More tic index of T lymphocytes, and the number of cells with vimentin expression in connective tissues in the tumor stroma. On the basis of these findings, the expression of RCAS1 plays pivotal factors in the acquirement of tumor aggressiveness through the reduction of immune response and connective tissue reaction.(2) The relationship between RCAS1 expression and a progression of the uterine endometrial neoplasias was checked, the expression of RCAS1 was statistically higher in adenocarcinoma than in the normal and hyperplastic endometrium. Moreover, RCAS1 was statistically detected more frequently in grade 3 than in grade 1 or 2. These results indicated that RCAS1 expression might be associated with the malignant transformation and poor differentiation observed in uterine endometrial adenocarcinoma.(3) The involvement ofRCAS1 and Fas-L was studied in the early stage of pregnancy. A reduction in RCAS1 and Fas-L expression was suggested to be closely related with activation and infiltration of maternal NK cells and destruction of uterine glands, resulting in rejection of the fetus. The expression of RCAS1 and Fas-L in the uterine glands and cytotrophoblasts may play a role in the downregulation of the maternal immune response, thereby maintaining pregnancy at early stage.Our findings demonstrate that RCAS1 plays an important role in the acquirement of tumor aggressiveness. Moreover, RCAS1 might be involved in the maintenance of early pregnancy. Following works are necessary to be done: (1) to identify RCAS1 associated molecules, (2) to clarify molecular mechanisms for RCAS1 induced apoptosis, and (3) to make clear different functions among Fas-L, TNF and RCAS1. Less