EBAG9/RCAS1 expression enhances tumor growth in renal cell carcinoma

简介和目标：EBAG 9以前被鉴定为雌激素应答基因，最近发现EBAG 9与RCAS 1相同，RCAS 1诱导免疫细胞如T、B和NE细胞的凋亡，并使肿瘤细胞从免疫监视中逃脱。在这项研究中，我们提供的证据表明，EBAG 9/RCAS 1可以调节肿瘤的进展使用animal models.Methods的潜在机制：我们比较了人EBAG 9转染的renca细胞与空载体转染的renca克隆在体外和体内的细胞生长。我们进一步检测了78例肾细胞癌标本中EBAG 9/RCAS 1的表达。结果：EBAG 9/RCAS 1的过表达对RCA细胞克隆的生长无明显促进作用。另一方面，将EBAG 9转染的renca细胞植入Balb/c小鼠的侧腹， ...更多信息 与载体对照相比，肿瘤显著增大（1712.1±506.4 mm^3 vs. 366.2±110.1 mm^3，p=0.0055）。携带EBAG 9转染的renca细胞肿瘤的小鼠的存活率明显低于携带对照肿瘤的动物。在Balb/c小鼠中生长的表达EBAG 9的肿瘤的组织学检查没有显示凋亡淋巴细胞通过TUNEL测定阳性染色。免疫组化结果显示肿瘤周围CD_8淋巴细胞数量减少（10.0 vs.5.8/10 HPF）。这些数据表明，EBAG 9在肿瘤细胞中的表达可能有助于通过抑制肿瘤浸润的CD 8淋巴细胞而不凋亡来抑制免疫应答。免疫组化结果显示，68/78例（87.2%）原发性肾细胞癌胞浆中可见强而弥漫的免疫组化染色。相反，在邻近的正常组织中观察到弱EBAG 9/RCAS 1表达。原发癌中EBAG 9/RCAS 1免疫染色阳性与晚期病理T分期和血管浸润显著相关（分别为p=0.0017和p=0.0109）。EBAG 9/RCAS 1免疫反应性高的患者比EBAG 9/RCAS 1表达低的患者的癌症特异性生存率显著更差。多因素分析显示EBAG 9/RCAS 1高表达是肿瘤特异性生存的独立预后预测因子（p=0.0485）。结论：EBAG 9/RCAS 1在大多数人肾癌中表达，EBAG 9/RCAS 1高表达与肿瘤侵袭性和预后不良有关。少

Introduction and Objectives : The EBAG9 was previously identified as an estrogen responsive gene, and it was lately revealed that the EBAG9 is identical with RCAS1 which induces apoptosis of immune cells such as T, B, and NE cells, and which allows tumor cells to escape of tumors from immune surveillance. In this study, we provide evidence that EBAG9/RCAS1 may modulate the potential mechanism of tumor progression using animal models.Methods : We compared the cell growth of human EBAG9-transfected renca cells with empty vector-transfected renca clones in vitro and in vivo. We further examined expression of EBAG9/RCAS1 immunohistochemically in 78 renal cell carcinoma specimens. We statistically analyzed correlation between EBAG9/RCAS1 expression and clinicapathological characteristics.Results : Overexpression of EBAG9 had no stimulatory effect on the growth of renca clones in cell culture. On the other hand EBAG9-transfected renca cells implanted in the flank of Balb/c mice established s … More ignificantly enlarged tumors compared with vector controls (1712.1±506.4 mm^3 vs. 366.2±110.1 mm^3, p=0.0055). Mice bearing tumors of EBAG9-transfected renca cells had significantly worse survival than animals bearing control tumors. Histological examination of EBAG9-expressing tumors grown in Balb/c mice did not show apoptotic lymphocytes positively stained by TUNEL assay. However, immunohistochemiclal analysis revealed the number of CD8 lymphocytes around tumors decreasing (10.0 vs. 5.8 /10HPF). These data suggested that EBAG9 expression in tumor cells may contribute to the suppression of immune response by inhibiting tumor-infiltrating CD8 lymphocytes without apoptosis. Immunohistochemical analysis showed that strong and diffuse immunostaining in the cytoplasm was identified in 68/78 (87.2%) of primary renal cell carcinoma cases. In contrast, weak-EBAG9/RCAS1 expression was observed in the adjacent normal tissue. Positive EBAG9/RCAS1 immunostaining in the primary cancers significantly correlated with advanced pathological T stages and vascular infiltration (p=0.0017 and p=0.0109, respectively). Patients with high EBAG9/RCAS1 immunoreactivity had significantly worse cancer-specific survival than those with low EBAG9/RCAS1 expression. Multivariate analysis revealed that high EBAG9/RCAS1 expression was an independent prognostic predictor for cancer-specific survival (p=0.0485).Conclusions : EBAG9/RCAS1 is expressed in the majority of human renal cell carcinomas and high EBAG9/RCAS1 immunoreactivity is associated with tumor aggressiveness and unfavorable prognosis. Less