Microenviroment and organ specific metastases in urological cancers as tools to elucidate molecular mechanism of carcinogenesis and tumor development.

采用免疫组化方法分析97例原发性肾细胞癌rcc中Snail、Slug、MMP2和MMP9蛋白的表达情况。蜗牛蛋白表达水平与肿瘤病理分期、组织学分级及是否存在肉瘤样癌呈正相关。由于蜗牛与RCC的恶性潜能呈正相关，我们在Matrigel侵袭实验中通过小干扰RNA（small interfering RNA, siRNA）下调基因表达来检测蜗牛参与了RCC细胞株786-O和ACHN的侵袭。在此条件下，体外Matrigel对细胞的侵袭受到抑制。此外，MMP2和MMP9的表达水平与肿瘤病理分期和肉瘤样癌的存在呈正相关。总之，这些数据表明Snail在rcc的侵袭和转移中起重要作用，并且沉默该基因可能是rcc的潜在治疗靶点。NF-κB受体激活因子配体（RANKL）及其受体NF-κB受体激活因子（RANK）在破骨细胞形成中起关键作用。RANKL蛋白表达水平与肿瘤原发分期和远处转移呈正相关。RANKL和RANK在骨和其他器官的转移性rcc中表达，提示它们在骨和其他器官的转移中起作用。在体外，重组RANKL蛋白刺激了透明细胞RCC细胞株Caki-1的迁移，重组OPG蛋白抑制了这种增强的迁移。这些数据提示RANKL-RANK-OPG系统不仅参与rcc骨转移，还通过刺激癌细胞迁移参与其他器官转移。

Ninety-seven primary(renal cell carcinomas) RCCs were analyzed for the protein expression of Snail, Slug, MMP2 and MMP9 by immunohistochemistry. Snail protein expression level was positively correlated with pathological tumor stage, histological grade and the presence of sarcomatoid carcinoma. Because Snail was positively associated with malignant potential of RCCs, involvement of Snail in the invasiveness of an RCC cell lines 786-O and ACHN were examined in the Matrigel invasion assay by down-regulating the gene expression with small interfering RNA(siRNA). Invasion of the cells through Matrigel in vitro was inhibited under this condition. Furthermore, expression levels of MMP2 and MMP9 were positively correlated with pathological tumor stage and the presence of sarcomatoid carcinoma. In conclusion, these data suggest that Snail has an important role in invasion and metastasis, and that silencing the gene may be a potenal therapeutic target in RCCs.Receptor activator of NF-κB ligand(RANKL) and its receptor, receptor activator of NF-κB(RANK), play a key role in osteoclastogenesis RANKL protein expression level showed positive correlations with the primary tumour stage and distant metastasis. RANKL and RANK expression was observed in metastatic RCCs in the bone and other organs, suggesting that they play a role in metastasis to the bone and other organs. Recombinant RANKL protein stimulated migration of a clear cell RCC cell line, Caki-1, in vitro, and this enhanced migration was inhibited by the administration of recombinant OPG protein. These data suggest that the RANKL-RANK-OPG system is involved not only in the bone metastasis of RCCs but also in metastasis to other organs through the stimulation of cancer cell migration.