Molecular Basis of Carcinogenesis of Aguired Cystic Disease of the Kidney

近年来，长期血液透析患者发生获得性肾囊性疾病（ACDK）已成为一个严重的问题，其合并肾细胞癌的发生率很高。为了阐明ACDK中肾细胞癌发生的机制，我们试图建立二苯基噻唑（DPT）诱导的大鼠多囊肾病（PKD）肾细胞瘤模型。此外，我们试图从分子水平上分析dpt诱导肾囊肿形成过程中的早期变化，以揭示dpt诱导的特异性基因表达。为了前一个目的，我们给患有dpt诱导的PKD的大鼠注射了n -亚硝基somorpholine (NNM)，这是一种强致癌物，并观察了10个肾脏中两个囊肿上皮的肿瘤病变。对于后者，我们通过层粘连蛋白、III型胶原和IV型胶原的免疫组织化学分析来检测细胞外基质的结构变化，并通过运行转录和RNA差异显示分析来追踪dpt诱导的囊肿形成早期特异性表达的基因。结果，我们观察到DPT给药后早期c-myc、c-fos和c-erbB_2等基因的表达降低。此外，我们获得了这些基因的四个候选基因，并确定了其中两个候选基因的部分cDNA序列，这些序列与已经确定的任何cDNA序列不相同。从现在开始，我们将鉴定其他特异性表达dpt诱导的基因，然后寻找nnm特异性基因。

Recently, it is becoming a serious problem that patients with long term hemodialysis frequently develop aquired cystic disease of the kidney (ACDK), which presents a high rate of complication with renal cell carcinoma. In order to elucidate the mechamism by which renal cell cancer occurs in ACDK,we tried to establish a model of renal cell tumor derived from diphenyl thiazole (DPT) -induced polycystic kidney disease (PKD) in rats. In addition, we tried to analyze the early changes at molecular level during DPT-induced renal cyst formation to reveal the gene expressions specific to DPT-induction. For the former purpose, we administered N-nitrosomorpholine (NNM) known as a powerful carcinogenic substance to the rats with DPT-induced PKD and observed the neoplastic lesions derived from epithelium of cysts in two of 10 kidneys. For the latter purpose, we examined the structural change of extracellular matrix by immunohistochemical analysis of laminin, collagen type III and IV and chased the genes expressing specifically to the early phase of DPT-induced cyst formation by the run-on transcription and the RNA differential display analysis. As a result, we observed the expression of several genes including c-myc, c-fos and c-erbB_2 decreased the early days after administration of DPT.In addition, we obtained four candidates of those genes and determined the partial cDNA sequences of two candidates, which were not identical to any cDNA sequence already determined. From now on, we are goning to identify other genes expressing specifically to DPT-induction and next to search NNM-specific genes.