Hepatocyte growth factor-stimulated renal tubular mitogenesis: effects on expression of c-myc, c-fos, c-met, VEGF and the VHL tumour-suppressor and related genes.
Hepatocyte growth factor-stimulated renal tubular mitogenesis: effects on expression of c-myc, c-fos, c-met, VEGF and the VHL tumour-suppressor and related genes.
复制标题
肝细胞生长因子刺激的肾小管有丝分裂：对C-MYC，C-FOS，C-MET，VEGF和VHL肿瘤抑制剂和相关基因的表达的影响。
DOI：
10.1038/bjc.1998.235
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发表时间：
1998-05
影响因子：
8.8
通讯作者：
Maher, E R
中科院分区：
文献类型：
--
作者：
Clifford, S C;Czapla, K;Richards, F M;O'Donoghue, D J;Maher, E R
肝细胞生长因子（HGF/SF）是一种有效的肾近端小管细胞（PTEC）丝裂原，参与肾脏发育。HGF/SF是c-met原癌基因的功能性配体，种系c-met突变与家族性乳头状肾细胞癌有关。散发性透明细胞肾细胞癌（RCC）中经常检测到体细胞von hipel - lindau病肿瘤抑制基因（VHL）突变，种系VHL突变是家族性透明细胞肾细胞癌（RCC）最常见的原因。pVHL结合三聚体长蛋白（SIII）复合物（长蛋白B和C）的正调控成分，并已被观察到解除对血管内皮生长因子（VEGF）基因的表达的调节。据报道，HGF/SF在非肾实验系统中也能上调VEGF基因的表达。为了研究HGF/SF在ptec中的作用机制，特别是HGF/ C -met与VHL介导的肾小管生长控制途径之间的潜在相互作用，我们从正常肾脏中分离出未转化的ptec，建立体外培养条件，并利用这些细胞研究HGF/SF暴露后VHL、长链蛋白A、B和C、VEGF、C -myc、C -fos和C -met基因mRNA水平的变化。HGF/SF刺激人PTECs后，VEGF、C -myc、C -fos、C -met和长链蛋白A、B和C的mRNA水平显著升高，但VHL无显著升高（P < 0.02），且在连续重复中观察到峰值水平的顺序一致（1小时C -fos， 2-4小时VEGF， 4小时C -myc，其次是8小时C -met和所有三个长链蛋白亚基）。本研究强调了在HGF/SF刺激后ptec中观察到的基因表达变化谱，并确定了HGF/SF诱导的有丝分裂反应的可能候选介质。我们的证据表明，HGF/SF诱导的PTEC VEGF表达变化是由一个不依赖于vhl的途径介导的。
Hepatocyte growth factor (HGF/SF) is a potent renal proximal tubular cell (PTEC) mitogen involved in renal development. HGF/SF is the functional ligand for the c-met proto-oncogene, and germline c-met mutations are associated with familial papillary renal cell carcinoma. Somatic von Hippel-Lindau disease tumour-suppressor gene (VHL) mutations are frequently detected in sporadic clear cell renal cell carcinomas (RCC), and germline VHL mutations are the commonest cause of familial clear cell RCC. pVHL binds to the positive regulatory components of the trimeric elongin (SIII) complex (elongins B and C) and has been observed to deregulate expression of the vascular endothelial growth factor (VEGF) gene. HGF/SF has similarly been reported to up-regulate expression of the VEGF gene in non-renal experimental systems. To investigate the mechanism of HGF/SF action in PTECs and, specifically, to examine potential interactions between the HGF/c-met and the VHL-mediated pathways for renal tubular growth control, we have isolated untransformed PTECs from normal kidneys, developed conditions for their culture in vitro and used these cells to investigate changes in mRNA levels of the VHL, elongin A, B and C, VEGF, c-myc, c-fos and c-met genes after HGF/SF exposure. Significant elevations in the mRNA levels of VEGF, c-myc, c-fos, c-met and elongins A, B and C, but not VHL, were detected after HGF/SF stimulation of human PTECs (P < 0.02), with a consistent order of peak levels observed over successive replicates (c-fos at 1 h, VEGF at 2-4 h, c-myc, at 4 h, followed by c-met and all three elongin subunits at 8 h). This study highlights the spectrum of changes in gene expression observed in PTECs after HGF/SF stimulation and has identified possible candidate mediators of the HGF/SF-induced mitogenic response. Our evidence would suggest that the changes in PTEC VEGF expression induced by HGF/SF are mediated by a VHL-independent pathway.