Yamauchi Masamichi, Kataoka Hiroaki, Itoh Hiroshi, Seguchi Tomoko, Hasui Yoshiniro, Osada Yukio
Second Department of Pathology, Miyazaki Medical College, Kiyotake, Japan.
J Urol. 2004 Feb;171(2 Pt 1):890-6. doi: 10.1097/01.ju.0000092861.21122.d2.
Hepatocyte growth factor (HGF) and its receptor MET have been implicated in kidney development and renal cell carcinoma (RCC) progression. HGF is secreted as an inactive proform and it must be activated to initiate MET signaling. HGF activator (HGFA) activates pro-HGF in injured tissue. We evaluated the expression of HGFA and its endogenous inhibitors HAI-1 and HAI-2 in normal kidney and RCC.
We examined the gene expression of HGFA, HAI-1, HAI-2, HGF and MET in a normal kidney by laser captured microdissection, followed by reverse transcriptase-polymerase chain reaction. We also quantified the mRNA levels of these proteins in 14 RCC cases by real-time reverse transcriptase-polymerase chain reaction.
HAI-1 and HAI-2 were abundant in the normal kidney. The uriniferous tubules showed the highest levels of HAI-1 and HAI-2 mRNA. HGFA was hardly detectable in the normal kidney. However, in the kidney with RCC a low but distinct level of HGFA mRNA became detectable in the tumor and adjacent renal tissue. The HAI-1 mRNA level was significantly and consistently down-regulated in RCC relative to normal tissue. HAI-2 mRNA was also significantly low in the advanced stage of RCC. MET was up-regulated in most cases of RCC.
HAI-1 and HAI-2 were expressed in renal tubular epithelial cells. The expression of the 2 HAIs was significantly down-regulated in RCC, whereas HGFA expression was enhanced in the diseased kidney, suggesting an imbalance between HAI and its target proteinases, including HGFA, in favor of proteinase activities in RCC.
肝细胞生长因子（HGF）及其受体MET与肾脏发育和肾细胞癌（RCC）进展有关。HGF以无活性的前体形式分泌，必须被激活才能启动MET信号传导。HGF激活剂（HGFA）在损伤组织中激活前体HGF。我们评估了HGFA及其内源性抑制剂HAI-1和HAI-2在正常肾脏和RCC中的表达。
我们通过激光捕获显微切割技术检测了正常肾脏中HGFA、HAI-1、HAI-2、HGF和MET的基因表达，随后进行逆转录-聚合酶链反应。我们还通过实时逆转录-聚合酶链反应对14例RCC病例中这些蛋白的mRNA水平进行了定量。
HAI-1和HAI-2在正常肾脏中含量丰富。肾小管显示出最高水平的HAI-1和HAI-2 mRNA。在正常肾脏中几乎检测不到HGFA。然而，在患有RCC的肾脏中，肿瘤及相邻肾组织中可检测到低但明显水平的HGFA mRNA。与正常组织相比，RCC中HAI-1 mRNA水平显著且持续下调。在RCC晚期，HAI-2 mRNA也显著降低。在大多数RCC病例中，MET上调。
HAI-1和HAI-2在肾小管上皮细胞中表达。在RCC中，这两种HAI的表达显著下调，而在患病肾脏中HGFA表达增强，这表明HAI与其靶蛋白酶（包括HGFA）之间存在失衡现象，有利于RCC中的蛋白酶活性。
