Department of Urology, University of Texas Health Sciences Center at San Antonio, Texas, United States of America.
PLoS One. 2011;6(6):e21037. doi: 10.1371/journal.pone.0021037. Epub 2011 Jun 14.
Germline mutations of FH, the gene that encodes for the tricarboxylic acid TCA (TCA) cycle enzyme fumarate hydratase, are associated with an inherited form of cancer referred to as Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC). Individuals with HLRCC are predisposed to the development of highly malignant and lethal renal cell carcinoma (RCC). The mechanisms of tumorigenesis proposed have largely focused on the biochemical consequences of loss of FH enzymatic activity. While loss of the tumor suppressor gene von Hippel Lindau (VHL) is thought to be an initiating event for the majority of RCCs, a role for FH in sporadic renal cancer has not been explored. Here we report that FH mRNA and protein expression are reduced in clear cell renal cancer, the most common histologic variant of kidney cancer. Moreover, we demonstrate that reduced FH leads to the accumulation of hypoxia inducible factor- 2α (HIF-2α), a transcription factor known to promote renal carcinogenesis. Finally, we demonstrate that overexpression of FH in renal cancer cells inhibits cellular migration and invasion. These data provide novel insights into the tumor suppressor functions of FH in sporadic kidney cancer.
FH 基因的种系突变，该基因编码三羧酸循环 TCA（TCA）酶延胡索酸水合酶，与一种称为遗传性平滑肌瘤病和肾细胞癌（HLRCC）的遗传性癌症有关。HLRCC 个体易患高度恶性和致命的肾细胞癌（RCC）。提出的肿瘤发生机制主要集中在 FH 酶活性丧失的生化后果上。虽然失活抑癌基因 von Hippel Lindau（VHL）被认为是大多数 RCC 的起始事件，但 FH 在散发性肾肿瘤中的作用尚未得到探索。在这里，我们报告在肾透明细胞癌中 FH mRNA 和蛋白表达降低，肾透明细胞癌是肾癌最常见的组织学变异。此外，我们证明减少 FH 导致缺氧诱导因子-2α（HIF-2α）的积累，HIF-2α 是一种已知促进肾致癌作用的转录因子。最后，我们证明在肾癌细胞中过表达 FH 可抑制细胞迁移和侵袭。这些数据为 FH 在散发性肾肿瘤中的肿瘤抑制功能提供了新的见解。
