Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America.
PLoS One. 2013 Jul 29;8(7):e70030. doi: 10.1371/journal.pone.0070030. Print 2013.
Von Hippel-Lindau tumor suppressor (VHL) is lost in the majority of clear cell renal cell carcinomas (ccRCC). Folliculin (FLCN) is a tumor suppressor whose function is lost in Birt-Hogg-Dubé syndrome (BHD), a disorder characterized by renal cancer of multiple histological types including clear cell carcinoma, cutaneous fibrofolliculoma, and pneumothorax. Here we explored whether there is connection between VHL and FLCN in clear cell renal carcinoma cell lines and tumors. We demonstrate that VHL regulates expression of FLCN at the mRNA and protein levels in RCC cell lines, and that FLCN protein expression is decreased in human ccRCC tumors with VHL loss, as compared with matched normal kidney tissue. Knockdown of FLCN results in increased formation of tumors by RCC cells with wild-type VHL in orthotopic xenografts in nude mice, an indication that FLCN plays a role in the tumor-suppressing activity of VHL. Interestingly, FLCN, similarly to VHL, is necessary for the activity of LC3C-mediated autophagic program that we have previously characterized as contributing to the tumor suppressing activity of VHL. The results show the existence of functional crosstalk between two major tumor suppressors in renal cancer, VHL and FLCN, converging on regulation of autophagy.
希佩尔-林道肿瘤抑制因子（VHL）在大多数透明细胞肾细胞癌（ccRCC）中丢失。卵泡抑素（FLCN）是一种肿瘤抑制因子，其功能在 Birt-Hogg-Dubé 综合征（BHD）中丢失，BHD 是一种以多种组织学类型的肾癌为特征的疾病，包括透明细胞癌、皮肤纤维毛囊瘤和气胸。在这里，我们探讨了 VHL 和 FLCN 在透明细胞肾癌细胞系和肿瘤中的关系。我们证明 VHL 在 RCC 细胞系中调节 FLCN 的 mRNA 和蛋白水平的表达，并且与匹配的正常肾组织相比，VHL 丢失的人 ccRCC 肿瘤中 FLCN 蛋白表达降低。FLCN 的敲低导致具有野生型 VHL 的 RCC 细胞在裸鼠原位异种移植中形成更多的肿瘤，表明 FLCN 在 VHL 的肿瘤抑制活性中发挥作用。有趣的是，FLCN 与 VHL 相似，是我们之前描述的参与 VHL 肿瘤抑制活性的 LC3C 介导的自噬程序的活性所必需的。结果表明，在肾癌中，两个主要的肿瘤抑制因子 VHL 和 FLCN 之间存在功能相互作用，它们都集中在自噬的调节上。
