Hascoet Pauline, Chesnel Franck, Jouan Florence, Le Goff Cathy, Couturier Anne, Darrigrand Eric, Mahe Fabrice, Rioux-Leclercq Nathalie, Le Goff Xavier, Arlot-Bonnemains Yannick
CNRS, UMR 6290 IGDR, Université Rennes 1, BIOSIT, Rennes, France.
IRMAR, Université Rennes 1, Rennes, France.
Oncotarget. 2017 Jun 6;8(44):75989-76002. doi: 10.18632/oncotarget.18376. eCollection 2017 Sep 29.
The von Hippel-Lindau () tumor suppressor gene is often deleted or mutated in ccRCC (clear cell renal cell carcinoma) producing a non-functional protein. The gene encodes two mRNA, and three protein isoforms (pVHL, pVHL and pVHL). The pVHL protein is part of an E3 ligase complex involved in the ubiquitination and proteasomal degradation of different proteins, particularly hypoxia inducible factors (HIF) that drive the transcription of genes involved in the regulation of cell proliferation, angiogenesis or extracellular matrix remodelling. Other non-canonical (HIF-independent) pVHL functions have been described. A recent work reported the expression of the uncharacterized protein isoform pVHL which is translated from the variant 2 by alternative splicing of the exon 2. This splice variant is sometimes enriched in the ccRCCs and the protein has been identified in the respective samples of ccRCCs and different renal cell lines. Functional studies on pVHL have only concerned the pVHL and pVHL isoforms, but no function was assigned to pVHL. Here we show that pVHL stable expression in renal cancer cells does not regulate the level of HIF, exacerbates tumorigenicity when 786-O-pVHL cells were xenografted in mice. The pVHL-induced tumors developed a sarcomatoid phenotype. Moreover, pVHL expression was shown to up regulate a subset of pro-tumorigenic genes including , and . In summary we identified that pVHL is not a tumor suppressor. Furthermore our findings suggest an antagonistic function of this pVHL isoform in the HIF-independent aggressiveness of renal tumors compared to pVHL.
冯·希佩尔-林道（VHL）肿瘤抑制基因在透明细胞肾细胞癌（ccRCC）中常发生缺失或突变，产生无功能的蛋白质。该基因编码两种mRNA和三种蛋白质异构体（pVHL、pVHL和pVHL）。pVHL蛋白是E3连接酶复合物的一部分，参与不同蛋白质的泛素化和蛋白酶体降解，特别是驱动参与细胞增殖、血管生成或细胞外基质重塑调控的基因转录的缺氧诱导因子（HIF）。还描述了其他非经典（不依赖HIF）的pVHL功能。最近的一项研究报道了从未经鉴定的蛋白质异构体pVHL的表达，它是由外显子2的可变剪接从变体2翻译而来。这种剪接变体有时在ccRCC中富集，并且已在ccRCC的各个样本和不同肾细胞系中鉴定出该蛋白质。对pVHL的功能研究仅涉及pVHL和pVHL异构体，但未赋予pVHL任何功能。在这里，我们表明在肾癌细胞中稳定表达pVHL不会调节HIF水平，当786-O-pVHL细胞异种移植到小鼠体内时会加剧致瘤性。pVHL诱导的肿瘤呈现肉瘤样表型。此外，pVHL的表达被证明会上调包括 、 和 在内的一组促肿瘤基因。总之，我们确定pVHL不是肿瘤抑制因子。此外，我们的研究结果表明，与pVHL相比，这种pVHL异构体在肾肿瘤不依赖HIF的侵袭性中具有拮抗功能。
