Combined deletion of Vhl, Trp53 and Kif3a causes cystic and neoplastic renal lesions
Combined deletion of Vhl, Trp53 and Kif3a causes cystic and neoplastic renal lesions
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DOI：
10.1002/path.4736
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发表时间：
2016-07-01
影响因子：
7.3
通讯作者：
Frew, Ian J.
中科院分区：
文献类型：
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作者：
Guinot, Anna;Lehmann, Holger;Frew, Ian J.
在大多数透明细胞肾细胞癌（ccRCC）病例中，von Hippel-Lindau （VHL）肿瘤抑制基因双等位失活；然而，Vhl敲除小鼠模型不能重现人类ccRCC，这意味着肿瘤形成需要额外的突变。VHL的突变失活使肾上皮细胞敏感，在其他突变或细胞外刺激下失去初级纤毛。纤毛的丢失被认为是VHL突变细胞的第二次打击，导致囊性病变的发展，在某些情况下，可以发展为ccRCC。支持这一观点的是，通过缺失激酶家族成员3A （Kif3a）基因对初级纤毛的基因消融与Vhl的缺失协同作用，加速小鼠肾脏囊肿的形成。此外，老年Vhl/Trp53双突变小鼠发生肾囊肿和肿瘤的发生率相对较低，这表明Vhl和TP53突变在ccRCC的发生中存在遗传合作。在这里，我们生成肾上皮特异性Kif3a/Trp53和Vhl/Kif3a/Trp53突变小鼠，以研究原发性纤毛缺失是否会加速囊性前体病变的发展或导致其发展为ccRCC。纵向微计算机断层扫描（mu CT）成像和组织病理学分析显示，与Kif3a/Trp53或Vhl/Kif3a突变肾脏相比，Vhl/Kif3a/Trp53突变肾脏的囊肿形成率增加，囊肿中细胞增殖的比例增加，非典型囊肿的频率更高，肿瘤的发生也更高。这些发现表明，除了Vhl和Trp53的丢失外，原发性纤毛的丢失促进了向恶性肿瘤的转变，并进一步证明了原发性纤毛在肾脏中作为肿瘤抑制细胞器的功能。版权所有2016年英国和爱尔兰病理学会。约翰·威利父子有限公司出版。
The von Hippel-Lindau (VHL) tumour suppressor gene is bi-allelically inactivated in the majority of cases of clear cell renal cell carcinoma (ccRCC); however, Vhl knockout mouse models do not recapitulate human ccRCC, implying that additional mutations are required for tumour formation. Mutational inactivation of VHL sensitises renal epithelial cells to lose the primary cilium in response to other mutations or extracellular stimuli. Loss of cilia is believed to represent a second hit in VHL mutant cells that causes the development of cystic lesions that, in some cases, can progress to ccRCC. Supporting this idea, genetic ablation of the primary cilium by deletion of the kinesin family member 3A (Kif3a) gene cooperates with loss of Vhl to accelerate cyst formation in mouse kidneys. Additionally, aged Vhl/Trp53 double-mutant mice develop renal cysts and tumours at a relatively low incidence, suggesting that there is a genetic cooperation between VHL and TP53 mutation in the development of ccRCC. Here we generated renal epithelium-specific Kif3a/Trp53 and Vhl/Kif3a/Trp53 mutant mice to investigate whether primary cilium deletion would accelerate the development of cystic precursor lesions or cause their progression to ccRCC. Longitudinal microcomputed tomography (mu CT) imaging and histopathological analyses revealed an increased rate of cyst formation, increased proportion of cysts with proliferating cells, higher frequency of atypical cysts as well as the development of neoplasms in Vhl/Kif3a/Trp53 mutant kidneys compared to Kif3a/Trp53 or Vhl/Kif3a mutant kidneys. These findings demonstrate that primary cilium loss, in addition to Vhl and Trp53 losses, promotes the transition towards malignancy and provide further evidence that the primary cilium functions as a tumour suppressor organelle in the kidney. Copyright (C) 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.