端粒长度和结构的稳定与肿瘤及衰老的发生密切相关,端粒维持机制是细胞增殖的必要条件,端粒维持机制的激活是肿瘤细胞演化过程中的一个重要环节。这种端粒维持机制可能是通过重新激活端粒酶,使细胞快速增殖。在端粒酶失活或不足的情况下,也存在着一种或多种维持和增加端粒长度的机制,统称为端粒延长替代机制(Alterative lengthening of telomere,ALT)。其特点包括:具有不均一的端粒长度,存在与ALT相关的PML小体(APBs)以及同源重组增加。ALT细胞内存在的ALT相关蛋白及异常活跃的同源重组为ALT机制的激活和维持提供了可能。文章综述了ALT的特征性表型、与端粒酶的相关性及其可能的发生机制。对ALT机制的深入研究将有利于阐明衰老与肿瘤之间的辩证关系。
Objective: Polycystic kidney disease(PKD) is the major cause of kidney failure and mortality in humans. It has always been suspected that the development of cystic kidney disease shares features with tumorigenesis, although the evidence is unclear.Methods: We crossed p53 mutant mice(p53N236S, p53S) with Werner syndrome mice and analyzed the pathological phenotypes.The RNA-seq, ss GSEA analysis, and real-time PCR were performed to dissect the gene signatures involved in the development of disease phenotypes.Results: We found enlarged kidneys with fluid-filled cysts in offspring mice with a genotype of G3mTerc^(-/-)WRN^(-/-)p53^(S/S)(G3TM).Pathology analysis confirmed the occurrence of PKD, and it was highly correlated with the incidence of tumorigenesis. RNA-seq data revealed the gene signatures involved in PKD development, and demonstrated that PKD and tumorigenesis shared common pathways, including complement pathways, lipid metabolism, mitochondria energy homeostasis and others. Interestingly, this G3TM PKD and the classical PKD1/2 deficient PKD shared common pathways, possibly because the mutant p53S could regulate the expression levels of PKD1/2, Pkhd1, and Hnf1b.Conclusions: We established a dual mouse model for PKD and tumorigenesis derived from abnormal cellular proliferation and telomere dysfunction. The innovative point of our study is to report PKD occurring in conjunction with tumorigenesis. The gene signatures revealed might shed new light on the pathogenesis of PKD, and provide new molecular biomarkers for clinical diagnosis and prognosis.
