PDF(Pubmed)
Abstract：
We have recently shown that loss of ORP3 leads to aneuploidy induction and promotes tumor formation. However, the specific mechanisms by which ORP3 contributes to ploidy-control and cancer initiation and progression is still unknown. Here, we report that ORP3 is highly expressed in ureter and bladder epithelium while its expression is downregulated in invasive bladder cancer cell lines and during tumor progression, both in human and in mouse bladder cancer. Moreover, we observed an increase in the incidence of N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN)-induced invasive bladder carcinoma in the tissue-specific Orp3 knockout mice. Experimental data demonstrate that ORP3 protein interacts with γ-tubulin at the centrosomes and with components of actin cytoskeleton. Altering the expression of ORP3 induces aneuploidy and genomic instability in telomerase-immortalized urothelial cells with a stable karyotype and influences the migration and invasive capacity of bladder cancer cell lines. These findings demonstrate a crucial role of ORP3 in ploidy-control and indicate that ORP3 is a bona fide tumor suppressor protein. Of note, the presented data indicate that ORP3 affects both cell invasion and migration as well as genome stability through interactions with cytoskeletal components, providing a molecular link between aneuploidy and cell invasion and migration, two crucial characteristics of metastatic cells.
摘要：
我们最近表明，ORP3的缺失导致非整倍性诱导并促进肿瘤形成。然而,ORP3有助于倍性控制以及癌症发生和进展的具体机制尚不清楚.这里,我们报道，ORP3在输尿管和膀胱上皮中高表达，而其表达在浸润性膀胱癌细胞系和肿瘤进展过程中下调。在人类和小鼠膀胱癌中。此外，在组织特异性Orp3基因敲除小鼠中,我们观察到N-丁基-N-(4-羟丁基)-亚硝胺(BBN)诱导的浸润性膀胱癌的发生率增加.实验数据表明，ORP3蛋白在中心体处与γ-微管蛋白相互作用，并与肌动蛋白细胞骨架的成分相互作用。改变ORP3的表达会诱导具有稳定核型的端粒酶永生化尿路上皮细胞的非整倍体和基因组不稳定性，并影响膀胱癌细胞系的迁移和侵袭能力。这些发现证明了ORP3在倍性控制中的关键作用，并表明ORP3是真正的肿瘤抑制蛋白。值得注意的是，提供的数据表明，ORP3通过与细胞骨架成分的相互作用影响细胞侵袭和迁移以及基因组稳定性，提供非整倍性与细胞侵袭和迁移之间的分子联系，转移细胞的两个关键特征。
