Loss of ORP3 induces aneuploidy and promotes bladder cancer cell invasion through deregulated microtubule and actin dynamics

by Selleckchem | Jan 13 2024

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.

Comments:

Your study on ORP3's involvement in aneuploidy induction and its impact on tumor formation is fascinating! The findings suggest a multifaceted role for ORP3 in regulating ploidy and influencing cancer initiation and progression, particularly in bladder cancer. The observation of differential expression in healthy bladder epithelium versus invasive bladder cancer cell lines, along with its downregulation during tumor progression in both human and mouse models, provides valuable insight into its potential as a tumor suppressor.

The increase in BBN-induced invasive bladder carcinoma in tissue-specific Orp3 knockout mice further supports its role in bladder cancer development. The identified interactions between ORP3 and key cellular components such as γ-tubulin at centrosomes and elements of the actin cytoskeleton shed light on its mechanisms of action. Specifically, the influence of ORP3 on aneuploidy, genomic stability in urothelial cells, and its impact on migration and invasion of bladder cancer cell lines indicate its pivotal role in these crucial characteristics of metastatic cells.

Your study not only highlights ORP3's significance in ploidy regulation but also establishes a molecular link between aneuploidy, cell invasion, and migration, which are pivotal in understanding the metastatic process. This insight into ORP3's functions could potentially offer new avenues for therapeutic interventions targeting these mechanisms in bladder cancer and possibly in metastatic processes in other cancers as well.