Novel ploidy-control genes ORP3 and GJB3 link aneuploidy to tumor cell invasion through microtubule and actin dynamics

Aneuploidy is a hallmark of most cancer types, and it is closely related to cancer cell migration and invasion. However, the mechanistic association between aneuploidy and invasive potential of cancer cells is poorly understood. Here, we report that GJB3 and ORP3, two ploidy-control proteins identified in a previous RNAi screen, are highly expressed in ureter and bladder epithelium while their expression is downregulated in invasive bladder cancer cell lines and during tumor progression, both in human and in mouse bladder cancer. Experimental data demonstrate that both proteins interact with components of microtubules and actin cytoskeleton. Altering the expression of GJB3 or 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 molecular link between aneuploidy and cell invasion and migration, two crucial characteristics of metastatic cells.