Unveiling the Role of Nucleoporins in Glioblastoma

Glioblastoma (GBM) is the most common and lethal of primary brain tumors. It contains self-renewing, tumorigenic cancer stem cells (CSC) that are thought to be resistant to conventional therapy. These cells give rise to all cell populations in the tumor, and contribute to tumor heterogeneity, a hallmark of GBM. CSCs can originate either from direct transformation of neural stem cells or de-differentiation of transformed mature cells.

Transcription analysis of patient derived GBM samples revealed up-regulation of three nuclear pore complex (NPC)-related genes: NUP210L, NUP43 and NUP50. The NPCs, large channels penetrating the nuclear envelope, comprise of proteins called Nucleoporins (NUPs), that have functions in nucleocytoplasmic transport and gene regulation. NUPs expression varies between cell types, tissues and during development. They were recently found to play a role in processes including mitosis and chromatin organization, and to highly influence differentiation. These characteristics of NUPs, together with the up-regulation found in GBM, suggest an influence on CSCs transformation, self-renewal abilities and plasticity.

We hypothesize that the up-regulation of these three NUPs (or either one of them) affects GBM progression by altering the overall gene expression in glioma cells. We have confirmed the up-regulation of these NUPs in cancer cell lines and tumors, and created KO and KD cell lines using CRISPR/Cas9 system and shRNA methods, respectively. We have tested their roles in several cancer-related processes, and hope to elucidate their roles in gliomagenesis. Studying nucleoporin function in GBM may reveal novel mechanisms of oncogenesis and uncover surprising new mechanisms in cancer biology.