Role of PP2A phosphatases and miR-19b in DNA damage response and temozolomide resistance of GBM tumours

The preliminary results from the group revealed that attenuation of miR-19b results in major changes in the phospho-proteome, enhances phosphatase activity and reduces efficiency in TMZ-induced DNA damage response in a GBM cell line. miR-19b is potentially able to target PP2A subunits PPP2R2A, PPP2R1B, PPP2R5A and PPP2R5E. PPP2R5E targeting by miR-19b was confirmed experimentally. Consistent with these findings, miR-19b levels were inversely correlated with the expression of PP2A subunits in GBM tissues, suggesting that miR-19b controls the expression of PP2A.

Specific aims of the ongoing project would be:

A) Analysis of PP2A and DNA damage response genes in tissues of TMZ resistant recurrent GBM cases.

B) Mechanistic analysis of PP2A and miR-19b in patient-derived GBM stem cells (GSCs).

C) Assess PP2A regulation by miR-19b

D) Assess if targeting miR-19b can be exploited for anti-GBM adjuvant therapy in an orthotopic mouse model.