gms | German Medical Science

Objective: Programmed cell death 10 (PDCD10) is ubiquitously expressed in nearly all tissues and plays crucial roles in regulating angiogenesis and apoptosis. Recently we discovered the absence of PDCD10 expression in the majority of tumour cells and vessels of GBM patients. Moreover, loss of endothelial PDCD10 activated GBM tumour cells through releasing multiple growth factors and activation of EphB42-3. The present study further investigated the role of tumour-originated PDCD10 in GBM cell phenotyping and tumour progression.

Methods: PDCD10 was knocked down in U87 and T98g GBM cell lines by lentivirus-mediated shRNA transduction. The behaviour of GBM cells including proliferation, adhesion, invasion and migration were studied in PDCD10-knockdown and control cells. The role of PDCD10 in tumour growth was investigated in a human GBM xenograft mouse model. Real-time PCR, Western blot, ELISA and immunohistochemistry were performed to elucidate the potential molecule targets of PDCD10.

Results: Knockdown of PDCD10 in GBM cells significantly stimulated tumour cell proliferation, adhesion, invasion and migration, accompanied by an activation of EphB4 and Erk1/2. Moreover, the tumour mass was 2.4-fold larger in mice implanted with PDCD10-knockdown U87 cells than that implanted with control U87 cells. Immunostaining and ELISA revealed extensive Ki67-positive cells and a higher EphB4 activity in PDCD10-knockdown tumour, respectively. The treatment with NVP-BHG712, a specific EphB4 kinase inhibitor, not only inhibited the increase in EphB4 activity but also reversed tumour cell phenotype in vitro and suppressed tumour growth in vivo mediated by PDCD10-knockdown.

Conclusion: The present study characterized for the first time the tumour suppressor-like function of PDCD10 in GBM. EphB4 seems to be a key molecule involved in activation of GBM cells and in tumour progression caused by PDCD10-knockdown.

References: [1], [2], [3]