title: Silencing of PROS1 induces apoptosis and inhibits migration and invasion of glioblastoma multiforme cells.
abstract: Glioblastoma multiforme (GBM) is an aggressive brain tumor and most patients have poor prognosis. Despite many advances in research, there has been no significant improvement in the patient survival rate. New molecular therapies are being studied and RNA interference (RNAi) therapy is one of the promising approaches to improve prognosis and increase survival in patients with GBM. We performed a meta‑analysis of five different microarray datasets and identified 460 significantly upregulated genes in GBM. Loss‑of‑function screening of these upregulated genes using LN18 cells was performed to identify the significant target genes for glioma. Further investigations were performed using siRNA in LN18 cells and various functional assays were carried out on the selected candidate gene to understand further its role in GBM. We identified PROS1 as a candidate gene for GBM from the meta‑analysis and RNAi screening. Knockdown of PROS1 in LN18 cells significantly induced apoptosis compared to siPROS1‑untreated cells (p<0.05). Migration in cells treated with siPROS1 was reduced significantly (p<0.05) and this was confirmed with wound-healing assay. PROS1 knockdown showed substantial reduction in cell invasion up to 82% (p<0.01). In addition, inhibition of PROS1 leads to decrease in cellular proliferation by 18%. Knockdown of PROS1 in LN18 cells caused activation of both of the extrinsic and intrinsic apoptotic pathways. It caused major upregulation of FasL which is important for death receptor signaling activation and also downregulation of GAS6 and other members of TAM family of receptors. PROS1 may play an important role in the development of GBM through cellular proliferation, migration and invasion as well as apoptosis. Targeting PROS1 in GBM could be a novel therapeutic strategy in GBM treatment.
authors.affiliation: UKM Medical Molecular Biology Institute, Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur 56000, Malaysia.
authors.forename: Mohd Firdaus
authors.initials: MF
authors.lastname: Che Mat
authors.affiliation: UKM Medical Molecular Biology Institute, Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur 56000, Malaysia.
authors.forename: Nor Azian
authors.initials: NA
authors.lastname: Abdul Murad
authors.affiliation: UKM Medical Molecular Biology Institute, Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur 56000, Malaysia.
authors.forename: Kamariah
authors.initials: K
authors.lastname: Ibrahim
authors.affiliation: UKM Medical Molecular Biology Institute, Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur 56000, Malaysia.
authors.forename: Norfilza
authors.initials: N
authors.lastname: Mohd Mokhtar
authors.affiliation: UKM Medical Molecular Biology Institute, Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur 56000, Malaysia.
authors.forename: Wan Zurinah
authors.initials: WZ
authors.lastname: Wan Ngah
authors.affiliation: UKM Medical Molecular Biology Institute, Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur 56000, Malaysia.
authors.forename: Roslan
authors.initials: R
authors.lastname: Harun
authors.affiliation: UKM Medical Molecular Biology Institute, Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur 56000, Malaysia.
authors.forename: Rahman
authors.initials: R
authors.lastname: Jamal
mesh_terms: D017209:Apoptosis / Q000235:genetics*; D001798:Blood Proteins / Q000235:genetics*; D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics*; D049109:Cell Proliferation / Q000235:genetics*; D002470:Cell Survival / Q000235:genetics; D005909:Glioblastoma / Q000235:genetics* / Q000473:pathology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis; D009361:Neoplasm Invasiveness / Q000235:genetics; D017293:Protein S; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics / Q000627:therapeutic use; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis; D000076202:c-Mer Tyrosine Kinase; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6
chemical_list: D001798:Blood Proteins; D036341:Intercellular Signaling Peptides and Proteins; D017293:Protein S; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D020794:Receptor Protein-Tyrosine Kinases; D000076202:c-Mer Tyrosine Kinase; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6; C523390:PROS1 protein, human; C097072:MERTK protein, human; C084944:TYRO3 protein, human; C000722289:AXL protein, human