Silencing of PROS1 induces apoptosis and inhibits migration and invasion of glioblastoma multiforme cells

Mohd Firdaus Che Mat, Nor Azian Abdul Murad, Kamariah Ibrahim, Norfilza Mohd Mokhtar, Wan Zurinah Wan Ngah, Roslan Harun, A. Rahman A. Jamal

Research output: Contribution to journalArticle

4 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2359-2366
Number of pages8
JournalInternational Journal of Oncology
Volume49
Issue number6
DOIs
Publication statusPublished - 1 Dec 2016

Fingerprint

Glioblastoma
Apoptosis
Genes
RNA Interference
Meta-Analysis
Cell Proliferation
Death Domain Receptors
Therapeutics
Brain Neoplasms
Glioma
Wound Healing
Small Interfering RNA
Cell Movement
Up-Regulation
Down-Regulation
Survival Rate
Survival
Research

Keywords

  • Cancer
  • Glioblastoma
  • PROS1
  • RNA interference screening

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Silencing of PROS1 induces apoptosis and inhibits migration and invasion of glioblastoma multiforme cells. / Che Mat, Mohd Firdaus; Abdul Murad, Nor Azian; Ibrahim, Kamariah; Mohd Mokhtar, Norfilza; Ngah, Wan Zurinah Wan; Harun, Roslan; A. Jamal, A. Rahman.

In: International Journal of Oncology, Vol. 49, No. 6, 01.12.2016, p. 2359-2366.

Research output: Contribution to journalArticle

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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.",
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