A combined gene signature of hypoxia and notch pathway in human glioblastoma and its prognostic relevance.
Hypoxia is a hallmark of solid tumors including glioblastoma (GBM). Its synergism with Notch signaling promotes progression in different cancers. However, Notch signaling exhibits pleiotropic roles and the existing literature lacks a comprehensive understanding of its perturbations under hypoxia in GBM with respect to all components of the pathway. We identified the key molecular cluster(s) characteristic of the Notch pathway response in hypoxic GBM tumors and gliomaspheres. Expression of Notch and hypoxia genes was evaluated in primary human GBM tissues by q-PCR. Clustering and statistical analyses were applied to identify the combination of hypoxia markers correlated with upregulated Notch pathway components. We found well-segregated tumor-clusters representing high and low HIF-1α/PGK1-expressors which accounted for differential expression of Notch signaling genes. In combination, a five-hypoxia marker set (HIF-1α/PGK1/VEGF/CA9/OPN) was determined as the best predictor for induction of Notch1/Dll1/Hes1/Hes6/Hey1/Hey2. Similar Notch-axis genes were activated in gliomaspheres, but not monolayer cultures, under moderate/severe hypoxia (2%/0.2% O2). Preliminary evidence suggested inverse correlation between patient survival and increased expression of constituents of the hypoxia-Notch gene signature. Together, our findings delineated the Notch-axis maximally associated with hypoxia in resected GBM, which might be prognostically relevant. Its upregulation in hypoxia-exposed gliomaspheres signify them as a better in-vitro model for studying hypoxia-Notch interactions than monolayer cultures.
Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India.
Khushboo
K
Irshad
National Institute of Biomedical Genomics, Kalyani, West Bengal, India.
Saroj Kant
SK
Mohapatra
Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India.
Chitrangda
C
Srivastava
Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India.
Harshit
H
Garg
Department of Biochemistry, School of Life Science, University of Hyderabad, Hyderabad, India.
Seema
S
Mishra
Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India.
Bhawana
B
Dikshit
Department of Pathology, All India Institute of Medical Sciences, New Delhi, India.
Chitra
C
Sarkar
Department of Neurosurgery, All India Institute of Medical Sciences, New Delhi, India.
Deepak
D
Gupta
Department of Neurosurgery, All India Institute of Medical Sciences, New Delhi, India.
Poodipedi Sarat
PS
Chandra
Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India.
Parthaprasad
P
Chattopadhyay
National Brain Research Centre, Manesar, Gurgaon, Haryana, India.
Subrata
S
Sinha
Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India.
Kunzang
K
Chosdol
D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D001932:Brain Neoplasms / Q000175:diagnosis* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D015687:Cell Hypoxia; D016000:Cluster Analysis; D005909:Glioblastoma / Q000175:diagnosis* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D053495:Osteopontin / Q000235:genetics / Q000378:metabolism; D010735:Phosphoglycerate Kinase / Q000235:genetics / Q000378:metabolism; D025341:Principal Component Analysis; D011379:Prognosis; D060888:Real-Time Polymerase Chain Reaction; D051880:Receptors, Notch / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D000072056:Transcription Factor HES-1; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D051792:Basic Helix-Loop-Helix Proteins; D018398:Homeodomain Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D053495:Osteopontin; D010735:Phosphoglycerate Kinase; D051880:Receptors, Notch; D000072056:Transcription Factor HES-1; C078493:HES1 protein, human; C577282:PGK1 protein, human