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...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2015-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC4348203?pdf=render |
| _version_ | 1818995794195251200 |
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| author | Khushboo Irshad Saroj Kant Mohapatra Chitrangda Srivastava Harshit Garg Seema Mishra Bhawana Dikshit Chitra Sarkar Deepak Gupta Poodipedi Sarat Chandra Parthaprasad Chattopadhyay Subrata Sinha Kunzang Chosdol |
| author_facet | Khushboo Irshad Saroj Kant Mohapatra Chitrangda Srivastava Harshit Garg Seema Mishra Bhawana Dikshit Chitra Sarkar Deepak Gupta Poodipedi Sarat Chandra Parthaprasad Chattopadhyay Subrata Sinha Kunzang Chosdol |
| author_sort | Khushboo Irshad |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-20T21:19:30Z |
| format | Article |
| id | doaj.art-7eaa05ba853a4fef842c32732147ae93 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-20T21:19:30Z |
| publishDate | 2015-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-7eaa05ba853a4fef842c32732147ae932022-12-21T19:26:19ZengPublic Library of Science (PLoS)PLoS ONE1932-62032015-01-01103e011820110.1371/journal.pone.0118201A combined gene signature of hypoxia and notch pathway in human glioblastoma and its prognostic relevance.Khushboo IrshadSaroj Kant MohapatraChitrangda SrivastavaHarshit GargSeema MishraBhawana DikshitChitra SarkarDeepak GuptaPoodipedi Sarat ChandraParthaprasad ChattopadhyaySubrata SinhaKunzang ChosdolHypoxia 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.http://europepmc.org/articles/PMC4348203?pdf=render |
| spellingShingle | Khushboo Irshad Saroj Kant Mohapatra Chitrangda Srivastava Harshit Garg Seema Mishra Bhawana Dikshit Chitra Sarkar Deepak Gupta Poodipedi Sarat Chandra Parthaprasad Chattopadhyay Subrata Sinha Kunzang Chosdol A combined gene signature of hypoxia and notch pathway in human glioblastoma and its prognostic relevance. PLoS ONE |
| title | A combined gene signature of hypoxia and notch pathway in human glioblastoma and its prognostic relevance. |
| title_full | A combined gene signature of hypoxia and notch pathway in human glioblastoma and its prognostic relevance. |
| title_fullStr | A combined gene signature of hypoxia and notch pathway in human glioblastoma and its prognostic relevance. |
| title_full_unstemmed | A combined gene signature of hypoxia and notch pathway in human glioblastoma and its prognostic relevance. |
| title_short | A combined gene signature of hypoxia and notch pathway in human glioblastoma and its prognostic relevance. |
| title_sort | combined gene signature of hypoxia and notch pathway in human glioblastoma and its prognostic relevance |
| url | http://europepmc.org/articles/PMC4348203?pdf=render |
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