Hedgehog signaling pathway is active in GBM with GLI1 mRNA expression showing a single continuous distribution rather than discrete high/low clusters
Hedgehog (Hh) signaling pathway is a valid therapeutic target in a wide range of malignancies. We focus here on glioblastoma multiforme (GBM), a lethal malignancy of the central nervous system (CNS). By analyzing RNA-sequencing based transcriptomics data on 149 clinical cases of TCGA-GBM database we...
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| Veröffentlicht in: | PloS one 2015-03, Vol.10 (3), p.e0116390-e0116390 |
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| creator | Chandra, Vikas Das, Tapojyoti Gulati, Puneet Biswas, Nidhan K Rote, Sarang Chatterjee, Uttara Ghosh, Samarendra N Deb, Sumit Saha, Suniti K Chowdhury, Anup K Ghosh, Subhashish Rudin, Charles M Mukherjee, Ankur Basu, Analabha Dhara, Surajit |
| description | Hedgehog (Hh) signaling pathway is a valid therapeutic target in a wide range of malignancies. We focus here on glioblastoma multiforme (GBM), a lethal malignancy of the central nervous system (CNS). By analyzing RNA-sequencing based transcriptomics data on 149 clinical cases of TCGA-GBM database we show here a strong correlation (r = 0.7) between GLI1 and PTCH1 mRNA expression--as a hallmark of the canonical Hh-pathway activity in this malignancy. GLI1 mRNA expression varied in 3 orders of magnitude among the GBM patients of the same cohort showing a single continuous distribution-unlike the discrete high/low-GLI1 mRNA expressing clusters of medulloblastoma (MB). When compared with MB as a reference, the median GLI1 mRNA expression in GBM appeared 14.8 fold lower than that of the "high-Hh" cluster of MB but 5.6 fold higher than that of the "low-Hh" cluster of MB. Next, we demonstrated statistically significant up- and down-regulation of GLI1 mRNA expressions in GBM patient-derived low-passage neurospheres in vitro by sonic hedgehog ligand-enriched conditioned media (shh-CM) and by Hh-inhibitor drug vismodegib respectively. We also showed clinically achievable dose (50 μM) of vismodegib alone to be sufficient to induce apoptosis and cell cycle arrest in these low-passage GBM neurospheres in vitro. Vismodegib showed an effect on the neurospheres, both by down-regulating GLI1 mRNA expression and by inducing apoptosis/cell cycle arrest, irrespective of their relative endogenous levels of GLI1 mRNA expression. We conclude from our study that this single continuous distribution pattern of GLI1 mRNA expression technically puts almost all GBM patients in a single group rather than discrete high- or low-clusters in terms of Hh-pathway activity. That is suggestive of therapies with Hh-pathway inhibitor drugs in this malignancy without a need for further stratification of patients on the basis of relative levels of Hh-pathway activity among them. |
| doi_str_mv | 10.1371/journal.pone.0116390 |
| format | Article |
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We focus here on glioblastoma multiforme (GBM), a lethal malignancy of the central nervous system (CNS). By analyzing RNA-sequencing based transcriptomics data on 149 clinical cases of TCGA-GBM database we show here a strong correlation (r = 0.7) between GLI1 and PTCH1 mRNA expression--as a hallmark of the canonical Hh-pathway activity in this malignancy. GLI1 mRNA expression varied in 3 orders of magnitude among the GBM patients of the same cohort showing a single continuous distribution-unlike the discrete high/low-GLI1 mRNA expressing clusters of medulloblastoma (MB). When compared with MB as a reference, the median GLI1 mRNA expression in GBM appeared 14.8 fold lower than that of the "high-Hh" cluster of MB but 5.6 fold higher than that of the "low-Hh" cluster of MB. Next, we demonstrated statistically significant up- and down-regulation of GLI1 mRNA expressions in GBM patient-derived low-passage neurospheres in vitro by sonic hedgehog ligand-enriched conditioned media (shh-CM) and by Hh-inhibitor drug vismodegib respectively. We also showed clinically achievable dose (50 μM) of vismodegib alone to be sufficient to induce apoptosis and cell cycle arrest in these low-passage GBM neurospheres in vitro. Vismodegib showed an effect on the neurospheres, both by down-regulating GLI1 mRNA expression and by inducing apoptosis/cell cycle arrest, irrespective of their relative endogenous levels of GLI1 mRNA expression. We conclude from our study that this single continuous distribution pattern of GLI1 mRNA expression technically puts almost all GBM patients in a single group rather than discrete high- or low-clusters in terms of Hh-pathway activity. That is suggestive of therapies with Hh-pathway inhibitor drugs in this malignancy without a need for further stratification of patients on the basis of relative levels of Hh-pathway activity among them.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0116390</identifier><identifier>PMID: 25775002</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Anilides - pharmacology ; Apoptosis ; Apoptosis - drug effects ; Cancer therapies ; Cell cycle ; Cell Cycle Checkpoints - drug effects ; Central nervous system ; Clusters ; Conditioning ; Dose-Response Relationship, Drug ; Down-Regulation - drug effects ; Drug development ; Drugs ; FDA approval ; Gene expression ; Gene Expression Regulation, Neoplastic - drug effects ; Gene sequencing ; Genomics ; Glioblastoma ; Glioblastoma - genetics ; Glioblastoma - pathology ; Glioblastoma multiforme ; Gliomas ; Health aspects ; Hedgehog protein ; Hedgehog Proteins - metabolism ; Humans ; Inhibitors ; Kinases ; Ligands ; Malignancy ; Medical research ; Medulloblastoma ; Medulloblastoma - genetics ; Medulloblastoma - pathology ; Messenger RNA ; Mutation ; Neurology ; Neurospheres ; Oncogene Proteins - genetics ; Ovarian cancer ; Patients ; Pyridines - pharmacology ; Radiation therapy ; Ribonucleic acid ; RNA ; RNA, Messenger - genetics ; RNA, Messenger - metabolism ; Signal transduction ; Signal Transduction - drug effects ; Signaling ; Statistical analysis ; Trans-Activators - genetics ; Transcription factors ; Tumorigenesis ; Up-Regulation - drug effects ; Zinc Finger Protein GLI1</subject><ispartof>PloS one, 2015-03, Vol.10 (3), p.e0116390-e0116390</ispartof><rights>COPYRIGHT 2015 Public Library of Science</rights><rights>2015 Chandra et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2015 Chandra et al 2015 Chandra et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-78b0a6eee7287721973d4c1a06d85287cf4b3633a736b1f174d148f56067d30b3</citedby><cites>FETCH-LOGICAL-c692t-78b0a6eee7287721973d4c1a06d85287cf4b3633a736b1f174d148f56067d30b3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4361547/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4361547/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2102,2928,23866,27924,27925,53791,53793,79600,79601</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25775002$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Castresana, Javier S</contributor><creatorcontrib>Chandra, Vikas</creatorcontrib><creatorcontrib>Das, Tapojyoti</creatorcontrib><creatorcontrib>Gulati, Puneet</creatorcontrib><creatorcontrib>Biswas, Nidhan K</creatorcontrib><creatorcontrib>Rote, Sarang</creatorcontrib><creatorcontrib>Chatterjee, Uttara</creatorcontrib><creatorcontrib>Ghosh, Samarendra N</creatorcontrib><creatorcontrib>Deb, Sumit</creatorcontrib><creatorcontrib>Saha, Suniti K</creatorcontrib><creatorcontrib>Chowdhury, Anup K</creatorcontrib><creatorcontrib>Ghosh, Subhashish</creatorcontrib><creatorcontrib>Rudin, Charles M</creatorcontrib><creatorcontrib>Mukherjee, Ankur</creatorcontrib><creatorcontrib>Basu, Analabha</creatorcontrib><creatorcontrib>Dhara, Surajit</creatorcontrib><title>Hedgehog signaling pathway is active in GBM with GLI1 mRNA expression showing a single continuous distribution rather than discrete high/low clusters</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Hedgehog (Hh) signaling pathway is a valid therapeutic target in a wide range of malignancies. We focus here on glioblastoma multiforme (GBM), a lethal malignancy of the central nervous system (CNS). By analyzing RNA-sequencing based transcriptomics data on 149 clinical cases of TCGA-GBM database we show here a strong correlation (r = 0.7) between GLI1 and PTCH1 mRNA expression--as a hallmark of the canonical Hh-pathway activity in this malignancy. GLI1 mRNA expression varied in 3 orders of magnitude among the GBM patients of the same cohort showing a single continuous distribution-unlike the discrete high/low-GLI1 mRNA expressing clusters of medulloblastoma (MB). When compared with MB as a reference, the median GLI1 mRNA expression in GBM appeared 14.8 fold lower than that of the "high-Hh" cluster of MB but 5.6 fold higher than that of the "low-Hh" cluster of MB. Next, we demonstrated statistically significant up- and down-regulation of GLI1 mRNA expressions in GBM patient-derived low-passage neurospheres in vitro by sonic hedgehog ligand-enriched conditioned media (shh-CM) and by Hh-inhibitor drug vismodegib respectively. We also showed clinically achievable dose (50 μM) of vismodegib alone to be sufficient to induce apoptosis and cell cycle arrest in these low-passage GBM neurospheres in vitro. Vismodegib showed an effect on the neurospheres, both by down-regulating GLI1 mRNA expression and by inducing apoptosis/cell cycle arrest, irrespective of their relative endogenous levels of GLI1 mRNA expression. We conclude from our study that this single continuous distribution pattern of GLI1 mRNA expression technically puts almost all GBM patients in a single group rather than discrete high- or low-clusters in terms of Hh-pathway activity. That is suggestive of therapies with Hh-pathway inhibitor drugs in this malignancy without a need for further stratification of patients on the basis of relative levels of Hh-pathway activity among them.</description><subject>Anilides - pharmacology</subject><subject>Apoptosis</subject><subject>Apoptosis - drug effects</subject><subject>Cancer therapies</subject><subject>Cell cycle</subject><subject>Cell Cycle Checkpoints - drug effects</subject><subject>Central nervous system</subject><subject>Clusters</subject><subject>Conditioning</subject><subject>Dose-Response Relationship, Drug</subject><subject>Down-Regulation - drug effects</subject><subject>Drug development</subject><subject>Drugs</subject><subject>FDA approval</subject><subject>Gene expression</subject><subject>Gene Expression Regulation, Neoplastic - drug effects</subject><subject>Gene sequencing</subject><subject>Genomics</subject><subject>Glioblastoma</subject><subject>Glioblastoma - genetics</subject><subject>Glioblastoma - pathology</subject><subject>Glioblastoma multiforme</subject><subject>Gliomas</subject><subject>Health aspects</subject><subject>Hedgehog protein</subject><subject>Hedgehog Proteins - metabolism</subject><subject>Humans</subject><subject>Inhibitors</subject><subject>Kinases</subject><subject>Ligands</subject><subject>Malignancy</subject><subject>Medical research</subject><subject>Medulloblastoma</subject><subject>Medulloblastoma - genetics</subject><subject>Medulloblastoma - pathology</subject><subject>Messenger RNA</subject><subject>Mutation</subject><subject>Neurology</subject><subject>Neurospheres</subject><subject>Oncogene Proteins - genetics</subject><subject>Ovarian cancer</subject><subject>Patients</subject><subject>Pyridines - pharmacology</subject><subject>Radiation therapy</subject><subject>Ribonucleic acid</subject><subject>RNA</subject><subject>RNA, Messenger - genetics</subject><subject>RNA, Messenger - metabolism</subject><subject>Signal transduction</subject><subject>Signal Transduction - drug effects</subject><subject>Signaling</subject><subject>Statistical analysis</subject><subject>Trans-Activators - genetics</subject><subject>Transcription factors</subject><subject>Tumorigenesis</subject><subject>Up-Regulation - drug effects</subject><subject>Zinc Finger Protein GLI1</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNqNk89u1DAQxiMEoqXwBggsISE47NaOHTu5IJUK2pUKlcqfq-U4k8RV1t7aTrd9EN4Xp91WXdQD8iHW-DffxJ9nsuw1wXNCBdk_d6O3apivnIU5JoTTCj_JdklF8xnPMX36YL-TvQjhHOOClpw_z3byQogC43w3-3MMTQe961AwXZIztkMrFfu1ukYmIKWjuQRkLDr6_A2tTezR0cmCoOXZ9wMEVysPIRhnUejdekpVScZ2AyDtbDR2dGNAjQnRm3qME-iTNngUe2WnA-0hAupN1-8Pbo30MIYIPrzMnrVqCPBq893Lfn398vPweHZyerQ4PDiZaV7lcSbKGisOACIvhchJJWjDNFGYN2WRQrplNeWUKkF5TVoiWENY2RYcc9FQXNO97O2t7mpwQW4cDZLwZCYhJasSsbglGqfO5cqbpfLX0ikjbwLOd1L5aPQAkpOWC6VyVWvGiipXnOKm0ZRqJUquWdL6tKk21ktoNNjo1bAlun1iTS87dykZ5aRgIgl82Ah4dzFCiHKZLIRhUBaS09N_s1Q6F1Otd_-gj99uQ3UqXcDY1qW6ehKVBywvUkdVjCdq_giVVgNLkx4aWpPiWwkftxKmZoCr2KkxBLn4cfb_7Onvbfb9A7YHNcQ-uOGms8I2yG5B7V0IHtp7kwmW0_TcuSGn6ZGb6Ulpbx4-0H3S3bjQv3C8Fbs</recordid><startdate>20150316</startdate><enddate>20150316</enddate><creator>Chandra, Vikas</creator><creator>Das, Tapojyoti</creator><creator>Gulati, Puneet</creator><creator>Biswas, Nidhan K</creator><creator>Rote, Sarang</creator><creator>Chatterjee, Uttara</creator><creator>Ghosh, Samarendra N</creator><creator>Deb, Sumit</creator><creator>Saha, Suniti K</creator><creator>Chowdhury, Anup K</creator><creator>Ghosh, Subhashish</creator><creator>Rudin, Charles M</creator><creator>Mukherjee, Ankur</creator><creator>Basu, Analabha</creator><creator>Dhara, Surajit</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20150316</creationdate><title>Hedgehog signaling pathway is active in GBM with GLI1 mRNA expression showing a single continuous distribution rather than discrete high/low clusters</title><author>Chandra, Vikas ; Das, Tapojyoti ; Gulati, Puneet ; Biswas, Nidhan K ; Rote, Sarang ; Chatterjee, Uttara ; Ghosh, Samarendra N ; Deb, Sumit ; Saha, Suniti K ; Chowdhury, Anup K ; Ghosh, Subhashish ; Rudin, Charles M ; Mukherjee, Ankur ; Basu, Analabha ; Dhara, Surajit</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-78b0a6eee7287721973d4c1a06d85287cf4b3633a736b1f174d148f56067d30b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Anilides - 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genetics</topic><topic>Medulloblastoma - pathology</topic><topic>Messenger RNA</topic><topic>Mutation</topic><topic>Neurology</topic><topic>Neurospheres</topic><topic>Oncogene Proteins - genetics</topic><topic>Ovarian cancer</topic><topic>Patients</topic><topic>Pyridines - pharmacology</topic><topic>Radiation therapy</topic><topic>Ribonucleic acid</topic><topic>RNA</topic><topic>RNA, Messenger - genetics</topic><topic>RNA, Messenger - metabolism</topic><topic>Signal transduction</topic><topic>Signal Transduction - drug effects</topic><topic>Signaling</topic><topic>Statistical analysis</topic><topic>Trans-Activators - genetics</topic><topic>Transcription factors</topic><topic>Tumorigenesis</topic><topic>Up-Regulation - drug effects</topic><topic>Zinc Finger Protein GLI1</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Chandra, Vikas</creatorcontrib><creatorcontrib>Das, Tapojyoti</creatorcontrib><creatorcontrib>Gulati, Puneet</creatorcontrib><creatorcontrib>Biswas, Nidhan K</creatorcontrib><creatorcontrib>Rote, Sarang</creatorcontrib><creatorcontrib>Chatterjee, Uttara</creatorcontrib><creatorcontrib>Ghosh, Samarendra N</creatorcontrib><creatorcontrib>Deb, Sumit</creatorcontrib><creatorcontrib>Saha, Suniti K</creatorcontrib><creatorcontrib>Chowdhury, Anup K</creatorcontrib><creatorcontrib>Ghosh, Subhashish</creatorcontrib><creatorcontrib>Rudin, Charles M</creatorcontrib><creatorcontrib>Mukherjee, Ankur</creatorcontrib><creatorcontrib>Basu, Analabha</creatorcontrib><creatorcontrib>Dhara, Surajit</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Chandra, Vikas</au><au>Das, Tapojyoti</au><au>Gulati, Puneet</au><au>Biswas, Nidhan K</au><au>Rote, Sarang</au><au>Chatterjee, Uttara</au><au>Ghosh, Samarendra N</au><au>Deb, Sumit</au><au>Saha, Suniti K</au><au>Chowdhury, Anup K</au><au>Ghosh, Subhashish</au><au>Rudin, Charles M</au><au>Mukherjee, Ankur</au><au>Basu, Analabha</au><au>Dhara, Surajit</au><au>Castresana, Javier S</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Hedgehog signaling pathway is active in GBM with GLI1 mRNA expression showing a single continuous distribution rather than discrete high/low clusters</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2015-03-16</date><risdate>2015</risdate><volume>10</volume><issue>3</issue><spage>e0116390</spage><epage>e0116390</epage><pages>e0116390-e0116390</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Hedgehog (Hh) signaling pathway is a valid therapeutic target in a wide range of malignancies. We focus here on glioblastoma multiforme (GBM), a lethal malignancy of the central nervous system (CNS). By analyzing RNA-sequencing based transcriptomics data on 149 clinical cases of TCGA-GBM database we show here a strong correlation (r = 0.7) between GLI1 and PTCH1 mRNA expression--as a hallmark of the canonical Hh-pathway activity in this malignancy. GLI1 mRNA expression varied in 3 orders of magnitude among the GBM patients of the same cohort showing a single continuous distribution-unlike the discrete high/low-GLI1 mRNA expressing clusters of medulloblastoma (MB). When compared with MB as a reference, the median GLI1 mRNA expression in GBM appeared 14.8 fold lower than that of the "high-Hh" cluster of MB but 5.6 fold higher than that of the "low-Hh" cluster of MB. Next, we demonstrated statistically significant up- and down-regulation of GLI1 mRNA expressions in GBM patient-derived low-passage neurospheres in vitro by sonic hedgehog ligand-enriched conditioned media (shh-CM) and by Hh-inhibitor drug vismodegib respectively. We also showed clinically achievable dose (50 μM) of vismodegib alone to be sufficient to induce apoptosis and cell cycle arrest in these low-passage GBM neurospheres in vitro. Vismodegib showed an effect on the neurospheres, both by down-regulating GLI1 mRNA expression and by inducing apoptosis/cell cycle arrest, irrespective of their relative endogenous levels of GLI1 mRNA expression. We conclude from our study that this single continuous distribution pattern of GLI1 mRNA expression technically puts almost all GBM patients in a single group rather than discrete high- or low-clusters in terms of Hh-pathway activity. That is suggestive of therapies with Hh-pathway inhibitor drugs in this malignancy without a need for further stratification of patients on the basis of relative levels of Hh-pathway activity among them.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>25775002</pmid><doi>10.1371/journal.pone.0116390</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2015-03, Vol.10 (3), p.e0116390-e0116390 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1663911849 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Public Library of Science (PLoS) Journals Open Access; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Anilides - pharmacology Apoptosis Apoptosis - drug effects Cancer therapies Cell cycle Cell Cycle Checkpoints - drug effects Central nervous system Clusters Conditioning Dose-Response Relationship, Drug Down-Regulation - drug effects Drug development Drugs FDA approval Gene expression Gene Expression Regulation, Neoplastic - drug effects Gene sequencing Genomics Glioblastoma Glioblastoma - genetics Glioblastoma - pathology Glioblastoma multiforme Gliomas Health aspects Hedgehog protein Hedgehog Proteins - metabolism Humans Inhibitors Kinases Ligands Malignancy Medical research Medulloblastoma Medulloblastoma - genetics Medulloblastoma - pathology Messenger RNA Mutation Neurology Neurospheres Oncogene Proteins - genetics Ovarian cancer Patients Pyridines - pharmacology Radiation therapy Ribonucleic acid RNA RNA, Messenger - genetics RNA, Messenger - metabolism Signal transduction Signal Transduction - drug effects Signaling Statistical analysis Trans-Activators - genetics Transcription factors Tumorigenesis Up-Regulation - drug effects Zinc Finger Protein GLI1 |
| title | Hedgehog signaling pathway is active in GBM with GLI1 mRNA expression showing a single continuous distribution rather than discrete high/low clusters |
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