Effect of the sonic hedgehog inhibitor GDC-0449 on an in vitro isogenic cellular model simulating odontogenic keratocysts View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2019-03

AUTHORS

Jiemei Zhai, Heyu Zhang, Jianyun Zhang, Ran Zhang, Yingying Hong, Jiafei Qu, Feng Chen, Tiejun Li

ABSTRACT

Odontogenic keratocysts (OKCs) are common cystic lesions of odontogenic epithelial origin that can occur sporadically or in association with naevoid basal cell carcinoma syndrome (NBCCS). OKCs are locally aggressive, cause marked destruction of the jaw bones and have a propensity to recur. PTCH1 mutations (at ∼80%) are frequently detected in the epithelia of both NBCCS-related and sporadic OKCs, suggesting that PTCH1 inactivation might constitutively activate sonic hedgehog (SHH) signalling and play a major role in disease pathogenesis. Thus, small molecule inhibitors of SHH signalling might represent a new treatment strategy for OKCs. However, studies on the molecular mechanisms associated with OKCs have been hampered by limited epithelial cell yields during OKC explant culture. Here, we constructed an isogenic PTCH1R135X/+ cellular model of PTCH1 inactivation by introducing a heterozygous mutation, namely, c.403C>T (p.R135X), which has been identified in OKC patients, into a human embryonic stem cell line using the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated 9 (Cas9) system. This was followed by the induction of epithelial differentiation. Using this in vitro isogenic cellular model, we verified that the PTCH1R135X/+ heterozygous mutation causes ligand-independent activation of SHH signalling due to PTCH1 haploinsufficiency. This activation was found to be downregulated in a dose-dependent manner by the SHH pathway inhibitor GDC-0449. In addition, through inhibition of activated SHH signalling, the enhanced proliferation observed in these induced cells was suppressed, suggesting that GDC-0449 might represent an effective inhibitor of the SHH pathway for use during OKC treatment. More... »

PAGES

4

References to SciGraph publications

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/s41368-018-0034-x

DOI

http://dx.doi.org/10.1038/s41368-018-0034-x

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1111061176

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/30610186


Indexing Status Check whether this publication has been indexed by Scopus and Web Of Science using the SN Indexing Status Tool
Incoming Citations Browse incoming citations for this publication using opencitations.net

JSON-LD is the canonical representation for SciGraph data.

TIP: You can open this SciGraph record using an external JSON-LD service: JSON-LD Playground Google SDTT

[
  {
    "@context": "https://springernature.github.io/scigraph/jsonld/sgcontext.json", 
    "about": [
      {
        "id": "http://purl.org/au-research/vocabulary/anzsrc-for/2008/0601", 
        "inDefinedTermSet": "http://purl.org/au-research/vocabulary/anzsrc-for/2008/", 
        "name": "Biochemistry and Cell Biology", 
        "type": "DefinedTerm"
      }, 
      {
        "id": "http://purl.org/au-research/vocabulary/anzsrc-for/2008/06", 
        "inDefinedTermSet": "http://purl.org/au-research/vocabulary/anzsrc-for/2008/", 
        "name": "Biological Sciences", 
        "type": "DefinedTerm"
      }
    ], 
    "author": [
      {
        "affiliation": {
          "alternateName": "Kunming Medical University", 
          "id": "https://www.grid.ac/institutes/grid.285847.4", 
          "name": [
            "Department of Oral Pathology, Peking University School and Hospital of Stomatology, 22 South Zhongguancun Avenue, Beijing, Haidian District, China", 
            "Department of Oral Pathology, School of Stomatology Kunming Medical University, 1088 Middle Haiyuan Road, High-tech Zone, Kunming, China"
          ], 
          "type": "Organization"
        }, 
        "familyName": "Zhai", 
        "givenName": "Jiemei", 
        "id": "sg:person.011401410421.72", 
        "sameAs": [
          "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.011401410421.72"
        ], 
        "type": "Person"
      }, 
      {
        "affiliation": {
          "alternateName": "Peking University", 
          "id": "https://www.grid.ac/institutes/grid.11135.37", 
          "name": [
            "Central Laboratory, Peking University School and Hospital of Stomatology, 22 South Zhongguancun Avenue, Beijing, Haidian District, China"
          ], 
          "type": "Organization"
        }, 
        "familyName": "Zhang", 
        "givenName": "Heyu", 
        "id": "sg:person.01325660770.98", 
        "sameAs": [
          "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01325660770.98"
        ], 
        "type": "Person"
      }, 
      {
        "affiliation": {
          "alternateName": "Peking University", 
          "id": "https://www.grid.ac/institutes/grid.11135.37", 
          "name": [
            "Department of Oral Pathology, Peking University School and Hospital of Stomatology, 22 South Zhongguancun Avenue, Beijing, Haidian District, China"
          ], 
          "type": "Organization"
        }, 
        "familyName": "Zhang", 
        "givenName": "Jianyun", 
        "id": "sg:person.01257545570.14", 
        "sameAs": [
          "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01257545570.14"
        ], 
        "type": "Person"
      }, 
      {
        "affiliation": {
          "alternateName": "Peking University", 
          "id": "https://www.grid.ac/institutes/grid.11135.37", 
          "name": [
            "Department of Oral Pathology, Peking University School and Hospital of Stomatology, 22 South Zhongguancun Avenue, Beijing, Haidian District, China"
          ], 
          "type": "Organization"
        }, 
        "familyName": "Zhang", 
        "givenName": "Ran", 
        "id": "sg:person.0756413340.27", 
        "sameAs": [
          "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.0756413340.27"
        ], 
        "type": "Person"
      }, 
      {
        "affiliation": {
          "alternateName": "Peking University Stomatological Hospital", 
          "id": "https://www.grid.ac/institutes/grid.479981.a", 
          "name": [
            "Peking University Hospital of Stomatology First Clinical Division, 37A Xishiku Street, Xicheng District, Beijing, China"
          ], 
          "type": "Organization"
        }, 
        "familyName": "Hong", 
        "givenName": "Yingying", 
        "id": "sg:person.01027070570.51", 
        "sameAs": [
          "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01027070570.51"
        ], 
        "type": "Person"
      }, 
      {
        "affiliation": {
          "alternateName": "Peking University", 
          "id": "https://www.grid.ac/institutes/grid.11135.37", 
          "name": [
            "Department of Oral Pathology, Peking University School and Hospital of Stomatology, 22 South Zhongguancun Avenue, Beijing, Haidian District, China"
          ], 
          "type": "Organization"
        }, 
        "familyName": "Qu", 
        "givenName": "Jiafei", 
        "id": "sg:person.0712642170.30", 
        "sameAs": [
          "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.0712642170.30"
        ], 
        "type": "Person"
      }, 
      {
        "affiliation": {
          "alternateName": "Peking University", 
          "id": "https://www.grid.ac/institutes/grid.11135.37", 
          "name": [
            "Central Laboratory, Peking University School and Hospital of Stomatology, 22 South Zhongguancun Avenue, Beijing, Haidian District, China"
          ], 
          "type": "Organization"
        }, 
        "familyName": "Chen", 
        "givenName": "Feng", 
        "id": "sg:person.01072341356.69", 
        "sameAs": [
          "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01072341356.69"
        ], 
        "type": "Person"
      }, 
      {
        "affiliation": {
          "alternateName": "Peking University", 
          "id": "https://www.grid.ac/institutes/grid.11135.37", 
          "name": [
            "Department of Oral Pathology, Peking University School and Hospital of Stomatology, 22 South Zhongguancun Avenue, Beijing, Haidian District, China"
          ], 
          "type": "Organization"
        }, 
        "familyName": "Li", 
        "givenName": "Tiejun", 
        "id": "sg:person.0623760132.98", 
        "sameAs": [
          "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.0623760132.98"
        ], 
        "type": "Person"
      }
    ], 
    "citation": [
      {
        "id": "https://doi.org/10.1016/j.bbrc.2014.12.108", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1000990537"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "sg:pub.10.1007/pl00000654", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1001288452", 
          "https://doi.org/10.1007/pl00000654"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1634/stemcells.2007-0501", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1001563970"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "sg:pub.10.1038/35023008", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1003045945", 
          "https://doi.org/10.1038/35023008"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "sg:pub.10.1038/35023008", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1003045945", 
          "https://doi.org/10.1038/35023008"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1001/jamadermatol.2013.7444", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1003640756"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1016/j.ejca.2005.08.039", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1004129529"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1002/biot.201500099", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1005974340"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1242/dmm.012054", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1008319149"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1016/s0959-437x(03)00002-9", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1008939423"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1016/s0959-437x(03)00002-9", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1008939423"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "sg:pub.10.4248/ijos.08013", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1010836263", 
          "https://doi.org/10.4248/ijos.08013"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1056/nejmoa1113713", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1011121733"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1016/j.tips.2009.03.007", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1011670227"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1067/moe.2001.113109", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1016330500"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1002/jbmr.2815", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1019377053"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1126/science.1231143", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1019873131"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1126/science.1232033", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1022072971"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1093/emboj/17.18.5497", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1023693632"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1016/s1097-2765(00)80275-0", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1024825914"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1016/j.oraloncology.2009.02.003", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1025282296"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1111/j.1600-0714.1995.tb01171.x", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1025934412"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1016/j.ijom.2012.02.008", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1026563274"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1111/j.1600-0714.1994.tb01110.x", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1026706010"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "sg:pub.10.1038/nmeth.1593", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1028183020", 
          "https://doi.org/10.1038/nmeth.1593"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1001/archdermatol.2011.50", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1028220353"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1126/science.282.5391.1145", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1028898955"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1016/j.oraloncology.2014.09.016", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1030103179"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1093/carcin/23.5.727", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1032540934"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.4103/2231-0746.161049", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1034072888"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1371/journal.pone.0077305", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1036632461"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1016/j.stem.2015.12.002", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1037548797"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "sg:pub.10.1186/1750-1172-3-32", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1038424533", 
          "https://doi.org/10.1186/1750-1172-3-32"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1016/j.cell.2014.05.010", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1039182708"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1126/science.1225829", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1041850060"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1016/j.scr.2009.09.002", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1044653092"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "sg:pub.10.1038/384129a0", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1045740576", 
          "https://doi.org/10.1038/384129a0"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1016/s0092-8674(00)81268-4", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1047995155"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1111/j.1600-0714.1995.tb01207.x", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1050161140"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1089/ten.tec.2013.0011", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1059317647"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1126/science.272.5268.1668", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1062553319"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1177/0022034510379016", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1063628910"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1177/0022034510379016", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1063628910"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://app.dimensions.ai/details/publication/pub.1077137553", 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1016/s0733-8635(18)30114-1", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1082476000"
        ], 
        "type": "CreativeWork"
      }
    ], 
    "datePublished": "2019-03", 
    "datePublishedReg": "2019-03-01", 
    "description": "Odontogenic keratocysts (OKCs) are common cystic lesions of odontogenic epithelial origin that can occur sporadically or in association with naevoid basal cell carcinoma syndrome (NBCCS). OKCs are locally aggressive, cause marked destruction of the jaw bones and have a propensity to recur. PTCH1 mutations (at \u223c80%) are frequently detected in the epithelia of both NBCCS-related and sporadic OKCs, suggesting that PTCH1 inactivation might constitutively activate sonic hedgehog (SHH) signalling and play a major role in disease pathogenesis. Thus, small molecule inhibitors of SHH signalling might represent a new treatment strategy for OKCs. However, studies on the molecular mechanisms associated with OKCs have been hampered by limited epithelial cell yields during OKC explant culture. Here, we constructed an isogenic PTCH1R135X/+ cellular model of PTCH1 inactivation by introducing a heterozygous mutation, namely, c.403C>T (p.R135X), which has been identified in OKC patients, into a human embryonic stem cell line using the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated 9 (Cas9) system. This was followed by the induction of epithelial differentiation. Using this in vitro isogenic cellular model, we verified that the PTCH1R135X/+ heterozygous mutation causes ligand-independent activation of SHH signalling due to PTCH1 haploinsufficiency. This activation was found to be downregulated in a dose-dependent manner by the SHH pathway inhibitor GDC-0449. In addition, through inhibition of activated SHH signalling, the enhanced proliferation observed in these induced cells was suppressed, suggesting that GDC-0449 might represent an effective inhibitor of the SHH pathway for use during OKC treatment.", 
    "genre": "research_article", 
    "id": "sg:pub.10.1038/s41368-018-0034-x", 
    "inLanguage": [
      "en"
    ], 
    "isAccessibleForFree": true, 
    "isFundedItemOf": [
      {
        "id": "sg:grant.7174982", 
        "type": "MonetaryGrant"
      }
    ], 
    "isPartOf": [
      {
        "id": "sg:journal.1041424", 
        "issn": [
          "1674-2818", 
          "2049-3169"
        ], 
        "name": "International Journal of Oral Science", 
        "type": "Periodical"
      }, 
      {
        "issueNumber": "1", 
        "type": "PublicationIssue"
      }, 
      {
        "type": "PublicationVolume", 
        "volumeNumber": "11"
      }
    ], 
    "name": "Effect of the sonic hedgehog inhibitor GDC-0449 on an in vitro isogenic cellular model simulating odontogenic keratocysts", 
    "pagination": "4", 
    "productId": [
      {
        "name": "readcube_id", 
        "type": "PropertyValue", 
        "value": [
          "a07c0d1be6256bfb79a3137ffeb77f93c819c791182213fc650634fe25669214"
        ]
      }, 
      {
        "name": "pubmed_id", 
        "type": "PropertyValue", 
        "value": [
          "30610186"
        ]
      }, 
      {
        "name": "nlm_unique_id", 
        "type": "PropertyValue", 
        "value": [
          "101504351"
        ]
      }, 
      {
        "name": "doi", 
        "type": "PropertyValue", 
        "value": [
          "10.1038/s41368-018-0034-x"
        ]
      }, 
      {
        "name": "dimensions_id", 
        "type": "PropertyValue", 
        "value": [
          "pub.1111061176"
        ]
      }
    ], 
    "sameAs": [
      "https://doi.org/10.1038/s41368-018-0034-x", 
      "https://app.dimensions.ai/details/publication/pub.1111061176"
    ], 
    "sdDataset": "articles", 
    "sdDatePublished": "2019-04-11T08:35", 
    "sdLicense": "https://scigraph.springernature.com/explorer/license/", 
    "sdPublisher": {
      "name": "Springer Nature - SN SciGraph project", 
      "type": "Organization"
    }, 
    "sdSource": "s3://com-uberresearch-data-dimensions-target-20181106-alternative/cleanup/v134/2549eaecd7973599484d7c17b260dba0a4ecb94b/merge/v9/a6c9fde33151104705d4d7ff012ea9563521a3ce/jats-lookup/v90/0000000312_0000000312/records_1294_00000000.jsonl", 
    "type": "ScholarlyArticle", 
    "url": "https://www.nature.com/articles/s41368-018-0034-x"
  }
]
 

Download the RDF metadata as:  json-ld nt turtle xml License info

HOW TO GET THIS DATA PROGRAMMATICALLY:

JSON-LD is a popular format for linked data which is fully compatible with JSON.

curl -H 'Accept: application/ld+json' 'https://scigraph.springernature.com/pub.10.1038/s41368-018-0034-x'

N-Triples is a line-based linked data format ideal for batch operations.

curl -H 'Accept: application/n-triples' 'https://scigraph.springernature.com/pub.10.1038/s41368-018-0034-x'

Turtle is a human-readable linked data format.

curl -H 'Accept: text/turtle' 'https://scigraph.springernature.com/pub.10.1038/s41368-018-0034-x'

RDF/XML is a standard XML format for linked data.

curl -H 'Accept: application/rdf+xml' 'https://scigraph.springernature.com/pub.10.1038/s41368-018-0034-x'


 

This table displays all metadata directly associated to this object as RDF triples.

259 TRIPLES      21 PREDICATES      71 URIs      21 LITERALS      9 BLANK NODES

Subject Predicate Object
1 sg:pub.10.1038/s41368-018-0034-x schema:about anzsrc-for:06
2 anzsrc-for:0601
3 schema:author N44a6eeb752474a97bb7f5e4683beb549
4 schema:citation sg:pub.10.1007/pl00000654
5 sg:pub.10.1038/35023008
6 sg:pub.10.1038/384129a0
7 sg:pub.10.1038/nmeth.1593
8 sg:pub.10.1186/1750-1172-3-32
9 sg:pub.10.4248/ijos.08013
10 https://app.dimensions.ai/details/publication/pub.1077137553
11 https://doi.org/10.1001/archdermatol.2011.50
12 https://doi.org/10.1001/jamadermatol.2013.7444
13 https://doi.org/10.1002/biot.201500099
14 https://doi.org/10.1002/jbmr.2815
15 https://doi.org/10.1016/j.bbrc.2014.12.108
16 https://doi.org/10.1016/j.cell.2014.05.010
17 https://doi.org/10.1016/j.ejca.2005.08.039
18 https://doi.org/10.1016/j.ijom.2012.02.008
19 https://doi.org/10.1016/j.oraloncology.2009.02.003
20 https://doi.org/10.1016/j.oraloncology.2014.09.016
21 https://doi.org/10.1016/j.scr.2009.09.002
22 https://doi.org/10.1016/j.stem.2015.12.002
23 https://doi.org/10.1016/j.tips.2009.03.007
24 https://doi.org/10.1016/s0092-8674(00)81268-4
25 https://doi.org/10.1016/s0733-8635(18)30114-1
26 https://doi.org/10.1016/s0959-437x(03)00002-9
27 https://doi.org/10.1016/s1097-2765(00)80275-0
28 https://doi.org/10.1056/nejmoa1113713
29 https://doi.org/10.1067/moe.2001.113109
30 https://doi.org/10.1089/ten.tec.2013.0011
31 https://doi.org/10.1093/carcin/23.5.727
32 https://doi.org/10.1093/emboj/17.18.5497
33 https://doi.org/10.1111/j.1600-0714.1994.tb01110.x
34 https://doi.org/10.1111/j.1600-0714.1995.tb01171.x
35 https://doi.org/10.1111/j.1600-0714.1995.tb01207.x
36 https://doi.org/10.1126/science.1225829
37 https://doi.org/10.1126/science.1231143
38 https://doi.org/10.1126/science.1232033
39 https://doi.org/10.1126/science.272.5268.1668
40 https://doi.org/10.1126/science.282.5391.1145
41 https://doi.org/10.1177/0022034510379016
42 https://doi.org/10.1242/dmm.012054
43 https://doi.org/10.1371/journal.pone.0077305
44 https://doi.org/10.1634/stemcells.2007-0501
45 https://doi.org/10.4103/2231-0746.161049
46 schema:datePublished 2019-03
47 schema:datePublishedReg 2019-03-01
48 schema:description Odontogenic keratocysts (OKCs) are common cystic lesions of odontogenic epithelial origin that can occur sporadically or in association with naevoid basal cell carcinoma syndrome (NBCCS). OKCs are locally aggressive, cause marked destruction of the jaw bones and have a propensity to recur. PTCH1 mutations (at ∼80%) are frequently detected in the epithelia of both NBCCS-related and sporadic OKCs, suggesting that PTCH1 inactivation might constitutively activate sonic hedgehog (SHH) signalling and play a major role in disease pathogenesis. Thus, small molecule inhibitors of SHH signalling might represent a new treatment strategy for OKCs. However, studies on the molecular mechanisms associated with OKCs have been hampered by limited epithelial cell yields during OKC explant culture. Here, we constructed an isogenic PTCH1<sup>R135X/+</sup> cellular model of PTCH1 inactivation by introducing a heterozygous mutation, namely, c.403C&gt;T (p.R135X), which has been identified in OKC patients, into a human embryonic stem cell line using the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated 9 (Cas9) system. This was followed by the induction of epithelial differentiation. Using this in vitro isogenic cellular model, we verified that the PTCH1<sup>R135X/+</sup> heterozygous mutation causes ligand-independent activation of SHH signalling due to PTCH1 haploinsufficiency. This activation was found to be downregulated in a dose-dependent manner by the SHH pathway inhibitor GDC-0449. In addition, through inhibition of activated SHH signalling, the enhanced proliferation observed in these induced cells was suppressed, suggesting that GDC-0449 might represent an effective inhibitor of the SHH pathway for use during OKC treatment.
49 schema:genre research_article
50 schema:inLanguage en
51 schema:isAccessibleForFree true
52 schema:isPartOf N33a85f7aeb2c45aea736652332b5cb35
53 Na5fe41cd1dff4fd7910bd711aae7b310
54 sg:journal.1041424
55 schema:name Effect of the sonic hedgehog inhibitor GDC-0449 on an in vitro isogenic cellular model simulating odontogenic keratocysts
56 schema:pagination 4
57 schema:productId N8f1cf6941f3149d6879830aab0755078
58 N9be7b4da4e654e429d90f6ef84c708ae
59 Nacbc02b7271544f188c8237b0593a6da
60 Ne4c7decb41c9422cbd915694cc8df761
61 Nf71cb25ee3074a8fbf3e2c8d6247d2f8
62 schema:sameAs https://app.dimensions.ai/details/publication/pub.1111061176
63 https://doi.org/10.1038/s41368-018-0034-x
64 schema:sdDatePublished 2019-04-11T08:35
65 schema:sdLicense https://scigraph.springernature.com/explorer/license/
66 schema:sdPublisher N019b666c31c34b94a9b3513d356437e8
67 schema:url https://www.nature.com/articles/s41368-018-0034-x
68 sgo:license sg:explorer/license/
69 sgo:sdDataset articles
70 rdf:type schema:ScholarlyArticle
71 N019b666c31c34b94a9b3513d356437e8 schema:name Springer Nature - SN SciGraph project
72 rdf:type schema:Organization
73 N2956716021d641f29f1614ef1f6c25d7 rdf:first sg:person.0712642170.30
74 rdf:rest N7051a4a11fdc4455acd9319ca79a67f8
75 N33a85f7aeb2c45aea736652332b5cb35 schema:volumeNumber 11
76 rdf:type schema:PublicationVolume
77 N44a6eeb752474a97bb7f5e4683beb549 rdf:first sg:person.011401410421.72
78 rdf:rest Na8a0a9838116405a8d57421e16aafdc7
79 N5946e9a024794187b0de6837a2bbf3bc rdf:first sg:person.01027070570.51
80 rdf:rest N2956716021d641f29f1614ef1f6c25d7
81 N7051a4a11fdc4455acd9319ca79a67f8 rdf:first sg:person.01072341356.69
82 rdf:rest Naed26c4356964b5bb3702d317cb5e500
83 N79b5856090cc4d9c95ac032d445a1001 rdf:first sg:person.0756413340.27
84 rdf:rest N5946e9a024794187b0de6837a2bbf3bc
85 N7e203def184646b8a6552ca5a1ed3b9d rdf:first sg:person.01257545570.14
86 rdf:rest N79b5856090cc4d9c95ac032d445a1001
87 N8f1cf6941f3149d6879830aab0755078 schema:name dimensions_id
88 schema:value pub.1111061176
89 rdf:type schema:PropertyValue
90 N9be7b4da4e654e429d90f6ef84c708ae schema:name nlm_unique_id
91 schema:value 101504351
92 rdf:type schema:PropertyValue
93 Na5fe41cd1dff4fd7910bd711aae7b310 schema:issueNumber 1
94 rdf:type schema:PublicationIssue
95 Na8a0a9838116405a8d57421e16aafdc7 rdf:first sg:person.01325660770.98
96 rdf:rest N7e203def184646b8a6552ca5a1ed3b9d
97 Nacbc02b7271544f188c8237b0593a6da schema:name readcube_id
98 schema:value a07c0d1be6256bfb79a3137ffeb77f93c819c791182213fc650634fe25669214
99 rdf:type schema:PropertyValue
100 Naed26c4356964b5bb3702d317cb5e500 rdf:first sg:person.0623760132.98
101 rdf:rest rdf:nil
102 Ne4c7decb41c9422cbd915694cc8df761 schema:name pubmed_id
103 schema:value 30610186
104 rdf:type schema:PropertyValue
105 Nf71cb25ee3074a8fbf3e2c8d6247d2f8 schema:name doi
106 schema:value 10.1038/s41368-018-0034-x
107 rdf:type schema:PropertyValue
108 anzsrc-for:06 schema:inDefinedTermSet anzsrc-for:
109 schema:name Biological Sciences
110 rdf:type schema:DefinedTerm
111 anzsrc-for:0601 schema:inDefinedTermSet anzsrc-for:
112 schema:name Biochemistry and Cell Biology
113 rdf:type schema:DefinedTerm
114 sg:grant.7174982 http://pending.schema.org/fundedItem sg:pub.10.1038/s41368-018-0034-x
115 rdf:type schema:MonetaryGrant
116 sg:journal.1041424 schema:issn 1674-2818
117 2049-3169
118 schema:name International Journal of Oral Science
119 rdf:type schema:Periodical
120 sg:person.01027070570.51 schema:affiliation https://www.grid.ac/institutes/grid.479981.a
121 schema:familyName Hong
122 schema:givenName Yingying
123 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01027070570.51
124 rdf:type schema:Person
125 sg:person.01072341356.69 schema:affiliation https://www.grid.ac/institutes/grid.11135.37
126 schema:familyName Chen
127 schema:givenName Feng
128 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01072341356.69
129 rdf:type schema:Person
130 sg:person.011401410421.72 schema:affiliation https://www.grid.ac/institutes/grid.285847.4
131 schema:familyName Zhai
132 schema:givenName Jiemei
133 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.011401410421.72
134 rdf:type schema:Person
135 sg:person.01257545570.14 schema:affiliation https://www.grid.ac/institutes/grid.11135.37
136 schema:familyName Zhang
137 schema:givenName Jianyun
138 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01257545570.14
139 rdf:type schema:Person
140 sg:person.01325660770.98 schema:affiliation https://www.grid.ac/institutes/grid.11135.37
141 schema:familyName Zhang
142 schema:givenName Heyu
143 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01325660770.98
144 rdf:type schema:Person
145 sg:person.0623760132.98 schema:affiliation https://www.grid.ac/institutes/grid.11135.37
146 schema:familyName Li
147 schema:givenName Tiejun
148 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.0623760132.98
149 rdf:type schema:Person
150 sg:person.0712642170.30 schema:affiliation https://www.grid.ac/institutes/grid.11135.37
151 schema:familyName Qu
152 schema:givenName Jiafei
153 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.0712642170.30
154 rdf:type schema:Person
155 sg:person.0756413340.27 schema:affiliation https://www.grid.ac/institutes/grid.11135.37
156 schema:familyName Zhang
157 schema:givenName Ran
158 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.0756413340.27
159 rdf:type schema:Person
160 sg:pub.10.1007/pl00000654 schema:sameAs https://app.dimensions.ai/details/publication/pub.1001288452
161 https://doi.org/10.1007/pl00000654
162 rdf:type schema:CreativeWork
163 sg:pub.10.1038/35023008 schema:sameAs https://app.dimensions.ai/details/publication/pub.1003045945
164 https://doi.org/10.1038/35023008
165 rdf:type schema:CreativeWork
166 sg:pub.10.1038/384129a0 schema:sameAs https://app.dimensions.ai/details/publication/pub.1045740576
167 https://doi.org/10.1038/384129a0
168 rdf:type schema:CreativeWork
169 sg:pub.10.1038/nmeth.1593 schema:sameAs https://app.dimensions.ai/details/publication/pub.1028183020
170 https://doi.org/10.1038/nmeth.1593
171 rdf:type schema:CreativeWork
172 sg:pub.10.1186/1750-1172-3-32 schema:sameAs https://app.dimensions.ai/details/publication/pub.1038424533
173 https://doi.org/10.1186/1750-1172-3-32
174 rdf:type schema:CreativeWork
175 sg:pub.10.4248/ijos.08013 schema:sameAs https://app.dimensions.ai/details/publication/pub.1010836263
176 https://doi.org/10.4248/ijos.08013
177 rdf:type schema:CreativeWork
178 https://app.dimensions.ai/details/publication/pub.1077137553 schema:CreativeWork
179 https://doi.org/10.1001/archdermatol.2011.50 schema:sameAs https://app.dimensions.ai/details/publication/pub.1028220353
180 rdf:type schema:CreativeWork
181 https://doi.org/10.1001/jamadermatol.2013.7444 schema:sameAs https://app.dimensions.ai/details/publication/pub.1003640756
182 rdf:type schema:CreativeWork
183 https://doi.org/10.1002/biot.201500099 schema:sameAs https://app.dimensions.ai/details/publication/pub.1005974340
184 rdf:type schema:CreativeWork
185 https://doi.org/10.1002/jbmr.2815 schema:sameAs https://app.dimensions.ai/details/publication/pub.1019377053
186 rdf:type schema:CreativeWork
187 https://doi.org/10.1016/j.bbrc.2014.12.108 schema:sameAs https://app.dimensions.ai/details/publication/pub.1000990537
188 rdf:type schema:CreativeWork
189 https://doi.org/10.1016/j.cell.2014.05.010 schema:sameAs https://app.dimensions.ai/details/publication/pub.1039182708
190 rdf:type schema:CreativeWork
191 https://doi.org/10.1016/j.ejca.2005.08.039 schema:sameAs https://app.dimensions.ai/details/publication/pub.1004129529
192 rdf:type schema:CreativeWork
193 https://doi.org/10.1016/j.ijom.2012.02.008 schema:sameAs https://app.dimensions.ai/details/publication/pub.1026563274
194 rdf:type schema:CreativeWork
195 https://doi.org/10.1016/j.oraloncology.2009.02.003 schema:sameAs https://app.dimensions.ai/details/publication/pub.1025282296
196 rdf:type schema:CreativeWork
197 https://doi.org/10.1016/j.oraloncology.2014.09.016 schema:sameAs https://app.dimensions.ai/details/publication/pub.1030103179
198 rdf:type schema:CreativeWork
199 https://doi.org/10.1016/j.scr.2009.09.002 schema:sameAs https://app.dimensions.ai/details/publication/pub.1044653092
200 rdf:type schema:CreativeWork
201 https://doi.org/10.1016/j.stem.2015.12.002 schema:sameAs https://app.dimensions.ai/details/publication/pub.1037548797
202 rdf:type schema:CreativeWork
203 https://doi.org/10.1016/j.tips.2009.03.007 schema:sameAs https://app.dimensions.ai/details/publication/pub.1011670227
204 rdf:type schema:CreativeWork
205 https://doi.org/10.1016/s0092-8674(00)81268-4 schema:sameAs https://app.dimensions.ai/details/publication/pub.1047995155
206 rdf:type schema:CreativeWork
207 https://doi.org/10.1016/s0733-8635(18)30114-1 schema:sameAs https://app.dimensions.ai/details/publication/pub.1082476000
208 rdf:type schema:CreativeWork
209 https://doi.org/10.1016/s0959-437x(03)00002-9 schema:sameAs https://app.dimensions.ai/details/publication/pub.1008939423
210 rdf:type schema:CreativeWork
211 https://doi.org/10.1016/s1097-2765(00)80275-0 schema:sameAs https://app.dimensions.ai/details/publication/pub.1024825914
212 rdf:type schema:CreativeWork
213 https://doi.org/10.1056/nejmoa1113713 schema:sameAs https://app.dimensions.ai/details/publication/pub.1011121733
214 rdf:type schema:CreativeWork
215 https://doi.org/10.1067/moe.2001.113109 schema:sameAs https://app.dimensions.ai/details/publication/pub.1016330500
216 rdf:type schema:CreativeWork
217 https://doi.org/10.1089/ten.tec.2013.0011 schema:sameAs https://app.dimensions.ai/details/publication/pub.1059317647
218 rdf:type schema:CreativeWork
219 https://doi.org/10.1093/carcin/23.5.727 schema:sameAs https://app.dimensions.ai/details/publication/pub.1032540934
220 rdf:type schema:CreativeWork
221 https://doi.org/10.1093/emboj/17.18.5497 schema:sameAs https://app.dimensions.ai/details/publication/pub.1023693632
222 rdf:type schema:CreativeWork
223 https://doi.org/10.1111/j.1600-0714.1994.tb01110.x schema:sameAs https://app.dimensions.ai/details/publication/pub.1026706010
224 rdf:type schema:CreativeWork
225 https://doi.org/10.1111/j.1600-0714.1995.tb01171.x schema:sameAs https://app.dimensions.ai/details/publication/pub.1025934412
226 rdf:type schema:CreativeWork
227 https://doi.org/10.1111/j.1600-0714.1995.tb01207.x schema:sameAs https://app.dimensions.ai/details/publication/pub.1050161140
228 rdf:type schema:CreativeWork
229 https://doi.org/10.1126/science.1225829 schema:sameAs https://app.dimensions.ai/details/publication/pub.1041850060
230 rdf:type schema:CreativeWork
231 https://doi.org/10.1126/science.1231143 schema:sameAs https://app.dimensions.ai/details/publication/pub.1019873131
232 rdf:type schema:CreativeWork
233 https://doi.org/10.1126/science.1232033 schema:sameAs https://app.dimensions.ai/details/publication/pub.1022072971
234 rdf:type schema:CreativeWork
235 https://doi.org/10.1126/science.272.5268.1668 schema:sameAs https://app.dimensions.ai/details/publication/pub.1062553319
236 rdf:type schema:CreativeWork
237 https://doi.org/10.1126/science.282.5391.1145 schema:sameAs https://app.dimensions.ai/details/publication/pub.1028898955
238 rdf:type schema:CreativeWork
239 https://doi.org/10.1177/0022034510379016 schema:sameAs https://app.dimensions.ai/details/publication/pub.1063628910
240 rdf:type schema:CreativeWork
241 https://doi.org/10.1242/dmm.012054 schema:sameAs https://app.dimensions.ai/details/publication/pub.1008319149
242 rdf:type schema:CreativeWork
243 https://doi.org/10.1371/journal.pone.0077305 schema:sameAs https://app.dimensions.ai/details/publication/pub.1036632461
244 rdf:type schema:CreativeWork
245 https://doi.org/10.1634/stemcells.2007-0501 schema:sameAs https://app.dimensions.ai/details/publication/pub.1001563970
246 rdf:type schema:CreativeWork
247 https://doi.org/10.4103/2231-0746.161049 schema:sameAs https://app.dimensions.ai/details/publication/pub.1034072888
248 rdf:type schema:CreativeWork
249 https://www.grid.ac/institutes/grid.11135.37 schema:alternateName Peking University
250 schema:name Central Laboratory, Peking University School and Hospital of Stomatology, 22 South Zhongguancun Avenue, Beijing, Haidian District, China
251 Department of Oral Pathology, Peking University School and Hospital of Stomatology, 22 South Zhongguancun Avenue, Beijing, Haidian District, China
252 rdf:type schema:Organization
253 https://www.grid.ac/institutes/grid.285847.4 schema:alternateName Kunming Medical University
254 schema:name Department of Oral Pathology, Peking University School and Hospital of Stomatology, 22 South Zhongguancun Avenue, Beijing, Haidian District, China
255 Department of Oral Pathology, School of Stomatology Kunming Medical University, 1088 Middle Haiyuan Road, High-tech Zone, Kunming, China
256 rdf:type schema:Organization
257 https://www.grid.ac/institutes/grid.479981.a schema:alternateName Peking University Stomatological Hospital
258 schema:name Peking University Hospital of Stomatology First Clinical Division, 37A Xishiku Street, Xicheng District, Beijing, China
259 rdf:type schema:Organization
 




Preview window. Press ESC to close (or click here)


...