首页> 中文期刊> 《国际口腔科学杂志》 >Effect of the sonic hedgehog inhibitor GDC-0449 on an in vitro isogenic cellular model simulating odontogenic keratocysts

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

             

摘要

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.

著录项

  • 来源
    《国际口腔科学杂志》 |2019年第1期|P.33-41|共9页
  • 作者单位

    [1]Department of Oral Pathology;

    Peking University School and Hospital of Stomatology;

    22 South Zhongguancun Avenue;

    Haidian District;

    Beijing;

    China;

    [2]Department of Oral Pathology;

    School of Stomatology Kunming Medical University;

    1088 Middle Haiyuan Road;

    High-tech Zone;

    Kunming;

    China;

    [3]Central Laboratory;

    Peking University School and Hospital of Stomatology;

    22 South Zhongguancun Avenue;

    Haidian District;

    Beijing;

    China;

    [1]Department of Oral Pathology;

    Peking University School and Hospital of Stomatology;

    22 South Zhongguancun Avenue;

    Haidian District;

    Beijing;

    China;

    [1]Department of Oral Pathology;

    Peking University School and Hospital of Stomatology;

    22 South Zhongguancun Avenue;

    Haidian District;

    Beijing;

    China;

    [4]Peking University Hospital of Stomatology First Clinical Division;

    37A Xishiku Street;

    Xicheng District;

    Beijing;

    China;

    [1]Department of Oral Pathology;

    Peking University School and Hospital of Stomatology;

    22 South Zhongguancun Avenue;

    Haidian District;

    Beijing;

    China;

    [3]Central Laboratory;

    Peking University School and Hospital of Stomatology;

    22 South Zhongguancun Avenue;

    Haidian District;

    Beijing;

    China;

    [1]Department of Oral Pathology;

    Peking University School and Hospital of Stomatology;

    22 South Zhongguancun Avenue;

    Haidian District;

    Beijing;

    China;

  • 原文格式 PDF
  • 正文语种 CHI
  • 中图分类 医药、卫生;
  • 关键词

    NBCCS; the SHH pathway inhibitor GDC-0449;

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