PTCH/SMO gene mutations in odontogenic keratocysts and drug interventions
PTCH/SMO gene mutations in odontogenic keratocysts and drug interventions
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DOI：
10.1111/jop.13473
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发表时间：
2023-08-08
影响因子：
3.3
通讯作者：
Li，Tiejun
中科院分区：
文献类型：
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作者：
Wang，Shan;Hong，Yingying;Li，Tiejun
牙源性角化囊肿（odontogenic keratocysts，OKC）是一种引起颌骨破坏和功能障碍的牙源性颌骨病变。OKC可以是散发性的或与痣样基底细胞癌综合征（NBCCS）相关。然而，引发OKC的因素和囊肿形成的机制仍不清楚。在这里，我们研究了PTCH 1和SMO突变对疾病进展的影响，以及音刺猬（SHH）信号通路抑制剂GDC-0449和GANT 61对OKC fibroblasts. Methods 8散发OKC成纤维细胞无基因突变作为对照，和6 NBCCS相关的成纤维细胞体外培养。通过EdU测定检查PTCH 1非截短突变3499 G>A（p.G1167R）和SMO c.2081C>G（p.P694R）突变对OKC成纤维细胞增殖的影响。CCK 8和伤口愈合试验检测了携带PTCH 1 c.3499G>A（p.G1167R）和SMO c.2081C>G（p.P694R）突变的OKC成纤维细胞在共培养后对HaCaT细胞增殖和迁移的影响。结果PTCH 1 c.3499G>A（p.G1167R）和SMO c.2081C>G（p.P694R）突变可促进NBCCS相关OKC成纤维细胞增殖。HaCaT细胞的增殖和迁移受到携带PTCH 1 c.3499G>A（p.G1167R）和SMO c.2081C>G（p.P694R）突变的NBCCS相关OKC成纤维细胞的影响。GDC-0449显著抑制具有PTCH 1截短突变的NBCCS相关OKC成纤维细胞中的SHH信号通路。1例携带PTCH 1 c.3499G>A（p.G1167R）和SMO c.2081C>G（p.P694R）突变的NBCCS相关OKC对GDC-0449耐药，但GANT 61可抑制该突变。GDC-0449可用于治疗OKC，特别是具有PTCH 1截短突变的NBCCS相关OKC。SMO c.2081C>G（p.P694R）可能导致对GDC-0449的耐药性;然而，GANT 61可用作替代抑制剂。
BackgroundOdontogenic keratocysts (OKCs) are odontogenic jaw lesions that cause destruction and dysfunction of the jawbone. OKCs can be sporadic or associated with nevoid basic cell carcinoma syndrome (NBCCS). However, the factors that initiate OKCs and the mechanism of cyst formation remain unclear. Here, we investigated the impact of PTCH1 and SMO mutations on disease progression, as well as the effects of sonic hedgehog (SHH) signaling pathway inhibitors GDC‐0449 and GANT61 on OKC fibroblasts.MethodsEight sporadic OKC fibroblasts without gene mutations were used as the control, and six NBCCS‐related fibroblasts were cultured in vitro. The effect of PTCH1 non‐truncated mutation 3499G>A (p.G1167R) and SMO c.2081C>G (p.P694R) mutation on OKC fibroblast proliferation was examined by EdU assay. CCK8 and wound‐healing assays detected the effects of OKC fibroblasts carrying PTCH1 c.3499G>A (p.G1167R) and SMO c.2081C>G (p.P694R) mutations on the proliferation and migration of HaCaT cells after co‐culture. Quantitative real‐time PCR detected the effects of GDC‐0449 or GANT61 on the SHH signaling pathway in NBCCS‐related OKCs with PTCH1 truncated mutations and PTCH1 c.3499G>A (p.G1167R) and/or SMO c.2081C>G (p.P694R) mutations.ResultsPTCH1 c.3499G>A (p.G1167R) and SMO c.2081C>G (p.P694R) promoted the proliferation of OKC fibroblasts. The proliferation and migration of HaCaT cells were affected by NBCCS‐related OKC fibroblasts carrying PTCH1 c.3499G>A (p.G1167R) and SMO c.2081C>G (p.P694R) mutations. GDC‐0449 significantly inhibited the SHH signaling pathway in NBCCS‐related OKC fibroblasts with PTCH1 truncated mutations. An NBCCS‐related OKC carrying PTCH1 c.3499G>A (p.G1167R) and SMO c.2081C>G (p.P694R) mutations were resistant to GDC‐0449 but inhibited by GANT61.ConclusionsGenetic mutations in OKC fibroblasts may affect the biological behavior of epithelial and stromal cells and cause disease. GDC‐0449 could be used to treat OKCs, especially NBCCS‐related OKCs with PTCH1 truncated mutations. SMO c.2081C>G (p.P694R) may lead to resistance to GDC‐0449; however, GANT61 may be used as an alternative inhibitor.