机构：[1]Department of Basic Science, School of Stomatology, Kunming Medical University, Kunming, China[2]Yunnan Key Laboratory of Stomatology, Kunming, China[3]First Clinical Division, Peking University School and Hospital of Stomatology & National Center of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices & Beijing Key Laboratory of Digital Stomatology, Beijing, China[4]International VIP Dental Clinic, Tianjin Stomatological Hospital, School of Medicine, Nankai University, Tianjin Key Laboratory of Oral and Maxillofacial Function Reconstruction, Tianjin, China[5]Tianjin Key Laboratory of Oral and Maxillofacial Function Reconstruction, Tianjin, China[6]Department of Oral Pathology, Peking University School and Hospital of Stomatology & National Center of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Laboratory for Digital and Material Technology of Stomatology & Beijing Key Laboratory of Digital Stomatology, Beijing, China[7]Department of Stomatology, The First People's Hospital of Yunnan Province, Kunming, China门急诊片口腔医学中心云南省第一人民医院
Background: Odontogenic 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.Methods: Eight 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.Results: PTCH1 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.Conclusions: Genetic 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.
基金：
National Natural Science Foundation of China [81960203, 82101032]; Science and Technology Plan Project of Yunnan Provincial Science and Technology Department [2019FE001-089, 202305AC160001]; Yunnan Innovation Team Project [202105AE160004]
第一作者机构：[1]Department of Basic Science, School of Stomatology, Kunming Medical University, Kunming, China[2]Yunnan Key Laboratory of Stomatology, Kunming, China
通讯作者：
通讯机构：[1]Department of Basic Science, School of Stomatology, Kunming Medical University, Kunming, China[2]Yunnan Key Laboratory of Stomatology, Kunming, China[6]Department of Oral Pathology, Peking University School and Hospital of Stomatology & National Center of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Laboratory for Digital and Material Technology of Stomatology & Beijing Key Laboratory of Digital Stomatology, Beijing, China[*1]Department of Basic Science, School of Stomatology, Kunming Medical University, 1088 Haiyuan Middle Road, High-tech Zone, Kunming 650106, China[*2]Department of Oral Pathology, Peking University School and Hospital of Stomatology & National Center of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Laboratory for Digital and Material Technology of Stomatology & Beijing Key Laboratory of Digital Stomatology, Beijing 100081, China
推荐引用方式(GB/T 7714)：
Wang Shan,Hong Yingying,Qu Jiafei,et al.PTCH/SMO gene mutations in odontogenic keratocysts and drug interventions[J].JOURNAL OF ORAL PATHOLOGY & MEDICINE.2023,52(9):867-876.doi:10.1111/jop.13473.
APA：
Wang, Shan,Hong, Yingying,Qu, Jiafei,Zhang, Jianyun,Zhang, Yuhao...&Li, Tiejun.(2023).PTCH/SMO gene mutations in odontogenic keratocysts and drug interventions.JOURNAL OF ORAL PATHOLOGY & MEDICINE,52,(9)
MLA：
Wang, Shan,et al."PTCH/SMO gene mutations in odontogenic keratocysts and drug interventions".JOURNAL OF ORAL PATHOLOGY & MEDICINE 52..9(2023):867-876
