SMOi>基因突变在成釉细胞瘤中的研究进展

doi:10.7518/gjkq.2020003

摘要/Abstract

摘要：

SMO基因编码的蛋白质SMO是sonic hedgehog（SHH）信号通路中至关重要的信号转换器。SHH信号通路与多种人类肿瘤的发生、发展密切相关,异常激活的SHH信号通路通过影响细胞的增殖、分化和凋亡,导致肿瘤发生。研究发现在成釉细胞瘤中,SMO基因是除BRAF基因之外第二常见突变的基因,其较高的突变率使得SMO基因成为成釉细胞瘤分子病理研究领域中的热点。现在已有大量的研究证实,SMO基因突变与成釉细胞瘤的临床特征（如发病部位、组织学、年龄和预后等）有关,这些研究结果为成釉细胞瘤的靶向治疗提供了新的治疗思路,本文就SMO基因突变在成釉细胞瘤中的研究进展及其潜在的临床意义进行综述。

关键词: SMO基因, sonic hedgehog信号通路, 成釉细胞瘤, 基因突变

Abstract:

The SMO protein encoded by the smoothened oncogene SMO is a crucial signal converter in the sonic hedgehog (SHH) signalling pathway. This signalling pathway is closely related to the occurrence and development of a variety of human tumours. The abnormally activated SHH signalling pathway leads to tumorigenesis by affecting cell proliferation, differentiation and apoptosis. The study found that in the ameloblastoma, the SMO gene is the second most common mutated gene in addition to the BRAF gene, and this high mutation makes the SMO gene a hotspot in ameloblastoma molecular pathology. Many studies confirmed that the SMO gene mutations are related to the clinical features of ameloblastoma, such as location, histology, age and prognosis. These findings provided new therapeutic ideas for targeted therapy of ameloblastoma. This paper reviewed the research progress of the SMO gene mutations in ameloblastoma and their potential clinical significance.

Key words: SMO gene, sonic hedgehog signalling pathway, ameloblastoma, gene mutation

中图分类号:

Q754

何优雅,季彤. SMOi>基因突变在成釉细胞瘤中的研究进展[J]. 国际口腔医学杂志, 2020, 47(1): 63-67.

He Youya,Ji Tong. Research advances in SMO gene mutation in ameloblastoma[J]. Int J Stomatol, 2020, 47(1): 63-67.

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https://www.gjkqyxzz.cn/CN/Y2020/V47/I1/63

参考文献 29

[1] Davanian H, Balasiddaiah A, Heymann R , et al. Ameloblastoma RNA profiling uncovers a distinct non-coding RNA signature[J]. Oncotarget, 2017,8(3):4530-4542.

[2] McClary AC, West RB, McClary AC , et al. Amelo-blastoma: a clinical review and trends in manage-ment[J]. Eur Arch Otorhinolaryngol, 2016,273(7):1649-1661.

[3] Zhang B, Zhang J, Huang HZ , et al. Inhibition of ameloblastoma invasion in vitro and in vivo by in-hibitor of metalloproteinase-2 activity[J]. J Oral Pa-thol Med, 2009,38(9):731-736.

[4] Oikawa M, Miki Y, Shimizu Y , et al. Assessment of protein expression and gene status of human epidermal growth factor receptor (HER) family molecules in ameloblastomas[J]. J Oral Pathol Med, 2013,42(5):424-434.

[5] Brown NA, Rolland D ,McHugh JB , et al.Activating FGFR2-RAS-BRAF mutations in ameloblastoma[J]. Clin Cancer Res, 2014,20(21):5517-5526.

[6] Sweeney RT , et al.Identi-fication of recurrent SMO and BRAF mutations in ameloblastomas[J]. Nat Genet, 2014,46(7):722-725.

[7] Nüsslein-Volhard C, Wieschaus E . Mutations affec-ting segment number and polarity in Drosophila[J]. Nature, 1980,287(5785):795-801.

[8] Hardcastle Z, Mo R, Hui CC , et al. The Shh signal-ling pathway in tooth development: defects in Gli2 and Gli3 mutants[J]. Development, 1998,125(15):2803-2811.

[9] Jernvall J, Thesleff I . Reiterative signaling and pat-terning during mammalian tooth morphogenesis[J]. Mech Dev, 2000,92(1):19-29.

[10] Kumamoto H, Ohki K, Ooya K . Expression of Sonic hedgehog (SHH) signaling molecules in ameloblas-tomas[J]. J Oral Pathol Med, 2004,33(3):185-190.

[11] Vestergaard J, Bak M, Larsen LA . The Hedgehog signaling pathway in cancer//Macieira-Coelho A. Developmental biology of neoplastic growth. Pro-gress in molecular and subcellular biology[M]. Berlin: Springer, 2005: 1-28.

[12] Mishra P, Panda A, Bandyopadhyay A , et al.Sonic hedgehog signalling pathway and ameloblastoma—a review[J]. J Clin Diagn Res, 2015, 9(11):ZE10-3.

[13] Zhang L, Chen XM, Sun ZJ , et al. Epithelial expre-ssion of SHH signaling pathway in odontogenic tumors[J]. Oral Oncol, 2006,42(4):398-408.

[14] Vered M, Peleg O, Taicher S , et al. The immunopro-file of odontogenic keratocyst (keratocystic odonto-genic tumor) that includes expression of PTCH, SMO, GLI-1 and bcl-2 is similar to ameloblastoma but different from odontogenic cysts[J]. J Oral Pathol Med, 2009,38(7):597-604.

[15] Heikinheimo K, Jee KJ, Niini T , et al. Gene expre-ssion profiling of ameloblastoma and human tooth germ by means of a cDNA microarray[J]. J Dent Res, 2002,81(8):525-530.

[16] Diniz MG, Gomes CC, Guimarães BV , et al. Assess-ment of BRAFV600E and SMOF412E mutations in epithelial odontogenic tumours[J]. Tumour Biol, 2015,36(7):5649-5653.

[17] 张旭东 . 成釉细胞瘤BRAF、SMO、RECK基因突变与其生物学行为的关系[D]. 石家庄: 河北医科大学, 2016.

Zhang XD . The relationship between BRAF, SMO and biological behavior of ameloblastoma[D]. Shi-jiazhuang: Hebei Medical University, 2016.

[18] Gültekin SE, Aziz R, Heydt C , et al. The landscape of genetic alterations in ameloblastomas relates to clinical features[J]. Virchows Arch, 2018,472(5):807-814.

[19] Heikinheimo K, Huhtala JM, Thiel A , et al. The mutational profile of unicystic ameloblastoma[J]. J Dent Res, 2019,98(1):54-60.

[20] DeVilliers P, Suggs C, Simmons D , et al. Microge-nomics of ameloblastoma[J]. J Dent Res, 2011,90(4):463-469.

[21] Gurgel CA, Buim ME, Carvalho KC , et al. Transcrip- tional profiles of SHH pathway genes in keratocystic odontogenic tumor and ameloblastoma[J]. J Oral Pathol Med, 2014,43(8):619-626.

[22] Rimkus TK, Carpenter RL, Qasem S , et al. Targeting the sonic hedgehog signaling pathway: review of smoothened and GLI inhibitors[J]. Cancers (Basel), 2016,8(2). doi: 10.3390/cancers8020022.

[23] List A, Beran M ,DiPersio J, et al. Opportunities for Trisenox (arsenic trioxide) in the treatment of myelo-dysplastic syndromes[J]. Leukemia, 2003,17(8):1499-1507.

[24] Rudin CM, Hann CL, Laterra J , et al. Treatment of medulloblastoma with hedgehog pathway inhibitor GDC-0449[J]. N Engl J Med, 2009,361(12):1173-1178.

[25] Yauch RL, Dijkgraaf GJ, Alicke B , et al. Smoothened mutation confers resistance to a Hedgehog pathway inhibitor in medulloblastoma[J]. Science, 2009,326(5952):572-574.

[26] Metcalfe C, de Sauvage FJ . Hedgehog fights back: mechanisms of acquired resistance against Smoo-thened antagonists[J]. Cancer Res, 2011,71(15):5057-5061.

[27] Chen JK, Taipale J, Cooper MK , et al. Inhibition of Hedgehog signaling by direct binding of cyclopamine to Smoothened[J]. Genes Dev, 2002,16(21):2743-2748.

[28] Hoch L, Faure H, Roudaut H , et al. MRT-92 inhibits Hedgehog signaling by blocking overlapping binding sites in the transmembrane domain of the Smoo-thened receptor[J]. FASEB J, 2015,29(5):1817-1829.

[29] Sauk JJ, Nikitakis NG, Scheper MA . Are we on the brink of nonsurgical treatment for ameloblastoma[J]. Oral Surg Oral Med Oral Pathol Oral Radiol Endod, 2010,110(1):68-78.

相关文章 15

[1] 钱颖,龚佳幸,俞梦飞,刘宇,魏栋,朱子羽,陆科杰,王慧明. 从分子生物学角度对成釉细胞瘤诊断及治疗的考量[J]. 国际口腔医学杂志, 2021, 48(5): 570-578.

[2] 李文超, 阮宁, 徐江. 保留第二磨牙的开窗减压术治疗单囊型成釉细胞瘤[J]. 国际口腔医学杂志, 2017, 44(2): 157-160.

[3] 李思洁, 肖雪, 赵玮. 外胚叶发生不全发病机制的研究进展[J]. 国际口腔医学杂志, 2017, 44(2): 244-248.

[4] 刘敏，王旭霞. 口腔鳞状细胞癌中的鼠肉瘤病毒基因[J]. 国际口腔医学杂志, 2015, 42(2): 237-242.

[5] 杨彬1,2 张志光1. SHem>3PXDem>2b基因突变与颅颌面畸形和中耳炎[J]. 国际口腔医学杂志, 2013, 40(6): 795-798.

[6] 郭华1，周银梅1，唐休发2，华成舸2，王斯华1. 扭曲基因在成釉细胞瘤中的表达及其意义[J]. 国际口腔医学杂志, 2009, 36(1): 9-9～11,125.

[7] 周银梅,唐休发,. 成釉细胞瘤的侵袭性研究进展[J]. 国际口腔医学杂志, 2008, 35(S1): -.

[8] 杨荣涛综述李祖兵审校. 骨纤维异样增殖症病因及其发病机制的研究进展[J]. 国际口腔医学杂志, 2008, 35(4): 424-424～426.

[9] 陈杰,于丹妮,. 变形链球菌菌斑生物膜相关基因突变的研究进展[J]. 国际口腔医学杂志, 2007, 34(04): 256-258.

[10] 王旭,王洁,. p53基因与涎腺肿瘤[J]. 国际口腔医学杂志, 2006, 33(06): 460-462.

[11] 单一旦,王国云,平飞云,. 骨成釉细胞瘤的组织起源[J]. 国际口腔医学杂志, 2006, 33(04): 272-274.

[12] 申静,陈新明,汪说之. PTCH基因与牙源性囊肿[J]. 国际口腔医学杂志, 2005, 32(02): 110-112.

[13] 宋亚玲,边专. 釉质发育不全临床表型与基因变异[J]. 国际口腔医学杂志, 2005, 32(02): 107-109.

[14] 孟秀萍,王万成. 遗传性牙龈纤维瘤病发病机制的研究[J]. 国际口腔医学杂志, 2004, 31(06): 429-431.

[15] 张彬黄洪章. 成釉细胞瘤凋亡相关基因研究进展[J]. 国际口腔医学杂志, 2003, 30(03): 178-180.

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SMOi>基因突变在成釉细胞瘤中的研究进展

Research advances in SMO gene mutation in ameloblastoma

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[1]	Davanian H, Balasiddaiah A, Heymann R , et al. Ameloblastoma RNA profiling uncovers a distinct non-coding RNA signature[J]. Oncotarget, 2017,8(3):4530-4542.
[2]	McClary AC, West RB, McClary AC , et al. Amelo-blastoma: a clinical review and trends in manage-ment[J]. Eur Arch Otorhinolaryngol, 2016,273(7):1649-1661.
[3]	Zhang B, Zhang J, Huang HZ , et al. Inhibition of ameloblastoma invasion in vitro and in vivo by in-hibitor of metalloproteinase-2 activity[J]. J Oral Pa-thol Med, 2009,38(9):731-736.
[4]	Oikawa M, Miki Y, Shimizu Y , et al. Assessment of protein expression and gene status of human epidermal growth factor receptor (HER) family molecules in ameloblastomas[J]. J Oral Pathol Med, 2013,42(5):424-434.
[5]	Brown NA, Rolland D ,McHugh JB , et al.Activating FGFR2-RAS-BRAF mutations in ameloblastoma[J]. Clin Cancer Res, 2014,20(21):5517-5526.
[6]	Sweeney RT , et al.Identi-fication of recurrent SMO and BRAF mutations in ameloblastomas[J]. Nat Genet, 2014,46(7):722-725.
[7]	Nüsslein-Volhard C, Wieschaus E . Mutations affec-ting segment number and polarity in Drosophila[J]. Nature, 1980,287(5785):795-801.
[8]	Hardcastle Z, Mo R, Hui CC , et al. The Shh signal-ling pathway in tooth development: defects in Gli2 and Gli3 mutants[J]. Development, 1998,125(15):2803-2811.
[9]	Jernvall J, Thesleff I . Reiterative signaling and pat-terning during mammalian tooth morphogenesis[J]. Mech Dev, 2000,92(1):19-29.
[10]	Kumamoto H, Ohki K, Ooya K . Expression of Sonic hedgehog (SHH) signaling molecules in ameloblas-tomas[J]. J Oral Pathol Med, 2004,33(3):185-190.
[11]	Vestergaard J, Bak M, Larsen LA . The Hedgehog signaling pathway in cancer//Macieira-Coelho A. Developmental biology of neoplastic growth. Pro-gress in molecular and subcellular biology[M]. Berlin: Springer, 2005: 1-28.
[12]	Mishra P, Panda A, Bandyopadhyay A , et al.Sonic hedgehog signalling pathway and ameloblastoma—a review[J]. J Clin Diagn Res, 2015, 9(11):ZE10-3.
[13]	Zhang L, Chen XM, Sun ZJ , et al. Epithelial expre-ssion of SHH signaling pathway in odontogenic tumors[J]. Oral Oncol, 2006,42(4):398-408.
[14]	Vered M, Peleg O, Taicher S , et al. The immunopro-file of odontogenic keratocyst (keratocystic odonto-genic tumor) that includes expression of PTCH, SMO, GLI-1 and bcl-2 is similar to ameloblastoma but different from odontogenic cysts[J]. J Oral Pathol Med, 2009,38(7):597-604.
[15]	Heikinheimo K, Jee KJ, Niini T , et al. Gene expre-ssion profiling of ameloblastoma and human tooth germ by means of a cDNA microarray[J]. J Dent Res, 2002,81(8):525-530.
[16]	Diniz MG, Gomes CC, Guimarães BV , et al. Assess-ment of BRAFV600E and SMOF412E mutations in epithelial odontogenic tumours[J]. Tumour Biol, 2015,36(7):5649-5653.
[17]	张旭东 . 成釉细胞瘤BRAF、SMO、RECK基因突变与其生物学行为的关系[D]. 石家庄: 河北医科大学, 2016.
	Zhang XD . The relationship between BRAF, SMO and biological behavior of ameloblastoma[D]. Shi-jiazhuang: Hebei Medical University, 2016.
[18]	Gültekin SE, Aziz R, Heydt C , et al. The landscape of genetic alterations in ameloblastomas relates to clinical features[J]. Virchows Arch, 2018,472(5):807-814.
[19]	Heikinheimo K, Huhtala JM, Thiel A , et al. The mutational profile of unicystic ameloblastoma[J]. J Dent Res, 2019,98(1):54-60.
[20]	DeVilliers P, Suggs C, Simmons D , et al. Microge-nomics of ameloblastoma[J]. J Dent Res, 2011,90(4):463-469.
[21]	Gurgel CA, Buim ME, Carvalho KC , et al. Transcrip- tional profiles of SHH pathway genes in keratocystic odontogenic tumor and ameloblastoma[J]. J Oral Pathol Med, 2014,43(8):619-626.
[22]	Rimkus TK, Carpenter RL, Qasem S , et al. Targeting the sonic hedgehog signaling pathway: review of smoothened and GLI inhibitors[J]. Cancers (Basel), 2016,8(2). doi: 10.3390/cancers8020022.
[23]	List A, Beran M ,DiPersio J, et al. Opportunities for Trisenox (arsenic trioxide) in the treatment of myelo-dysplastic syndromes[J]. Leukemia, 2003,17(8):1499-1507.
[24]	Rudin CM, Hann CL, Laterra J , et al. Treatment of medulloblastoma with hedgehog pathway inhibitor GDC-0449[J]. N Engl J Med, 2009,361(12):1173-1178.
[25]	Yauch RL, Dijkgraaf GJ, Alicke B , et al. Smoothened mutation confers resistance to a Hedgehog pathway inhibitor in medulloblastoma[J]. Science, 2009,326(5952):572-574.
[26]	Metcalfe C, de Sauvage FJ . Hedgehog fights back: mechanisms of acquired resistance against Smoo-thened antagonists[J]. Cancer Res, 2011,71(15):5057-5061.
[27]	Chen JK, Taipale J, Cooper MK , et al. Inhibition of Hedgehog signaling by direct binding of cyclopamine to Smoothened[J]. Genes Dev, 2002,16(21):2743-2748.
[28]	Hoch L, Faure H, Roudaut H , et al. MRT-92 inhibits Hedgehog signaling by blocking overlapping binding sites in the transmembrane domain of the Smoo-thened receptor[J]. FASEB J, 2015,29(5):1817-1829.
[29]	Sauk JJ, Nikitakis NG, Scheper MA . Are we on the brink of nonsurgical treatment for ameloblastoma[J]. Oral Surg Oral Med Oral Pathol Oral Radiol Endod, 2010,110(1):68-78.

[1]	钱颖,龚佳幸,俞梦飞,刘宇,魏栋,朱子羽,陆科杰,王慧明. 从分子生物学角度对成釉细胞瘤诊断及治疗的考量[J]. 国际口腔医学杂志, 2021, 48(5): 570-578.
[2]	李文超, 阮宁, 徐江. 保留第二磨牙的开窗减压术治疗单囊型成釉细胞瘤[J]. 国际口腔医学杂志, 2017, 44(2): 157-160.
[3]	李思洁, 肖雪, 赵玮. 外胚叶发生不全发病机制的研究进展[J]. 国际口腔医学杂志, 2017, 44(2): 244-248.
[4]	刘敏，王旭霞. 口腔鳞状细胞癌中的鼠肉瘤病毒基因[J]. 国际口腔医学杂志, 2015, 42(2): 237-242.
[5]	杨彬1,2 张志光1. SHem>3PXDem>2b基因突变与颅颌面畸形和中耳炎[J]. 国际口腔医学杂志, 2013, 40(6): 795-798.
[6]	郭华1，周银梅1，唐休发2，华成舸2，王斯华1. 扭曲基因在成釉细胞瘤中的表达及其意义[J]. 国际口腔医学杂志, 2009, 36(1): 9-9～11,125.
[7]	周银梅,唐休发,. 成釉细胞瘤的侵袭性研究进展[J]. 国际口腔医学杂志, 2008, 35(S1): -.
[8]	杨荣涛综述李祖兵审校. 骨纤维异样增殖症病因及其发病机制的研究进展[J]. 国际口腔医学杂志, 2008, 35(4): 424-424～426.
[9]	陈杰,于丹妮,. 变形链球菌菌斑生物膜相关基因突变的研究进展[J]. 国际口腔医学杂志, 2007, 34(04): 256-258.
[10]	王旭,王洁,. p53基因与涎腺肿瘤[J]. 国际口腔医学杂志, 2006, 33(06): 460-462.
[11]	单一旦,王国云,平飞云,. 骨成釉细胞瘤的组织起源[J]. 国际口腔医学杂志, 2006, 33(04): 272-274.
[12]	申静,陈新明,汪说之. PTCH基因与牙源性囊肿[J]. 国际口腔医学杂志, 2005, 32(02): 110-112.
[13]	宋亚玲,边专. 釉质发育不全临床表型与基因变异[J]. 国际口腔医学杂志, 2005, 32(02): 107-109.
[14]	孟秀萍,王万成. 遗传性牙龈纤维瘤病发病机制的研究[J]. 国际口腔医学杂志, 2004, 31(06): 429-431.
[15]	张彬黄洪章. 成釉细胞瘤凋亡相关基因研究进展[J]. 国际口腔医学杂志, 2003, 30(03): 178-180.