Sousa Sílvia F, Gomez Ricardo S, Diniz Marina G, Bernardes Vanessa F, Soares Flávia F C, Brito João Artur R, Liu Sophie, Pontes Hélder Antônio R, Stratakis Constantine A, Gomes Carolina C
Department of Oral Surgery and PathologySchool of DentistryDepartment of PathologyBiological Sciences Institute, Universidade Federal de Minas Gerais (UFMG), Avenida Antônio Carlos, 6627, Belo Horizonte, Minas Gerais CEP 31270-901, BrazilSection on Endocrinology and GeneticsProgram on Developmental Endocrinology and Genetics (PDEGEN), NIH, Bethesda, Maryland, USAJoão de Barros Barreto University HospitalUniversidade Federal do Pará (UFPA), Belém, Brazil.
Department of Oral Surgery and PathologySchool of DentistryDepartment of PathologyBiological Sciences Institute, Universidade Federal de Minas Gerais (UFMG), Avenida Antônio Carlos, 6627, Belo Horizonte, Minas Gerais CEP 31270-901, BrazilSection on Endocrinology and GeneticsProgram on Developmental Endocrinology and Genetics (PDEGEN), NIH, Bethesda, Maryland, USAJoão de Barros Barreto University HospitalUniversidade Federal do Pará (UFPA), Belém, Brazil
Endocr Relat Cancer. 2015 Jun;22(3):399-408. doi: 10.1530/ERC-15-0094. Epub 2015 Apr 13.
The surgical treatment of some odontogenic tumors often leads to tooth and maxillary bone loss as well as to facial deformity. Therefore, the identification of genes involved in the pathogenesis of odontogenic tumors may result in alternative molecular therapies. The PRKAR1A gene displays a loss of protein expression as well as somatic mutations in odontogenic myxomas, an odontogenic ectomesenchymal neoplasm. We used a combination of quantitative RT-PCR (qRT-PCR), immunohistochemistry, loss of heterozygosity (LOH) analysis, and direct sequencing of all PRKAR1A exons to assess if this gene is altered in mixed odontogenic tumors. Thirteen tumors were included in the study: six ameloblastic fibromas, four ameloblastic fibro-odontomas, one ameloblastic fibrodentinoma, and two ameloblastic fibrosarcomas. The epithelial components of the tumors were separated from the mesenchymal by laser microdissection in most of the cases. We also searched for odontogenic pathology in Prkar1a(+) (/) (-) mice. PRKAR1A mRNA/protein expression was decreased in the benign mixed odontogenic tumors in association with LOH at markers around the PRKAR1A gene. We also detected a missense and two synonymous mutations along with two 5'-UTR and four intronic mutations in mixed odontogenic tumors. Prkar1a(+) (/) (-) mice did not show evidence of odontogenic tumor formation, which indicates that additional genes may be involved in the pathogenesis of such tumors, at least in rodents. We conclude that the PRKAR1A gene and its locus are altered in mixed odontogenic tumors. PRKAR1A expression is decreased in a subset of tumors but not in all, and Prkar1a(+) (/) (-) mice do not show abnormalities, which indicates that additional genes play a role in this tumor's pathogenesis.
某些牙源性肿瘤的外科治疗常常导致牙齿和上颌骨缺失以及面部畸形。因此，鉴定参与牙源性肿瘤发病机制的基因可能会带来替代性的分子疗法。PRKAR1A基因在牙源性黏液瘤（一种牙源性外胚间叶性肿瘤）中表现出蛋白表达缺失以及体细胞突变。我们采用定量逆转录聚合酶链反应（qRT-PCR）、免疫组织化学、杂合性缺失（LOH）分析以及对所有PRKAR1A外显子进行直接测序相结合的方法，来评估该基因在混合性牙源性肿瘤中是否发生改变。本研究纳入了13个肿瘤：6个成釉细胞纤维瘤、4个成釉细胞纤维-牙瘤、1个成釉细胞纤维牙本质瘤以及2个成釉细胞纤维肉瘤。在大多数病例中，通过激光显微切割将肿瘤的上皮成分与间叶成分分离。我们还在Prkar1a(+)/(-)小鼠中寻找牙源性病变。在良性混合性牙源性肿瘤中，PRKAR1A mRNA/蛋白表达降低，同时在PRKAR1A基因周围的标记处存在杂合性缺失。我们在混合性牙源性肿瘤中还检测到1个错义突变、2个同义突变以及2个5'-非翻译区和4个内含子突变。Prkar1a(+)/(-)小鼠未表现出牙源性肿瘤形成的迹象，这表明至少在啮齿动物中，可能还有其他基因参与此类肿瘤的发病机制。我们得出结论，PRKAR1A基因及其位点在混合性牙源性肿瘤中发生改变。PRKAR1A表达在部分肿瘤中降低，但并非全部，并且Prkar1a(+)/(-)小鼠未表现出异常，这表明还有其他基因在该肿瘤的发病机制中发挥作用。
