Section on Endocrinology & Genetics (SEGEN), Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, 20892, USA.
Group for Advanced Molecular Investigation (NIMA), Graduate Program in Health Sciences (PPGCS), School of Medicine (EM), Pontifícia Universidade Católica do Paraná (PUCPR), Curitiba, Brazil.
Endocrine. 2022 Aug;77(2):281-290. doi: 10.1007/s12020-022-03068-x. Epub 2022 May 18.
Papillary thyroid carcinoma (PTC) is the most common type of thyroid carcinoma and its incidence has greatly increased in the last 30 years. Ubiquitin-specific protease 13 (USP13) is a class of deubiquitinating enzymes (DUBs) and plays an important role in cellular functions such as cell cycle regulation, DNA damage repair, and different cell signaling pathways. Studies regarding the role of USP13 in cancer development and progression are divergent and there are no previous data regarding the role of USP13 gene in PTCs. In this study, we investigated the genetic cause of PTC diagnosed in multiple members of a Brazilian family.
Whole exome sequencing (WES) was performed to identify the genetic cause of PTC. Cycloheximide chase assay and clonogenic assay were performed to study USP13 stability and function in vitro.
WES analysis identified a heterozygous missense variant c.1483G > A (p.V495M) in the USP13 gene that fully segregates with the disease. In silico modeling suggests that this variant may cause protein structural perturbations. USP13 overexpression increased the potential of a single cell to form colonies. The USP13 c.1483G > A variant enhanced the effects seen in USP13 overexpression and preserved protein stability for longer hours compared to the non-mutated USP13 protein.
Our study suggests that USP13 overexpression may play a role in tumorigenesis of PTCs; and that the USP13 p.V495M (c.1483G > A) variant enhances USP13 estability.
甲状腺乳头状癌（PTC）是最常见的甲状腺癌类型，其发病率在过去 30 年中大幅增加。泛素特异性蛋白酶 13（USP13）是一类去泛素化酶（DUBs），在细胞周期调控、DNA 损伤修复和不同细胞信号通路等细胞功能中发挥重要作用。关于 USP13 在癌症发展和进展中的作用的研究结果存在分歧，并且之前没有关于 USP13 基因在 PTC 中的作用的数据。在这项研究中，我们研究了一个巴西家庭中多名成员所患的 PTC 的遗传原因。
进行全外显子组测序（WES）以鉴定 PTC 的遗传原因。进行环己酰亚胺追踪实验和集落形成实验，以研究 USP13 在体外的稳定性和功能。
WES 分析鉴定出 USP13 基因中的杂合错义变异 c.1483G > A（p.V495M），该变异与疾病完全分离。计算机建模表明，该变异可能导致蛋白质结构的改变。USP13 过表达增加了单个细胞形成集落的潜力。与非突变 USP13 蛋白相比，USP13 c.1483G > A 变异增强了 USP13 过表达的效果，并保持了更长时间的蛋白质稳定性。
我们的研究表明，USP13 过表达可能在 PTC 的肿瘤发生中起作用；并且 USP13 p.V495M（c.1483G > A）变异增强了 USP13 的稳定性。
