Zhang Lizhuo, Zhou Lingyan, Feng Qingqing, Li Qinglin, Ge Minghua
Department of Head and Neck Surgery, Center of Otolaryngology-Head and Neck Surgery, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Key Laboratory of Endocrine Gland Diseases of Zhejiang Province, Hangzhou, China.
Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China.
Front Oncol. 2021 Dec 21;11:813802. doi: 10.3389/fonc.2021.813802. eCollection 2021.
Clinical studies have shown similarities in the genetic background and biological functional characteristics between Hashimoto's thyroiditis (HT) and papillary thyroid carcinoma (PTC), and that HT may increase risks of PTC. Here, we set to determine the gene expression specificity of HT and PTC by screening related genes or co-expressed genes and exploring their genetic correlation. Referencing the Oncomine database, HT-related genes were discovered to be expressed in many different types of thyroid cancer, such as TSHR that is highly expressed in thyroid cancer. An in-depth genetic analysis and verification of 35 cancer and paracancerous tissue pairs from patients with thyroid cancer, and 35 tissues and blood cells pairs from patients with Hashimoto's thyroiditis was conducted. Gene chip technology research showed that TSHR, BACH2, FOXE1, RNASET2, CTLA4, PTPN22, IL2RA and other HT-related genes were all expressed in PTC, in which TSHR was significantly over-expressed in PTC patients sensitive to radioactive iodine therapy, while BACH2 was significantly under-expressed in these patients. The biologically significant candidate Tag SNP highlighted from HT-related genes was screened by the high-throughput detection method. Somatic mutations in patients with HT and PTC were detected by target region capture technique, and 75 mutations were found in patients with HT and PTC. The upstream regulatory factors of the different genes shared by HT and PTC were analyzed based on Ingenuity Pathway Analysis (IPA), and it was found that HIF-1α and PD-L1 could be used as important upstream regulatory signal molecules. These results provide a basis for screening key diagnostic genes of PTC by highlighting the relationship between some HT-related genes and their polymorphisms in the pathogenesis of PTC.
临床研究表明，桥本甲状腺炎（HT）和甲状腺乳头状癌（PTC）在遗传背景和生物学功能特征方面存在相似性，且HT可能增加PTC的发病风险。在此，我们通过筛选相关基因或共表达基因并探索它们的遗传相关性，来确定HT和PTC的基因表达特异性。参考Oncomine数据库，发现HT相关基因在许多不同类型的甲状腺癌中均有表达，如在甲状腺癌中高表达的促甲状腺激素受体（TSHR）。对35例甲状腺癌患者的癌组织和癌旁组织对，以及35例桥本甲状腺炎患者的组织和血细胞对进行了深入的基因分析和验证。基因芯片技术研究表明，TSHR、BACH2、叉头框E1（FOXE1）、核糖核酸酶T2（RNASET2）、细胞毒性T淋巴细胞相关蛋白4（CTLA4）、蛋白酪氨酸磷酸酶非受体型22（PTPN22）、白细胞介素2受体α链（IL2RA）等HT相关基因在PTC中均有表达，其中TSHR在对放射性碘治疗敏感的PTC患者中显著过表达，而BACH2在这些患者中显著低表达。通过高通量检测方法筛选出HT相关基因中具有生物学意义的候选标签单核苷酸多态性（Tag SNP）。采用目标区域捕获技术检测HT和PTC患者的体细胞突变，在HT和PTC患者中发现了75个突变。基于 Ingenuity 通路分析（IPA）对HT和PTC共有的不同基因的上游调控因子进行分析，发现缺氧诱导因子-1α（HIF-1α）和程序性死亡受体配体1（PD-L1）可作为重要的上游调控信号分子。这些结果通过突出一些HT相关基因及其多态性在PTC发病机制中的关系，为筛选PTC的关键诊断基因提供了依据。
