Ruan Xianhui, Liu Yu, Wu Shuping, Fu Guiming, Tao Mei, Huang Yue, Li Dapeng, Wei Songfeng, Gao Ming, Guo Shicheng, Ning Junya, Zheng Xiangqian
Department of Thyroid and Neck Tumor, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China.
Department of Head and Neck Surgery, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou 350014, Fujian, China.
Aging (Albany NY). 2024 Apr 4;16(7):6488-6509. doi: 10.18632/aging.205718.
Thyroid cancer represents the most prevalent malignant endocrine tumour, with rising incidence worldwide and high mortality rates among patients exhibiting dedifferentiation and metastasis. Effective biomarkers and therapeutic interventions are warranted in aggressive thyroid malignancies. The transcription factor 19 (TCF19) gene has been implicated in conferring a malignant phenotype in cancers. However, its contribution to thyroid neoplasms remains unclear.
In this study, we performed genome-wide and phenome-wide association studies to identify a potential causal relationship between TCF19 and thyroid cancer. Our analyses revealed significant associations between TCF19 and various autoimmune diseases and human cancers, including cervical cancer and autoimmune thyroiditis, with a particularly robust signal for the deleterious missense variation rs2073724 that is associated with thyroid function, hypothyroidism, and autoimmunity. Furthermore, functional assays and transcriptional profiling in thyroid cancer cells demonstrated that TCF19 regulates important biological processes, especially inflammatory and immune responses. We demonstrated that TCF19 could promote the progression of thyroid cancer and and the C>T variant of rs2073724 disrupted TCF19 protein binding to target gene promoters and their expression, thus reversing the effect of TCF19 protein.
Taken together, these findings implicate TCF19 as a promising therapeutic target in aggressive thyroid malignancies and designate rs2073724 as a causal biomarker warranting further investigation in thyroid cancer.
甲状腺癌是最常见的恶性内分泌肿瘤，全球发病率呈上升趋势，在出现去分化和转移的患者中死亡率很高。侵袭性甲状腺恶性肿瘤需要有效的生物标志物和治疗干预措施。转录因子19（TCF19）基因与癌症的恶性表型有关。然而，其对甲状腺肿瘤的作用仍不清楚。
在本研究中，我们进行了全基因组和全表型关联研究，以确定TCF19与甲状腺癌之间的潜在因果关系。我们的分析揭示了TCF19与各种自身免疫性疾病和人类癌症之间的显著关联，包括宫颈癌和自身免疫性甲状腺炎，对于与甲状腺功能、甲状腺功能减退和自身免疫相关的有害错义变异rs2073724有特别强烈的信号。此外，甲状腺癌细胞中的功能测定和转录谱分析表明，TCF19调节重要的生物学过程，尤其是炎症和免疫反应。我们证明TCF19可以促进甲状腺癌的进展，并且rs2073724的C>T变异破坏了TCF19蛋白与靶基因启动子的结合及其表达，从而逆转了TCF19蛋白的作用。
综上所述，这些发现表明TCF19是侵袭性甲状腺恶性肿瘤中有前景的治疗靶点，并将rs2073724指定为因果生物标志物，值得在甲状腺癌中进一步研究。
