Liu Hongzhou, Hu Xiaodong, Li Tan, Wang Yuhan, Fu Xiaomin
Department of Endocrinology, First Hospital of Handan City, Handan, 056002, Hebei Province, China.
Department of Endocrinology, The First Medical Center, Chinese PLA General Hospital, Beijing, 100853, China.
Mol Med. 2025 Jul 5;31(1):252. doi: 10.1186/s10020-025-01298-z.
Tripartite motif 47 (TRIM47) plays a vital role in the carcinogenesis and drug resistance of various cancers, whereas the function of TRIM47 in thyroid carcinoma (TC) remains unclear.
Human study and animal experiments were performed. Mass spectrometry, cellular invasion/metastasis assay, chemo-resistance assay, and ubiquitination evaluation were conducted to investigate the interaction between TRIM47 and adenosine deaminases acting on RNA (ADAR).
TRIM47 expression was increased in human tissues and cell lines of TC. Functional experiments demonstrated that TRIM47 expression enhanced malignant biological behaviors. With mass spectrometry, TRIM47 silencing could significantly decrease the chemo-resistance of TC cells to chemotherapeutic drugs. The interaction between TRIM47 and ADAR was mediated through the ubiquitin-proteasome pathway (UPP), which was approved by RNA interference procedure and co-immunoprecipitation.
Comprehensively, glycogen synthase kinase-3β (GSK-3β)-associated ubiquitination is critical in the TRIM47-ADAR-GSK-3β axis. This study demonstrates that TRIM47 interacted with ADAR to facilitate ADAR protein degradation via ubiquitination and GSK-3β-associated phosphorylation, which serves as a novel therapeutic avenue for TC.
三联基序蛋白47（TRIM47）在多种癌症的发生发展和耐药性中起着至关重要的作用，而TRIM47在甲状腺癌（TC）中的功能尚不清楚。
进行了人体研究和动物实验。采用质谱分析、细胞侵袭/转移实验、化疗耐药实验和泛素化评估来研究TRIM47与作用于RNA的腺苷脱氨酶（ADAR）之间的相互作用。
TRIM47在TC的人体组织和细胞系中表达增加。功能实验表明，TRIM47表达增强了恶性生物学行为。通过质谱分析，TRIM47沉默可显著降低TC细胞对化疗药物的耐药性。TRIM47与ADAR之间的相互作用是通过泛素-蛋白酶体途径（UPP）介导的，这一点通过RNA干扰实验和免疫共沉淀得到了证实。
综合来看，糖原合酶激酶-3β（GSK-3β）相关的泛素化在TRIM47-ADAR-GSK-3β轴中至关重要。本研究表明，TRIM47与ADAR相互作用，通过泛素化和GSK-3β相关的磷酸化促进ADAR蛋白降解，这为TC提供了一条新的治疗途径。
