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Gadd45B Deficiency Drives Radio-Resistance in BRAFV600E-Mutated Differentiated Thyroid Cancer by Disrupting Iodine Metabolic Genes
by
,
Shan Jiang
1,†, 
Zhiwen Hong
1,†,
Qianjiang Wu
2,
Rouhan A
1,
Zhaobo Wang
1,
Xue Guan
3,
Xinghua Wang
1,
Ari A. Kassardjian
4,
Yali Cui
1,* and
Tengchuang Ma
1,* 1
Department of Nuclear Medicine, Harbin Medical University Cancer Hospital, Harbin 150081, China
2
Institute of Cancer Prevention and Treatment, Harbin Medical University Cancer Hospital, Harbin 150081, China
3
Animal Laboratory Center, The Second Affiliated Hospital of Harbin Medical University, Harbin 150081, China
4
Department of Radiation Oncology, City of Hope National Medical Center, 1500 E. Duarte Rd, Duarte, CA 91010, USA
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Cancers 2025, 17(19), 3201; https://doi.org/10.3390/cancers17193201
Submission received: 8 July 2025
/
Revised: 12 September 2025
/
Accepted: 16 September 2025
/
Published: 30 September 2025
(This article belongs to the Special Issue Advanced Research on Radioresistant Tumors)
Simple Summary
Radioactive iodine (RAI) is a cornerstone therapy for differentiated thyroid cancer, but many tumours—especially those with the BRAFV600E mutation—become RAI-refractory and stop taking up iodine. We analysed patient tissues and public datasets and found that Gadd45B is consistently reduced in RAI-refractory disease. Using thyroid cancer cell lines and mouse models (including patient-derived xenografts), we show that restoring Gadd45B re-sensitises tumours to RAI, increases uptake, and slows growth. Mechanistically, Gadd45B modulates two complementary axes: it interacts with MAP3K4 to dampen MAPK signalling, and it restrains MYCBP–c-Myc–TERT activity. Together, these effects upregulate iodine-handling genes (e.g., NIS, TPO, Tg) and improve tumour differentiation. Clinically, low Gadd45B correlates with poor outcomes, supporting its potential as a biomarker and therapeutic target. While intratumoural recombinant Gadd45B showed benefit in vivo, we did not directly confirm its cellular entry; future studies will test delivery strategies and validate safety in patients.
Abstract
Background: Differentiated thyroid cancer (DTC) is commonly treated with radioactive iodine (RAI), but resistance to RAI remains a significant clinical challenge. The molecular mechanisms driving dedifferentiation and RAI refractoriness, particularly in BRAFV600E-mutated tumors, are not fully understood. Methods: RNA sequencing was conducted on BRAFV600E-mutated DTC and RAIR-DTC tissue samples to identify differentially expressed genes. Gadd45B was identified as significantly downregulated in RAIR-DTC. Functional studies including overexpression and knockdown experiments were performed in thyroid cancer cell lines and xenograft models. Downstream targets, including MAP3K4 and MYCBP, were evaluated through co-immunoprecipitation, luciferase assays, and Western blot. The therapeutic efficacy of recombinant Gadd45B protein in combination with BRAFV600E and TERT inhibitors was assessed in patient-derived xenograft (PDX) models. Results: Gadd45B overexpression suppressed MAPK pathway activity by interacting with MAP3K4 and downregulated c-MYC stability through competition with MYCBP. These interactions enhanced the expression of iodine-metabolism genes (NIS, TPO, Tg), increased RAI uptake, and reversed tumor dedifferentiation. In vivo, Gadd45B restoration reduced tumor burden and improved RAI uptake. Combined treatment with Gadd45B protein, PLX4720, and BIBR1532 produced synergistic therapeutic effects in PDX models. Conclusions: Gadd45B plays a pivotal role in regulating the differentiation status and RAI sensitivity of BRAFV600E-mutated thyroid cancer. These findings identify Gadd45B as a promising therapeutic target for restoring RAI responsiveness in RAIR-DTC patients.
