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Advances in the molecular mechanism and targeted therapy of radioactive-iodine refractory differentiated thyroid cancer

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Abstract

Most patients with differentiated thyroid cancer have a good prognosis after radioactive iodine-131 treatment, but there are still a small number of patients who are not sensitive to radioiodine treatment and may subsequently show disease progression. Therefore, radioactive-iodine refractory differentiated thyroid cancer treated with radioiodine usually shows reduced radioiodine uptake. Thus, when sodium iodine symporter expression, basolateral membrane localization and recycling degradation are abnormal, radioactive-iodine refractory differentiated thyroid cancer may occur. In recent years, with the deepening of research into the pathogenesis of this disease, an increasing number of molecules have become or are expected to become therapeutic targets. The application of corresponding inhibitors or combined treatment regimens for different molecular targets may be effective for patients with advanced radioactive-iodine refractory differentiated thyroid cancer. Currently, some targeted drugs that can improve the progression-free survival of patients with radioactive-iodine refractory differentiated thyroid cancer, such as sorafenib and lenvatinib, have been approved by the FDA for the treatment of radioactive-iodine refractory differentiated thyroid cancer. However, due to the adverse reactions and drug resistance caused by some targeted drugs, their application is limited. In response to targeted drug resistance and high rates of adverse reactions, research into new treatment combinations is being carried out; in addition to kinase inhibitor therapy, gene therapy and rutin-assisted iodine-131 therapy for radioactive-iodine refractory thyroid cancer have also made some progress. Thus, this article mainly focuses on sodium iodide symporter changes leading to the main molecular mechanisms in radioactive-iodine refractory differentiated thyroid cancer, some targeted drug resistance mechanisms and promising new treatments.

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Abbreviations

FDA:

Food and drug administration

ATA:

American Thyroid Association

RAIR-DTC:

Radioactive-iodine refractory differentiated thyroid cancer

RAI:

Radioiodine

NIS:

Sodium iodine symporter

TERT:

Telomerase reverse transcriptase

TGF-β1:

Transforming growth factor-β1

SMAD3:

Mothers against DPP homolog 3 (Drosophila)

WNT1:

Wingless-type MMTV integration site family, member 1

ROS:

Reactive oxygen species

FDG:

β-2- [18 F]-Fluoro-2-deoxy-D-glucose

SLC5A5:

Solute carrier family 5

SCRIB:

Scribbled homolog (Drosophila)

AP-1A:

Adaptor protein complex-1A

AP-1B:

Adaptor protein complex-1B

TGN:

Trans-Golgi network

PTTG:

Pituitary tumor transforming gene

PBF/PTTG1IP:

Pituitary tumor transforming gene binding factor

TCF/LEF:

T-cell Factor/Lymphoid Enhancing Factor

DACT2:

Dapper, antagonist of beta-catenin, homolog 2 (Xenopus laevis)

HIF-1α:

Hypoxia-inducible factor-1α

KDM1A/LSD1:

Histone lysine-specific demethylase1

APC2:

Adenomatosis polyposis coli 2

DDK1:

Dickkopf-related protein 1

NOX1:

NADPH oxidase 1

NRX:

Nucleoredoxin

ARF4:

ADP-ribosylation factor 4

VCP:

Valosin protein

ERAD:

Endoplasmic reticulum-associated protein degradation

PM:

Plasma membrane

IGF2BP2:

Insulin-like growth factor 2 mRNA binding protein 2

RUNX2:

Runt-related transcription factor 2

SAHA:

N-Hydroxy-N'-phenyloctanediamide

PAX8:

Paired box gene 8

NKX2-1:

NK2 homeobox 1

TSHR:

Thyroid stimulating hormone receptor

TSH:

Thyroid stimulating hormone

PIGU:

One of the components of the glycosyl phosphatidylinositol aminositol transaminase (GPIT) complex

CREB3L1:

CAMP responsive element binding protein 3-like 1

mTORC1/2:

Mammalian target of rapamycin compelx1/2

NMTC:

Nonmyelinary thyroid cancer

AMPK:

Adenosine 5’-monophosphate (AMP)-activated protein kinase

ULK1:

Unc-51-like kinase 1 (C. elegans)

TFEB:

Transcription factor E3

CARM1:

Coactivator-associated arginine methyltransferase 1

SKP2:

S-phase kinase-associated protein 2 (p45)

SHP:

Small heterodimer partner

FOXO3:

Forkhead box O3

WT1:

Wilms’ tumor 1

FOXP3:

Forkhead box P3

NADPH:

(Reduced) Nicotinamide adenine dinucleotide phosphate

NOX4:

NADPH oxidase 1

DNMT1:

Recombinant DNA methyltransferase 1

HDAC:

Histone deacetylase

Src:

Nonreceptor tyrosine kinase

HMGB1:

High mobility group protein B1

ERS:

Endoplasmic reticulum stress

UPR:

Unfolded protein response

LC3-I:

Microtubule-associated protein 1 light chain 3

PERK:

PKR-like ER kinase

eIF2α:

Eukaryotic initiation factor 2α

ATF4:

Recombinant activating transcription factor4

CHOP:

C/EBP-homologous protein

ERO1α:

ER REDOX hormone 1α

IP3R1:

Inositol 1,4,5-triphosphate receptor 1

CaMMII:

Calmodulin-dependent protein kinase II

NOX2:

NADPH oxidase 2

SIRT6:

Sirtuin (silent mating type information regulation 2 homolog) 6 (S. cerevisiae)

NRROS:

Negative regulator of reactive oxygen species

TME:

Tumor microenvironment

MDSCs:

Myeloid-derived suppressor cells

Gpx4:

Glutathione peroxidase-4

GSH:

Glutathione

SLC3A2:

Solute carrier family 3 member 2

SLC7A11:

Solute carrier family 7 member 11

PHKG2:

Phosphorylase kinase G2

PUFAs:

Polyunsaturated fatty acids

ACSL4:

Acyl-CoA synthetase long-chain family 4

PTGS2:

Prostaglandin-endoperoxide synthase 2 (prostaglandin G/H synthase and cyclooxygenase)

IR:

Ionizing radiation

NRF2:

NFE2-related factor 2

NFE2L2:

Nuclear factor (erythroid-derived 2)-like 2

ESCC:

Esophageal squamous cell carcinoma

EZH2:

Enhancer of zeste homolog 2

ERBB2:

V-erb-b2 erythroblastic leukemia viral oncogene homolog 2

ICB:

Immune checkpoint blockade

CTLA4:

Cytotoxic T-lymphocyte antigen 4

PD1:

Programmed cell death protein 1

PDL1/2:

Programmed cell death-ligand 1/2

TBX3:

T-box transcription factor 3

CXCR2:

CXC-chemokine receptor 2

PMN-MDSCs:

Polymorphonuclear myeloid suppressor cells

RGI:

Reporter gene imaging

AIDS:

Acquired/immunodeficiency/syndrome

cAMP:

Cyclic adenosine monophosphate

CREB:

CAMP-response element binding protein

VnNp:

Vanadium pentoxide nanoparticles

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Acknowledgements

We thank AJE for the linguistic editing and proofreading of the manuscript.

Funding

This work was supported by the National Natural Science Foundation, Regional Science Foundation Project 81960322, 82160343; Joint Program of Applied Basic Research of Yunnan Provincial Department of Science and Technology—Kunming Medical University. NO. 202301AY070001-106; “Famous Doctor” Special Project of Ten Thousand People Plan of Yunnan Province (No. YNWR-MY-2020-095).

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  1. Department of Nuclear Medicine, The Third Affiliated Hospital of Kunming Medical University, Tumor Hospital of Yunnan Province, 519 Kunzhou Road, Xishan District, Kunming, KM, 650118, China

    Lu Zhang, Zhi Li, Meng Zhang, Huangren Zou, Yuke Bai, Yanlin Liu, Juan Lv, Ling Lv, Pengjie Liu, Zhiyong Deng & Chao Liu

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Contributions

Conception prepare: LZ, CL, ZL, MZ. Formal analysis: CL and LZ. Original draft preparation and visualization: LZ, ZL, MZ, HZ, YB, YL. Manuscript writing: LZ, CL, ZL, MZ, HZ, YB, YL. Supervision and review: JL, LL, PL. Administrative support and project administration: ZD, CL and JL. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Zhiyong Deng.

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Zhang, L., Li, Z., Zhang, M. et al. Advances in the molecular mechanism and targeted therapy of radioactive-iodine refractory differentiated thyroid cancer. Med Oncol 40, 258 (2023). https://doi.org/10.1007/s12032-023-02098-3

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