Molecular mechanisms of radioactive iodine refractoriness in differentiated thyroid cancer: Impaired sodium iodide symporter (NIS) expression owing to altered signaling pathway activity and intracellular localization of NIS

Abstract

The advanced, metastatic differentiated thyroid cancers (DTCs) have a poor prognosis mainly owing to radioactive iodine (RAI) refractoriness caused by decreased expression of sodium iodide symporter (NIS), diminished targeting of NIS to the cell membrane, or both, thereby decreasing the efficacy of RAI therapy. Genetic aberrations (such as BRAF, RAS, and RET/PTC rearrangements) have been reported to be prominently responsible for the onset, progression, and dedifferentiation of DTCs, mainly through the activation of mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/AKT signaling pathways. Eventually, these alterations result in a lack of NIS and disabling of RAI uptake, leading to the development of resistance to RAI therapy. Over the past decade, promising approaches with various targets have been reported to restore NIS expression and RAI uptake in preclinical studies. In this review, we summarized comprehensive molecular mechanisms underlying the dedifferentiation in RAI-refractory DTCs and reviews strategies for restoring RAI avidity by tackling the mechanisms.

Keywords: membrane targeting; radioactive iodine refractory thyroid cancer; redifferentiation; signaling pathways; sodium iodide symporter.

Figure 1

Principal mechanisms underlying the pathogenesis of thyroid cancer and radioactive iodine (RAI)-refractory in differentiated thyroid cancer. (A) Mitogen-activated protein kinase (MAPK) signaling pathway. (B) Phosphoinositide 3-kinase (PI3K)/AKT signaling pathway. Abbreviations: 4E-BP: 4E-binding protein; DNMT1: DNA methyltransferase 1; mTORC1: mTOR complex 1; mTORC2: mTOR complex 2; P: phosphorylation; PTEN: phosphatase and tensin homolog; TERT: telomerase reverse transcriptase. Images were created with BioRender.com.

Figure 2

Molecular mechanisms involved in the regulation of thyroid-specific genes including sodium iodide symporter (NIS) in RAI-refractory differentiated thyroid cancer. (A) Notch signaling pathway. (B) TGF-ß/Smad signaling pathway. (C) Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway. (D) Wnt/ß-catenin signaling pathway. Abbreviations: DNMT1: DNA methyltransferase 1; FoxP3: forkhead transcription factor 3; HIF1-ɑ: hypoxia-inducible factor-ɑ; IκB: Inhibitory κB; LRP5/6: low-density lipoprotein receptor-related protein 5/6; NECD: notch extracellular domain; NICD: notch intracellular domain; NOX4: NADPH oxidase 4; P: phosphorylation; ROS: reactive oxygen species; Ub: ubiquitination. Images were created with BioRender.com.

Figure 3

Molecular mechanisms involved in the regulation of thyroid-specific genes, including NIS in RAI-refractory differentiated thyroid cancer. (A) Epigenetic alterations, including DNA methylation and histone modification, and bromodomain-containing protein 4 (BRD4). (B) Nuclear receptors RAR, PPARɣ, LXRß and ERRɣ. (C) Autophagy. (D) MicroRNAs and PBF. Abbreviations: Ac: acetylation; BRD4: bromodomain-containing protein; DNMT1: DNA methyltransferase 1; ERRɣ: estrogen-related receptor ɣ; HDAC: histone deacetylase; HMGB1: high mobility group box 1; LXRß: liver X receptor ß; miR: microRNA; mTORC1: mTOR complex 1; PBF: pituitary tumor-transforming gene 1 (PTTG1)-binding factor; PPARɣ: peroxisome proliferator-activated receptor ɣ; RAR: retinoic acid receptor; ROS: reactive oxygen species; RXR: retinoid X receptor. Images were created with BioRender.com.

Figure 4

Schematic diagram of factors related to NIS membrane targeting in RAI-refractory differentiated thyroid cancer. Abbreviations: ARF4: ADP-ribosylation factor 4; ERAD: endoplasmic-reticulum-associated protein degradation; LARG: leukemia-associated RhoA guanine exchange factor; PBF: pituitary tumor-transforming gene 1 (PTTG1)-binding factor; PIGU: phosphatidylinositol glycan anchor biosynthesis class U; VCP: valosin-containing protein. Image was created with BioRender.com.

Figure 5

Comprehensive molecular mechanisms related to RAI refractoriness in differentiated thyroid cancer. Abbreviations: 4E-BP: 4E-binding protein; Ac: acetylation; BRD4: bromodomain-containing protein; DNMT1: DNA methyltransferase 1; ERRɣ: estrogen-related receptor ɣ; FoxP3: forkhead transcription factor 3; HDAC: histone deacetylase; HMGB1: high mobility group box 1; IκB: inhibitory κB; LXRß: liver X receptor ß; TERT: telomerase reverse transcriptase; TSHR: TSH receptor; miR: microRNA; mTORC1: mTOR complex 1; mTORC2: mTOR complex 2; P: phosphorylation. NECD: notch extracellular domain; NICD: notch intracellular domain; NOX4: NADPH oxidase 4; P: phosphorylation; PBF: pituitary tumor-transforming gene 1 (PTTG1)-binding factor; PTEN: phosphatase and tensin homolog; RAR: retinoic acid receptor; PPARɣ: peroxisome proliferator-activated receptor ɣ; ROS: reactive oxygen species; RAR: retinoic acid receptor; RXR: retinoid X receptor; TERT: telomerase reverse transcriptase; Ub: ubiquitination. Image was created with BioRender.com.