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Table of Contents
REVIEW ARTICLE
Year : 2019  |  Volume : 6  |  Issue : 4  |  Page : 162-169

Thyroid hormone, PD-L1, and cancer


1 Graduate Institute of Nanomedicine and Medical Engineering, College of Medical Engineering; Taipei Cancer Center, Taipei Medical University, Taipei, Taiwan
2 The Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Rensselaer; Department of Medicine, Albany Medical College, Albany, NY, USA
3 Taipei Cancer Center; Cancer Center, Wan Fang Hospital; Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
4 Taipei Cancer Center, Taipei Medical University, Taipei, Taiwan; The Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Rensselaer, NY, USA; Cancer Center, Wan Fang Hospital; Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology; TMU Research Center of Cancer Translational Medicine; Traditional Herbal Medicine Research Center, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan

Date of Submission06-Aug-2019
Date of Decision18-Sep-2019
Date of Acceptance04-Oct-2019
Date of Web Publication22-Nov-2019

Correspondence Address:
Dr. Hung-Yun Lin
Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, No. 250 Wu-Hsing Street, Taipei 11031

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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/JCRP.JCRP_26_19

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  Abstract 


Objective: Thyroid hormone plays a vital role in maintaining whole-body physiological activities. However, several different disorders can arise when thyroid hormone is abnormal. Even more, thyroid hormone has been shown to stimulate cancer cell proliferation at physiological concentration. By binding to cell surface integrin αvβ3, thyroid hormone, especially thyroxine activates ERK1/2 activation and sequentially stimulates cell proliferation. Different mechanisms have been demonstrated to be involved in thyroxine-induced cancer proliferation. Checkpoint, PD-1/PD-L1, has shown highly correlated to cancer proliferation and survival. Data Sources: We examined actions of thyroxine and Nano-diamino-tetrac (NDAT; Nanotetrac) on PD-L1 mRNA abundance (qPCR) and PD-L1 protein content in various cancer cells. Methodologies used are qPCR, Western blot analyses, confocal microscopy, and xenograft. Study Selection: We investigate mechanisms involved in thyroid hormone-induced PD-L1 expression and inhibitory effect of NDAT on thyroid hormone-induced PD-L1 expression. Either blocking thyroid hormone-binding on integrin αvβ3 or using NDAT can inhibit PD-L1 expression. Results: Our studies indicate that thyroid hormone induces PD-L1 expression via activating ERK1/2, PI3K, and STAT3 in different types of cancer cells. NDAT inhibits the cancer cell PI3-K and MAPK signal transduction pathways that are critical to PD-L1 gene expression. Other studies on PubMed also indicate thyroxine's actions are via integrin αvβ3. Conclusions: Thyroid hormone-induced PD-L1 expression not only facilitates cancer cell proliferation but also interferes with chemotherapy. In this current review, we will discuss mechanisms involved in thyroid hormone-induced PD-L1 expression. In addition, role of PD-L1 in thyroid hormone-induced cancer growth and metastasis will be addressed.

Keywords: Cancer proliferation, metastasis, NDAT, programmed death-ligand 1, tetrac, thyroxine


How to cite this article:
Chen YR, Li ZL, Shih YJ, Davis PJ, Whang-Peng J, Lin HY, Wang K. Thyroid hormone, PD-L1, and cancer. J Cancer Res Pract 2019;6:162-9

How to cite this URL:
Chen YR, Li ZL, Shih YJ, Davis PJ, Whang-Peng J, Lin HY, Wang K. Thyroid hormone, PD-L1, and cancer. J Cancer Res Pract [serial online] 2019 [cited 2019 Dec 6];6:162-9. Available from: http://www.ejcrp.org/text.asp?2019/6/4/162/271500




  Introduction Top


The two kinds of thyroid hormone, triiodothyronine (T3) and thyroxine (T4), are tyrosine-based hormones produced by the thyroid gland.[1] The major form of thyroid hormone in the blood is T4, which has a longer half-life than T3. The ratio of T4 to T3 in the serum is around 20:1. Thyroid hormone is either actively pumped into cells or passively transported into cells.[2] Major thyroxine will be deiodinazed by iodothyronine deiodinase 1 (D1) or D2 into triiodothyronine, which is called active thyroid hormone.[3] In addition, D3 converts T4 into reverse T3 (3,3',5'-triiodothyronine, rT3). Thyroid hormone plays a vital role in different physiological functions.[4] However, abnormal concentrations of thyroid hormone may cause side effects. Furthermore, thyroid hormone has been well demonstrated to potentiate cancer cell proliferation even at normal physiological concentration. Several signal transduction pathways and cancer-related molecules have been shown to play an important role in thyroid hormone-induced cancer growth. For example, programmed death-ligand 1 (PD-L1) is involved in cancer immune-surveillance and cancer proliferation.[5] In this review article, we will discuss the role of PD-L1 in thyroid hormone-induced cancer growth and metastasis.


  Thyroid Hormone Receptors and Functions Top


Thyroid hormone, mainly triiodothyronine, can increase cell metabolism[4] and facilitate normal growth and mental development.[6] In addition, triiodothyronine increases heart rate, cardiac contractility, and cardiac output[7] in all physiological activities in every organ. Thyroid hormone has been classified as a steroid hormone, although it does not have a steroid hormone basic structure.[8]

Classical thyroid hormone receptors

There are two types of thyroid hormone receptors, namely TRβ and TRα.[9] TRβ plays important roles in all thyroid hormone-regulated cellular activities.[10] It is also involved in cancer suppression, and TRα plays a role in cancer proliferation.[11] However, mutant TRβ may stimulate cancer growth.[12] Besides, the aberrant expression of TRs may also play a role in carcinogenesis.[13] Nevertheless, there is no conclusive evidence that links the pro-proliferative action of TRs to tumorigenesis. On the other hand, studies by Wang et al. indicated that TRα mutation is linked with the progress of distant (hematogenous) metastasis (P = 0.0084) and high expression level of a nucleoside diphosphate kinase, nonmetastatic clone 23 (Nm23) protein (P = 0.020) in gastric cancer. Their conclusion suggests that interactions between the TR α and Nm23 genes may play a role in hematogenous metastasis in gastric cancer.[14] The TRα locus also experiences loss of heterozygosity in breast cancer frequently.[15] The rearrangement of the TR α gene may occur in leukemia, breast cancer, and gastric cancer.[15] The roles of TRs in cancer growth are shown in [Figure 1].
Figure 1: Schematic diagram of the proposed mechanism of thyroid hormones in regulating cancer cell proliferation. T4, and to a lesser extent, T3 bind to integrin avβ3 to activate ERK1/2 phosphorylation and then stimulate cancer cell proliferation. T3 binds to integrin avβ3 to activate not only ERK1/2 phosphorylation but also PI3K activation. rT3 also binds integrin avβ3 to stimulate cell proliferation. Downstream PI3K/ERK1/2 STAT3 is activated. Activation of ERK1/2, PI3K, or STAT3 is involved in thyroxine-induced PD-L1 expression in different types of cancer cells. PD-L1 has been shown to play a vital role in cancer cell proliferation. T4 can also penetrate cell membrane through active transporters and converted to T3 by deiodinase (D1 or D2). T3 binds to TRβ1, and the consequences are normal thyroid hormone-dependent biological activities which also show anti-proliferative effect in cancer cells. However, the anti-proliferative effect of TRβ1 is reduced by the overexpression of D3 induced by TRa-enhanced β-catenin-dependent mechanisms. When T3 binds to thyroid hormone receptor a1 (TRa1), β-catenin abundance is enhanced and the protein translocates to the nucleus. As a result, it stimulates cell proliferation. In addition, PD-L1 interacts with β-catenin to enhance cancer cell growth. PI3K: Phosphatidylinositol 3-kinase, PD-L1:Programmed death-ligand 1. T3 induced expressions of PD-L1 is still not well demonstrated

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Nonclassical receptor, integrin αvβ3

In addition to the nuclear receptor, cell surface integrin αvβ3 recently has been shown to be a binding site of thyroid hormone.[16],[17],[18] Integrin αvβ3 is a cell surface-binding protein that plays important roles in cell attachment, migration, and interactions with extracellular matrix proteins such as laminin and fibronectin. Not only T4 and T3 but also tetrac binds to integrin αvβ3.[19],[20]In vitro, T4 and T3 act at the integrin receptor through ERK1/2 to support tumor cell proliferation in different types of cancer such as breast, glioma, head and neck, thyroid, ovary, pancreas, kidney, lung, prostate, colon cancer, and oral cancer.[18] In addition, integrin αvβ3 plays an important role in thyroid hormone-induced angiogenesis.[21],[22],[23] In T4-treated cancer cells, monomeric αv is recovered in the nucleus in a complex with pERK1/2, pSTAT1, and p300. Furthermore, it also forms a complex with corepressors, nuclear receptor corepressor, and silencing mediator of retinoic acid and thyroid hormone receptor (SMRT). Nuclear monomeric integrin αv binds to the promoter regions of HIF-1α, COX-2, TRβ1, and ERα. These results suggest that nuclear monomeric integrin αv is a novel coactivator regulated from the cell surface by thyroid hormone for the expression of genes involved in tumorigenesis and angiogenesis.[24]

Actions of thyroid hormone

Actions of thyroid hormone can be classified as nongenomic or genomic based on the involvement of TR-dependent transcription.

Nongenomic actions of thyroid hormone

Nongenomic actions of thyroid hormone begin at the hormone receptor on heterodimeric integrin αvβ3. Although thyroid hormone does not enter cell through binding with integrin αvβ3, it activates integrin downstream ERK1/2. The activated ERK1/2 drives cytoplasmic TRβ1[24] and ERα[25] into the cell nucleus nongenomically, each in a complex with activated pERK1/2. However, the translocated TRβ1 may not be the same as the thyroid hormone bound TRβ1 which is translocated to nuclei as ligand-receptor complex. After interacting with thyroxine, integrin αvβ3 is endocytosed into the cytosol. Only integrin αv monomer translocates to the nucleus and monomer integrin β3 is left in the cytosol.[24] Thyroid hormone can regulate the state of the actin cytoskeleton through a mechanism involving a TRα isoform. From αvβ3, the hormone can also drive intact cytoplasmic TRα1 into the nuclear compartment. Triiodothyronine modifies the activity of the plasma membrane Na+/H+ exchanger acting in the plasma membrane locally.[26] Similarly, triiodothyronine increases cellular membrane Na+, K+-ATPase activity by activating phosphatidylinositol 3-kinase (PI3K/Akt/PKB).

Genomic actions of thyroid hormone

Traditional genomic actions of thyroid hormone start with intranuclear binding of the hormone by heterodimeric nuclear TRs that are transcription factors.[1] T4 serves as a prohormone for T3 in genomic actions of thyroid hormone. Triiodothyronine has ten times higher affinity than thyroxine to TRs.[27] The complex of triiodothyronine bound with TRβ translocates into the nucleus. It sheds corepressors and attracts coactivator proteins. Thyroid hormone, T3 gains access to the nucleus and is bound by TRs to complete the generation of transcriptionally active receptor-hormone-coactivator complexes. On the other hand, thyroxine-induced activated ERK1/2 bound through serine phosphorylation to TRβ1 translocates to nuclei and dissociates with TRs and the corepressor SMRT.[28] Nuclear TRs are partially readied for transcriptional activity genomically in response to nongenomic signaling from hormone at αvβ3.[24] Although thyroid hormone can adjust the functions of plasma membrane Na+/H+ exchanger and Na+, K+-ATPase nongenomically, it can modulate transcription of the iron exchanger gene and sodium pump gene genomically.[1],[29],[30]


  Thyroid Hormone Induces Programmed Death-Ligand 1 Expression Top


Checkpoint PD-1/PD-L1 is an essential regulator of activated T-cell-tumor cell interactions. The checkpoint protects tumor cells against immune destruction. PD-L1 protein generated by tumor cells engages PD-1 to repress activated T-cell engagement with tumor cells. The interaction may also induce apoptosis of T-cells. Overexpression of PD-L1 is observed in melanoma, pancreatic, lung cancer cells, and others. It may correlate with decreased patient survival.

Thyroid hormone plays a significant role to modulate oxidative stress.[31] Hyperthyroidism has been shown to increase reactive oxygen species, the most important pro-oxidants.[32],[33] Thyroxine (T4)-induced expressions of pro-inflammatory genes to moderate inflammatory activities have also been well demonstrated,[34],[35] which may be linked to cancer progression.

Evidence indicates that proinflammatory cytokines, such as transforming growth factor-β (TGF-β)[36],[37] and interleukin-1 (IL-1),[38] can induce PD-L1 expression. Tumor necrosis factor-α (TNF-α) may enhance the adaptive immune resistance mediated by interferon-γ-induced PD-L1 in hepatocellular carcinoma cells.[39] Thyroid hormone induces PD-L1 expression and abundance of PD-L1 protein in human colon cancer,[40] oral cancer,[41] and ovarian cancer cells.[42] Activation of ERK1/2 and PI3K signal-transducing pathways is critical to the expression of PD-L1 gene in cancer cells.[40],[42] In addition, activated STAT3 plays a role in thyroxine-induced PD-L1 expression[41] [Figure 1].


  Thyroid Hormone Induces Cancer Proliferation Top


Clinical studies support that thyroid hormone is a risk factor for cancer growth and cancer chemotherapy. Altered thyroid hormone status also affects cancer proliferation. Thyroid hormones acting through the integrin αvβ3 receptor are crucial factors in tumor microenvironment affecting the pathophysiology of T-cell lymphoma cells.[43] Mouse xenograft studies of Lewis lung carcinoma cells (3LL) conducted by the Moeller group indicates that thyroxine treatment increases tumor growth.[44] On the other hand, tumor growth is reduced in hypothyroidism. Tumor weight and neoangiogenesis also significantly increase in thyroxine-treated mice.[44] Schmohl et al. also indicate that mesenchymal stem cells (MSCs) show significantly increased recruitment and invasion into tumors of hyperthyroid mice as compared to euthyroid and in particular, hypothyroid mice in a subcutaneous hepatocellular carcinoma (HCC) xenograft model.[6] An increased risk for colon, lung, prostate, and breast cancers with lower thyroid-stimulating hormone defined as a state of subclinical hyperthyroidism has been confirmed in epidemiological studies.[45] These studies suggest that thyroid hormone level affects the occurrence of cancer. Subclinical and clinical hyperthyroidism increases the risk of several solid malignancies, whereas hypothyroidism may reduce aggressiveness or delay the onset of cancer.[46] Indeed, the research indicates that hyperthyroidism may facilitate cancer growth. Moreover, higher thyroid hormone levels link with advanced clinical stage of breast and prostate cancers. In rodent models, thyroid hormone promotes growth and metastasis in xenografts. On the other hand, hypothyroidism has shown to suppress growth and metastasis.[45] In addition, pharmacologic induction of the euthyroid hypothyroxinemic state in advanced cancer patients who maintain normal circulating T3 levels and euthyroidism with a substantial reduction in circulating levels of T4 has been associated with stabilization of the tumor or reduction in tumor size in current clinical observation.[47] Several reports indicate that cancer patients develop hypothyroidism during chemotherapy. Tyrosine kinase inhibitors (TKIs) such as sunitinib are relatively new targeted therapy drugs used in chemotherapy, and hypothyroidism is often a side effect of this treatment.[48] Evidence from several clinical centers indicates that TKI-induced hypothyroidism may beneficially affect tumor course, for example, in renal cell carcinoma.[49] Therefore, future cancer therapy studies with substances that might induce hypothyroidism may need to be conducted in a way that allows for an analysis of thyroid function status and its contribution to treatment outcome.

Decreased nuclear thyroid hormone availability is related to elevated levels of deiodinase DIO3 in basal cell carcinomas as compared to that in normal keratinocytes, and increased DIO3 probably enhances the proliferation rate.[50] DIO3 expression is significantly higher in benign adenomas and colon carcinomas than in normal tissues. However, it is negatively correlated with the histologic grade of the lesions. Catenins are proteins involved in cell-cell adhesion. β-Catenin also has transcriptional functions in the nucleus. DIO3 is a direct transcriptional target of the β-catenin/TCF complex. Attenuation of β-catenin reduces D3 levels and induces D2, thereby increasing T3-dependent transcription.[51] In the absence of DIO3, supraphysiological concentration of T3 decreases cell proliferation and stimulates differentiation in cultured cells and xenograft mouse models. Thus, DIO3 may be a marker of the early stages of tumorigenesis.[50] Hepatic hemangiomas show high DIO3 activity resulting in an accelerated rate of thyroid hormones degradation.[52],[53] Although epidemiologic studies suggest the role of DIO2 in thyroid hormone-induced development of colon cancer cell remains vague, studies by Kojima et al. indicate that stromal DIO2 promotes the growth of intestinal tumors in ApcΔ716 mutant mice[54] and indicates the essential roles of stromal DIO2 and thyroid hormone signaling in promoting the growth of intestinal tumors.

Finally, reverse T3 is defined for the long term as an inactive naturally occurring analog of thyroid hormone. It is produced through DIO3. As other members of thyroid hormone family, rT3 binds to integrin αvβ3 to initiate signal transduction and to increase cancer proliferationin vitro of 50%–80% (P< 0.05–0.001) of human breast cancer and glioblastoma cells.[20] Thus, rT3 may be a host factor supporting cancer growth.


  Thyroid Hormone Promotes Angiogenesis Top


Angiogenesis is a highly regulated process to form new blood vessels from the existing vasculature. It is controlled by angiogenic factors.[55],[56] It responds to specific stimuli such as hypoxia and inflammation. In addition, angiogenesis is strictly related to tumor progression. It not only sustains tumor growth by providing oxygen and other nutrients but also facilitates metastasis. Angiogenesis can be promoted by cancer cell released vascular growth factors and their specific receptors on the endothelial cell surface that then transduce specific signals into angiogenesis-related events.

Generally, vascular endothelial growth factor (VEGF) stimulates angiogenesis under normal physiologic conditions and in the tumor environment. VEGF starts angiogenic procedure by stimulating the proliferation of endothelial cells, promoting their migration and mediating vascular permeability.[57],[58] Other major proangiogenic vascular growth factors include fibroblast growth factor 2 (FGF2 or basic fibroblast growth factor), platelet-derived growth factor, and angiopoietins.[59] In addition, other less specific factors such as epidermal growth factor, TGF-α and -β, and cytokines such as IL-1, IL-6, and IL-8, and their respective receptors may also contribute to the angiogenic process. On the other hand, thrombospondin 1 (THBS1), angiostatin, and endostatin are endogenous inhibitors of angiogenesis, which have been shown to inhibit the formation of new blood vessels.[56] These angiogenesis-relevant factors are produced by tumor cells, endothelial cells themselves, and by cells of the tumor stroma such as cancer-associated fibroblasts, pericytes, and infiltrating immune cells.[56]

Thyroid hormones, T3 and T4, stimulate new blood vessel formation in the chick chorioallantoic membrane (CAM) angiogenesis model,[21] and T4 shows greater activity at physiological concentration. Agarose-T4 is also able to stimulate angiogenic effect in CAM assay, suggesting that thyroid hormone may not enter cells to stimulate angiogenesis. The blockage of FGF2 by antibody against FGF2 abrogates T4-stimulated suggesting that the pro-angiogenic effect of T4 is partially mediated by increased FGF2 expression. Finally, blockage of ERK1/2 pathway completely abolishes thyroid hormone-induced angiogenesis. Both T3 and T4 increase myeloma adhesion to fibronectin and induce αvβ3 clustering.[60] In addition, hormones induce MMP9 expression.[60] Thyroid hormone negatively modulates aminopeptidase (AP) activity in the tumor. Accordingly, blockade of the membrane thyroid hormone receptor αvß3 integrin reduces tumor weight associated with an increase in VEGF, AP and AP activity.[61] Specifically, thyroid hormone-activated αvβ3 integrin signaling promoted T-cell lymphoma cells proliferation and induced angiogenic program through up-regulation of VEGF.[43] Interestingly, Moeller' group point out that T4 did not stimulate 3LL cell proliferationin vitro but promoted cancer growth in mouse xenograft. Put together, results suggest that T4 induces tumor-promoting effect to increase neoangiogenesis rather than directly stimulate Lewis lung carcinoma cell growth.[44]


  Expression of Programmed Death-Ligand 1 Is Essential for Cancer Cell Proliferation Top


Thyroxine has been shown to promote cancer cell proliferation through a receptor on plasma membrane integrin αvβ3. Integrin αv acts as a transcriptional factor, which is essential for the expression of thyroxine-dependent genes. Thyroxine induces PD-L1 expression through the activation of ERK1/2 and STAT3 in cancer cells. In addition, it also stimulates cancer cell proliferation. PD-L1 is involved in thyroid hormone-dependent cancer growth through the activation of ERK1/2, PI3K, and STAT3. Besides, PD-L1 may play a role in thyroxine-induced interference with the efficacy of anti-cancer therapy. Short hairpin PD-L1 RNA knocks down PD-L1 accumulation and inhibits proliferative gene PCNA and MCL-1 expression. Meanwhile, it increases THBS1 and CASP2 expression and blocks cancer cell proliferation.

PD-L1 is upregulated in colon cancer cells independent of the cellular p53 status.[62] PD-L1 blockade attenuates metastatic colon cancer growth in cAMP-response element-binding protein-binding protein/β-catenin inhibitor-treated livers.[63] Mutation and overexpression of β-catenin gene occur in a variety of cancers, including colon carcinoma, breast, and ovarian cancer.[64],[65] FGF receptor 2 (FGFR 2) causes tyrosine kinase domains to initiate a cascade of intracellular signals by binding to FGFs and dimerization (pairing of receptors), which is involved in tumorigenesis and progression. Positively correlated overexpression of PD-L1 and FGFR2 are frequently observed in colon cancers.[66] In addition, the expression of FGFR2 is significantly associated with lymph node metastasis and poor survival.[66] Tumor-derived-activated FGFR2 induces PD-L1 expression through JAK/STAT3 signaling pathway in human colon cancer cells (SW480 and NCI-H716), which induces apoptosis of Jurkat T cells. FGFR2 also promotes the expression of PD-L1 in a xenograft mouse model of colon cancers.[66] PD-L1 protein expression is associated with shorter survival in 12,505 patient cohort studies.[67] An elevated PD-L1 expression significantly correlates with high-risk prognostic indicators and decreased survival in patients with breast cancer.[67] Recently, our studies indicate that thyroid hormone-induced PD-L1 traps resveratrol-induced COX-2 accumulation in the cytosol and interferes with resveratrol-induced anti-proliferation.[42]


  Thyroxine Analog Derivatives Inhibit Thyroid Hormone-Induced Programmed Death-Ligand 1 Expression and Cancer Progress Top


Thyroxine deaminated analog (3,3', 5, 5'-Tetraiodothyroacetic acid) and its nanoparticulate derivative has been shown to block thyroid hormone-induced cancer growth. Interestingly, we have shown not only thyroid hormone but also NDAT binds to integrin αvβ3 as receptors, although NDAT generally inhibits constitutive ERK1/2 activation in most cancer cells, except in colon cancer HT29 cells.[19] Blocked activation of ERK1/2, PI3K, and STAT3 by NDAT inhibits PD-L1 expression by thyroid hormone[35],[40],[41] [Figure 2]. Tetrac and NDAT can inhibit thyroid hormone-induced proliferation and angiogenesis of different types of cancer cells in cell cultures and xenograft animal models.[18] Tetrac almost completely to eliminate MSC recruitment in a subcutaneous HCC xenograft model.[6] Tetrac and NDAT inhibit expression in tumor cells of cytokine genes, for example, specific ILs, and chemokine genes such as fractalkine (CX3CL1) and chemokine receptor genes (CX3CR1). Those genes have been identified as proinflammatory effectors of cancer progression. The possibility is also examined that tetrac and NDAT affect the function of inflammatory cells. Microarray studies conducted with NDAT in human breast cancer (MDA-MB-231) cells revealed a coherent proapoptosis pattern of gene expression. NDAT inhibits transcription of the X-linked inhibitor of apoptosis (XIAP) gene but upregulates a set of proapoptotic genes, including CASP2, CAP8AP2, DFFA, and BCL2 L14.[17],[68] Tetrac and NDAT suppress the expression of MMP2 and MMP9, which are induced by thyroid hormone.[60],[69],[70] NDAT increases the transcription of CBY1 gene,[69] the gene product, Chibby, of which is an inhibitor of nuclear functions of β-catenins.[70] The blockage of β-catenin-dependent transcription may play an important role in inhibiting PD-L1 expression.
Figure 2: Effect of thyroid hormone (T4) and NDAT on induction of PD-L1 expression in human cancer cells. (a) Colon cancer cell HT-29 cells, (b) Colon cancer cell HCT116 cells, (c) Breast cancer MDA-MB-231 cells, and (d) Oral cancer OEC-M1 cells were treated with 10 - 7 M T4, 10 - 7 M NDAT or combination for 24 h. Total RNA was extracted and qPCR of PD-L1 was performed. Number of independent experiments (n) for each figure (a-d) =3. A Student's t-test was used to assess statistical significance. Data are expressed as mean ± standard deviation; *P < 0.05, **P < 0.01, ***P < 0.001, compared with untreated control.#P < 0.05,##P < 0.01,###P < 0.001 compared groups with and without NDAT treatment. PD-L1:Programmed death-ligand 1, qPCR: quantitative polymerase chain reaction

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  Summary Remark Top


Although thyroid hormone plays important roles in maintaining normal biological activities at abnormal or even normal physiological concentrations, it might cause pathogenic effects. Recent research indicates that thyroid hormone may stimulate cancer growthin vitro and in vivo. Furthermore, thyroid hormone induces PD-L1 expression and this accumulation increases cancer resistance to anti-cancer therapy. NDAT promotes apoptosis, antagonizes anti-apoptotic (survival) defenses, disrupts control of the cell cycle, and interferes with the function of frequently mutated catenins.[17],[68],[71] As noted above in the review of angiogenesis, thyroid hormone and tetrac or its NDAT formulation affect matrix metalloproteinase gene expression. We would also note that thyroid hormone (T4) has protein-trafficking action on integrin αvβ3, directing internalizing the membrane protein – without the hormone ligand – with subsequent and nuclear uptake of the αv monomer but not β3. In the nuclear compartment, αv is a coactivator[24] involved in the transcription of several important cancer-relevant genes. The coherence of the effects of the agent on the expression of differentially regulated cancer cell genes is remarkable. NDAT has been shown to have antiproinflammatory effects and anti-PD-L1 expression. It may be a therapeutic strategy to include NDAT to reduce endogenous hormone effects on PD-L1 expression, which may interfere with chemotherapy.

Acknowledgments

Studies from our group described in this review article were supported in part by Research Award from Dr. Ta-Cheng Tung Foundation, by Chair Professor Research Fund to Dr. J Whang-Peng and Dr. K. Wang, by the “TMU Research Center of Cancer Translational Medicine” from The Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education (MOE) in Taiwan, by a gift from Dr. Paul J. Davis to Albany College of Pharmacy and Health Sciences, and by a general grant of Ministry of Science and Technology Taiwan (MOST108-2314-B-038-050 to H.Y. Lin, MOST108-2119-M-038-001 to J. Whang-Peng). The authors would like to extend their sincerest appreciation to Hsuan-Yu, Zi-Lin, ABu, and Ya-Jung for their prodigious contribution to research described in this review article. We thank Dr. Dana R. Crawford (Albany Medical College, Albany, NY) for critically reading the manuscript.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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