The Intriguing Thyroid Hormones-Lung Cancer Association as Exemplification of the Thyroid Hormones-Cancer Association: Three Decades of Evolving Research

Abstract

Exemplifying the long-pursued thyroid hormones (TH)-cancer association, the TH-lung cancer association is a compelling, yet elusive, issue. The present narrative review provides background knowledge on the molecular aspects of TH actions, with focus on the contribution of TH to hallmarks of cancer. Then, it provides a comprehensive overview of data pertinent to the TH-lung cancer association garnered over the last three decades and identifies obstacles that need to be overcome to enable harnessing this association in the clinical setting. TH contribute to all hallmarks of cancer through integration of diverse actions, currently classified according to molecular background. Despite the increasingly recognized implication of TH in lung cancer, three pending queries need to be resolved to empower a tailored approach: (1) How to stratify patients with TH-sensitive lung tumors? (2) How is determined whether TH promote or inhibit lung cancer progression? (3) How to mimic the antitumor and/or abrogate the tumor-promoting TH actions in lung cancer? To address these queries, research should prioritize the elucidation of the crosstalk between TH signaling and oncogenic signaling implicated in lung cancer initiation and progression, and the development of efficient, safe, and feasible strategies leveraging this crosstalk in therapeutics.

Keywords: genomic actions; integrin αvβ3; lung cancer; non-small cell lung cancer; non-thyroidal illness syndrome; nongenomic actions; tetrac; thyroid hormone receptors; thyroid hormones.

Figure 1

The main signaling cascades implicated in the four types of TH actions. A. Type 1 comprises the nuclear TRs-dependent TH actions, induced by recruitment of TRs to TREs. Binding of T3 (represented by the brown triangle) to TRs results in dissociation of CoR from the TR/RXR hetero-dimers and recruitment of CoA, inducing target gene transcription. B. Type 2 comprises the TRs-dependent actions of TH exerted through tethering to other chromatin proteins binding of T3-bound TRs to DNA. C. Type 3 TH actions comprises the nuclear TRs-independent TH actions exerted through direct or indirect binding to DNA. Especially, interaction of T3 with cytoplasmic TRs or with the truncated TRα isoforms p30 TRα1 at the plasma membrane stimulates signaling transduction that results in promotion of transcription; D. Type 4 comprises various nuclear TRs-independent TH actions as follows. D1. Binding of T3 to integrin αvβ3 activates the Src/PI3K/Akt pathway, leading to the shuttling of cytoplasmic TRα to the nucleus, promoting transcription. D2. Binding of T4 (represented by the green rhombus) and of T3 to integrin αvβ3 activates PI3K/Akt and MAPK)/ERK1/2 pathways via PLCP and KCα. Activated MAPK induces the sodium proton ex-changer (Na⁺/H⁺), increases activity of the sodium pump (Na, K-ATPase), and modulates intracellular protein trafficking of proteins, such as ERα and TRβ1, from the cytoplasm to nucleus, promoting the transcription. Activated PI3K transduces also signaling that promotes transcription. D3. Type 4 includes also the TH actions on polymerization of actin. D4. Type 4 includes the action of T3 as regulator of Crym. Abbreviations: A, sodium pump Na, K-ATPase; Akt/protein kinase B (PKB); AP, actin polymerization; CoA, coactivators; CoR, corepressors E, sodium proton exchanger (Na⁺/H⁺); ERK, extracellular signal-regulated kinase; P, proteins; PI3K, PKCα, protein kinase Cα; PLC, phospholipase C; PKGII, type II cGMP-dependent protein kinase; MAPK, mitogen-activated protein kinase; mTOR, mammalian target of rapamycin; NOS nitric oxide synthase; NP, nucleoproteins; RXR, retinoic acid X receptor; TR, thyroid hormone receptor; TRα1, TRalpha isoform 1; TRβ1, TRbeta isoform 1; TREs, thyroid response elements.

Figure 2

The contribution of TH to cancer hallmarks and the major involved signaling pathways. TH contributes to all the properties of cancer cells known as hallmarks of cancer, namely, to (i) proliferation, predominantly through SHH, UHRF1, mTOR, Ras, and E2F1; (ii) invasion/metastasis, predominantly through TSP-1, TSP-2, MMPs, miRNA, ERK1/2, and Wnt/β catenin; (iii) angiogenesis, predominantly through AGP-2 FGF VEGF, HIF-1α, and FGF; (iv) immune response, predominantly through PD-1 and PD-L1; (v) evasion of apoptosis, predominantly through BAX, p53, p21, cfos/cjun, XIAP, and BcLx-s; (vi) reprogramming of metabolism of cancer cells, predominantly through PKM2, KLF; and (vii) inflammation, predominantly through CXCR4, NF-κB, NLRP3, ROS, TLR4, HIF-1α, COX-2, MAPK, and PI3K. Abbreviations: AGP-2, angiopoietin 2, BAX, BcL-2 Associated X; COX-2, and cyclooxygenase 2; CXCR4, C-X-C motif chemokine receptor 4; E2F1, E2F Transcription Factor 1; ERK1/2, extracellular signal-regulated kinase 1/2; FGF, fibroblast growth factor 2; HIF-1α, hypoxia inducible factor 1; MAPK, mitogen-activated protein kinase; miRNA, microRNA; MMPs, matrix metalloproteinases; mTOR, mammalian tar-get of rapamycin; NF-κB, nuclear factor-κB; NLRP3, NLR Family Pyrin Domain Containing 3; TLR4, Toll Like Receptor 4; PD-1, programmed cell death protein 1; PD-L1, PD ligand 1; PI3K, phosphatidylinositol 3-kinase; PKM2, M2 isoform of the pyruvate kinase; ROS, reactive oxygen species; SHH, sonic hedgehog; TGFa, transforming growth factor alpha; TSP, Thrombospondin; UHRF1, ubiquitin-like with PHD and ring finger domains 1; VEGF, vascular endothelial growth factor; XIAP, X-linked inhibitor of apoptosis Wnt, a fusion of the words wingless and integrated or int-1.

Figure 3

The pending queries and the main corresponding research priorities relevant to a tailored approach to the TH–lung cancer association. The tertiles of the pie depict the three pending queries, and the corresponding rectangles depict the corresponding research priorities. To stratify patients with TH-sensitive lung tumors and to clarify the dual role of TH in lung cancer, the research priorities are similar and include identification of patient-/cancer-specific biomarkers/risk factors, transcriptional profiling of TH signaling cross-talking with oncogenic signaling, exploration of the metabolome signature of TH status to assess precisely the intracellular and intratissue TH status, and well-designed clinical studies. To leverage the TH-lung cancer association in the clinical setting, the research priorities include exploration of interventions in TH as anticancer strategies, such as euthyroid hypothyroxinemia or administration of LT3 instead of LT4 to treat hypothyroidism; development of thyromimetics and TH antagonists; exploration of the anticancer potential of tetrac, NDAT, and resveratrol; and establishment of combinations of interventions in TH with targeted therapies. Abbreviations: LT3, liothyronine; LT4, levothyroxine; NDAT, nano-diamino-tetrac; TH, thyroid hormones.