The role of thyroid hormone signaling in the prevention of digestive system cancers

Abstract

Thyroid hormones play a critical role in the growth and development of the alimentary tract in vertebrates. Their effects are mediated by nuclear receptors as well as the cell surface receptor integrin αVβ3. Systemic thyroid hormone levels are controlled via activation and deactivation by iodothyronine deiodinases in the liver and other tissues. Given that thyroid hormone signaling has been characterized as a major effector of digestive system growth and homeostasis, numerous investigations have examined its role in the occurrence and progression of cancers in various tissues of this organ system. The present review summarizes current findings regarding the effects of thyroid hormone signaling on cancers of the esophagus, stomach, liver, pancreas, and colon. Particular attention is given to the roles of different thyroid hormone receptor isoforms, the novel integrin αVβ3 receptor, and thyroid hormone-related nutrients as possible protective agents and therapeutic targets. Future investigations geared towards a better understanding of thyroid hormone signaling in digestive system cancers may provide preventive or therapeutic strategies to diminish risk, improve outcome and avert recurrence in afflicted individuals.

Figure 1

Current overview of the effects of TH signaling in liver cancers. T₃/T₄ was found to decrease cell proliferation by inducing the expression of tumor suppressors DKK4 and TGF-beta, while coincidentally suppressing the expression of proto-oncogenic SP1. Similarly, T₃ bound to TRβ1 was observed to inhibit the proliferative effects of growth factors and to promote mesenchymal-to-epithelial (MET) transition. The promotion of TH signaling leading to invasion and metastasis may occur through TH-induced TGF-β activation of furin expression and of TRβ1-associated decreased expression of the anti-metastatic protein NM23.

Figure 2

Schematic representation of downstream effects due to T₃/T₄ binding to distinct receptors in colorectal cancer. When bound to TRα1, TH induces sFRP2, in turn activating β-catenin and cellular proliferation. Colon β-catenin expression is reduced by selenium intake, and can induce expression of D3, which then antagonizes the anti-proliferative effects of T₃ (possibly through interactions with TRβ1). TRβ1 is associated with cellular differentiation and reduced metastasis. The TH surface receptor integrin αvβ3, on the other hand, is associated with reduced CRC survival and increased metastasis.