Impact of the thyroid hormone T3 and its nuclear receptor TRα1 on colon cancer stem cell phenotypes and response to chemotherapies.

Colorectal cancers (CRCs) are highly heterogeneous and show a hierarchical organization, with cancer stem cells (CSCs) responsible for tumor development, maintenance, and drug resistance. Our previous studies showed the importance of thyroid hormone-dependent signaling on intestinal tumor development and progression through action on stem cells. These results have a translational value, given that the thyroid hormone nuclear receptor TRα1 is upregulated in human CRCs, including in the molecular subtypes associated with CSC features.

Regulation of the THRA gene, encoding the thyroid hormone nuclear receptor TRα1, in intestinal lesions.

The THRA gene, encoding the thyroid hormone nuclear receptor TRα1, is expressed in an increasing gradient at the bottom of intestinal crypts, overlapping with high Wnt and Notch activities. Importantly, THRA is upregulated in colorectal cancers, particularly in the high-Wnt molecular subtype. The basis of this specific and/or altered expression pattern has remained unknown.

Thyroid hormone signaling in the intestinal stem cells and their niche.

Several studies emphasized the function of the thyroid hormones in stem cell biology. These hormones act through the nuclear hormone receptor TRs, which are T3-modulated transcription factors. Pioneer work on T3-dependent amphibian metamorphosis showed that the crosstalk between the epithelium and the underlying mesenchyme is absolutely required for intestinal maturation and stem cell emergence.

Thyroid Hormone Signaling and Function: News from Classical and Emerging Models.

According to Brown and Cai, Thyroid hormones (THs) have been considered "the first developmental morphogen ever discovered" [...

Thyroid Hormone Nuclear Receptor TRα1 and Canonical WNT Pathway Cross-Regulation in Normal Intestine and Cancer.

A pivotal role of thyroid hormones and their nuclear receptors in intestinal development and homeostasis have been described, whereas their involvement in intestinal carcinogenesis is still controversial. In this perspective article we briefly summarize the recent advances in this field and present new data regarding their functional interaction with one of the most important signaling pathway, such as WNT, regulating intestinal development and carcinogenesis. These complex interactions unveil new concepts and will surely be of importance for translational research.

Musashi1 Contribution to Glioblastoma Development via Regulation of a Network of DNA Replication, Cell Cycle and Division Genes.

RNA-binding proteins (RBPs) function as master regulators of gene expression. Alterations in their levels are often observed in tumors with numerous oncogenic RBPs identified in recent years. Musashi1 (Msi1) is an RBP and stem cell gene that controls the balance between self-renewal and differentiation.

Murine intestinal stem cells are highly sensitive to modulation of the T3/TRα1-dependent pathway.

The thyroid hormone T3 and its nuclear receptor TRα1 control gut development and homeostasis through the modulation of intestinal crypt cell proliferation. Despite increasing data, in-depth analysis on their specific action on intestinal stem cells is lacking. By using ex vivo 3D organoid cultures and molecular approaches, we observed early responses to T3 involving the T3-metabolizing enzyme Dio1 and the transporter Mct10, accompanied by a complex response of stem cell- and progenitor-enriched genes.

Deciphering the Role of Intestinal Crypt Cell Populations in Resistance to Chemotherapy.

Intestinal crypts are composed of heterogeneous and highly plastic cell populations. Lgr5-stem cells (SC) are responsible for homeostatic renewal, but other cells can revert to an SC-like phenotype to maintain epithelial integrity. Despite their distinct roles in orchestrating homeostasis, both populations have been designated as the putative "cell-of-origin" of colorectal cancer.

A Three-dimensional Model of Spheroids to Study Colon Cancer Stem Cells.

Colorectal cancers are characterized by heterogeneity and a hierarchical organization comprising a population of cancer stem cells (CSCs) responsible for tumor development, maintenance, and resistance to drugs. A better understanding of CSC properties for their specific targeting is, therefore, a pre-requisite for effective therapy. However, there is a paucity of suitable preclinical models for in-depth investigations.

MAVS deficiency induces gut dysbiotic microbiota conferring a proallergic phenotype.

Prominent changes in the gut microbiota (referred to as "dysbiosis") play a key role in the development of allergic disorders, but the underlying mechanisms remain unknown. Study of the delayed-type hypersensitivity (DTH) response in mice contributed to our knowledge of the pathophysiology of human allergic contact dermatitis. Here we report a negative regulatory role of the RIG-I-like receptor adaptor mitochondrial antiviral signaling (MAVS) on DTH by modulating gut bacterial ecology.

Increased expression of the thyroid hormone nuclear receptor TRα1 characterizes intestinal tumors with high Wnt activity.

Our previous work demonstrated a key function of the thyroid hormone nuclear receptor TRα1, a T3-modulated transcription factor, in controlling intestinal development and homeostasis the Wnt and Notch pathways. Importantly, increased expression of TRα1 in the intestinal epithelium in a mutated genetic background (-TRα1/Apc mice) accelerated tumorigenesis and contributed to a more aggressive tumor phenotype compared to that of the mutants alone. Therefore, the aim of this study was to determine the relevance of this synergistic effect in human colorectal cancers and to gain insights into the mechanisms involved.

Deletion of Stearoyl-CoA Desaturase-1 From the Intestinal Epithelium Promotes Inflammation and Tumorigenesis, Reversed by Dietary Oleate.

Background & Aims: The enzyme stearoyl-coenzyme A desaturase 1 (SCD or SCD1) produces monounsaturated fatty acids by introducing double bonds into saturated bonds between carbons 9 and 10, with oleic acid as the main product. SCD1 is present in the intestinal epithelium, and fatty acids regulate cell proliferation, so we investigated the effects of SCD1-induced production of oleic acid in enterocytes in mice.

Methods: We generated mice with disruption of Scd1 selectively in the intestinal epithelium (iScd1 mice) on a C57BL/6 background; iScd1 mice were used as controls.

In Vitro Approaches to Identify Thyroid Hormone Receptor-Dependent Transcriptional Response.

The thyroid hormones act through their nuclear receptor TRs that are T3-modulated transcription factors. To elucidate the molecular mechanisms at the basis of specific physiological responses to TH-TR, in vitro approaches are commonly used to demonstrate the activation or repression of target genes. These approaches allow identifying direct transcriptional targets of TRs which can eventually be confirmed by using in vivo chromatin binding assays.

Thyroid Hormone Receptors: Several Players for One Hormone and Multiple Functions.

Thyroid hormone receptors (TRs) were cloned based on their homology with the retroviral oncogene v-ERBA. In Vertebrates two genes, THRA and THRB, encode respectively many isotypes and isoforms of receptors TRα and TRβ, resulting from alternative splicing and/or internal transcription start sites. We present here a wide overview of this diversity and of their mechanisms of action as transcription regulators, as well as alternative actions through cytoplasmic signaling.

CRISPR/Cas9 Editing of the Mouse Thra Gene Produces Models with Variable Resistance to Thyroid Hormone.

Background: Resistance to thyroid hormone due to THRA mutations (RTHα) is a recently discovered genetic disease, displaying important variability in its clinical presentation. The mutations alter the function of TRα1, one of the two nuclear receptors for thyroid hormone.

Methods: The aim of this study was to understand the relationship between specific THRA mutations and phenotype.

Thyroid hormone regulation of intestinal epithelial stem cell biology.

The gastrointestinal tract is a well-characterized target of thyroid hormones and thyroid hormone nuclear receptors TRs, as extensively described in the literature. The paradigm is its important remodelling in amphibians during thyroid hormone-dependent metamorphosis. Interestingly, several studies have described the conservation of this hormonal signal during intestinal development in mammals.

The thyroid hormone nuclear receptors and the Wnt/β-catenin pathway: An intriguing liaison.

The thyroid hormones, T3 and T4, control several developmental and homeostatic processes. From a molecular point of view, most of their actions depend on the activity of the thyroid hormone nuclear receptors (TRs), which are T3-modulated transcription factors. Recent studies have not only highlighted that the physiological response induced by T3 within a cell depends on the expression of specific TRs, but also that the functions of TRs are coordinated by and integrated in other signalling pathways.

T3/TRs axis in hepatocellular carcinoma: new concepts for an old pair.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide, and its burden is expected to further increase in the next years. Chronic inflammation, induced by multiple viruses or metabolic alterations, and epigenetic and genetic modifications, cooperate in cancer development via a combination of common and distinct aetiology-specific pathways. In spite of the advances of classical therapies, the prognosis of this neoplasm has not considerably improved over the past few years.

The thyroid hormone nuclear receptor TRα1 controls the Notch signaling pathway and cell fate in murine intestine.

Thyroid hormones control various aspects of gut development and homeostasis. The best-known example is in gastrointestinal tract remodeling during amphibian metamorphosis. It is well documented that these hormones act via the TR nuclear receptors, which are hormone-modulated transcription factors.

The secreted Frizzled-Related Protein 2 modulates cell fate and the Wnt pathway in the murine intestinal epithelium.

The secreted Frizzled-Related Proteins (sFRPs) are generally considered antagonistic to Wnt signaling. However, several studies have described their synergy and/or activation of this pathway. Our own data indicated that in the intestinal epithelium, thyroid hormone induced-expression of sFRP2 stabilizes β-catenin, leading to induction of Wnt.

Thyroid hormones and their nuclear receptors: new players in intestinal epithelium stem cell biology?

Thyroid hormones participate in the development and homeostasis of several organs and tissues. It is well documented that they act via nuclear receptors, the TRs, which are transcription factors whose function is modulated by the hormone T3. Importantly, T3-induced physiological response within a cell depends on the specific TR expression and on the T3 bioavailability.