32 research outputs found
Disorders of H2O2 generation
No full textAfter the identification of thyroid H2O2 generation system (DUOX) and of its maturation factors (DUOXA), defects in DUOX2 and/or DUOXA2 were rapidly recognized as the possible cause of congenital hypothyroidism (CH) due to thyroid dyshormonogenesis. The present Review reports data on the prevalence of DUOX2 mutations, which is variable among different series but invariably high, pointing to DUOX2 defects as one of the leading causes of dyshormonogenesis. Differently, DUOXA defects seem to be rarely involved in the pathogenesis of CH. Genotype-phenotype correlations are also reported, highlighting the great intra- and inter-familial phenotype variability which appears to be a constant feature of the defects in the H2O2 generation systems. Finally, the hypotheses to explain the phenotypic variability of the DUOX2/A2
mutations are discussed, such as the existence of other H2O2 generating systems, the age variability in thyroid hormones requirements, the differences in ethnicity, in iodine intake, and in the methodological approaches
Update on Fundamental Mechanisms of Thyroid Cancer
No full textThe incidence of thyroid cancer (TC) has increased worldwide over the past four decades. TC is divided into three main histological types: differentiated (papillary and follicular TC), undifferentiated (poorly differentiated and anaplastic TC), and medullary TC, arising from TC cells. This review discusses the molecular mechanisms associated to the pathogenesis of different types of TC and their clinical relevance. In the last years, progresses in the genetic characterization of TC have provided molecular markers for diagnosis, risk stratification, and treatment targets. Recently, papillary TC, the most frequent form of TC, has been reclassified into two molecular subtypes, named BRAF-like and RAS-like, associated to a different range of cancer risks. Similarly, the genetic characterization of follicular TC has been proposed to complement the new histopathological classification in order to estimate the prognosis. New analyses characterized a comprehensive molecular profile of medullary TC, raising the role of RET mutations. More recent evidences suggested that immune microenvironment associated to TC may play a critical role in tumor invasion, with potential immunotherapeutic implications in advanced and metastatic TC. Several types of ancillary approaches have been developed to improve the diagnostic value of fine needle aspiration biopsies in indeterminate thyroid nodules. Finally, liquid biopsy, as a non-invasive diagnostic tool for body fluid genotyping, brings a new prospective of disease and therapy monitoring. Despite all these novelties, much work remains to be done to fully understand the pathogenesis and biological behaviors of the different types of TC and to transfer this knowledge in clinical practice
Combined Mutational and Clonality Analyses Support the Existence of Intra-Tumor Heterogeneity in Papillary Thyroid Cancer
No full textDespite its potential clinical impact, intra-tumor genetic heterogeneity (ITH) has been scantly investigated in papillary thyroid cancer (PTC). We studied ITH in PTC by combining, for the first time, data derived from the evaluation of the normalized allelic frequencies (NAF) of the mutation/s, using a customized MassARRAY panel, and those obtained by the HUMARA clonality assay. Among tumors with a single mutation, 80% of cases with NAF 50 +/- 5% were clonal, consistent with the presence of a single mutated clone, while 20% of cases showed a polyclonal pattern, suggesting the presence of the same mutation in two or more clones. Differently, all cases with NAF < 45% were polyclonal. Among tumors with double mutation, cases with both mutations showing NAF 50 +/- 5% were monoclonal, consistent with the presence of a single clone harboring both mutations. On the other hand, all cases with double mutation at NAF < 45% were polyclonal, indicating the presence of two clones with different mutations. Finally, no significant differences in the clinico-pathological characteristics were found between monoclonal and polyclonal tumors. In conclusion, the present study adds insights into the concept of ITH in PTC, which warrants attention because the occurrence of this phenomenon is likely to affect the response to targeted drugs
Genetics and management of congenital hypothyroidism
No full textSeveral evidences support a relevant genetic origin for Congenital Hypothyroidism (CH), however familial forms are uncommon. CH can be due to morphogenetic or functional defects and several genes have been originally associated either with thyroid dysgenesis or dyshormonogenesis, with a highly variable expressivity and a frequently incomplete penetrance of the genetic defects. The phenotype-driven genetic analyses rarely yielded positive results in more than 10% of cases, thus raising doubts on the genetic origin of CH. However, more recent unsupervised approaches with systematic Next Generation Sequencing (NGS) analysis revealed the existence of hypomorphic alleles of these candidate genes whose combination can explain a significant portion of CH cases. The co-segregation studies of the hypothyroid phenotype with multiple gene variants in pedigrees confirmed the potential oligogenic origin of CH, which finally represents a suitable explanation for the frequent sporadic occurrence of this disease
Canagliflozin reduces thyroid cancer cells migration in vitro by inhibiting CXCL8 and CCL2: An additional anti-tumor effect of the drug
No full textPurpose: Canagliflozin exert anti-cancer effects in several types of cancer including thyroid cancer (TC). However, whether it could modulate chemokines secreted in TC microenvironment is still unknown. The aim of the present study is to evaluate whether Canagliflozin could inhibit pro-tumorigenic chemokines CXCL8 and CCL2 and/or the TC cell migration induced by them.Experimental design: TC cell lines, TPC-1 and 8505C, HUVEC and normal thyroid cells NHT were treated with increasing concentrations of Canagliflozin. Viability was assessed by WST-1 and colony formation/proliferation by cristal violet. Chemokines were measured in cell supernatants by ELISA. mRNAs were evaluated by RT-PCR. TC migration (trans-well) and HUVEC proliferation (cristal violet) were assessed by treating cells with Canagliflozin alone or in combination with CXCL8 or CCL2.Results: Canagliflozin reduced TC, HUVEC and NHT cells viability. The ability to form colonies of TC and the HUVEC proliferation (basal and CXCL8 or CCL2-induced) was also inhibited. mRNA and the secretion of CXCL8 was reduced in all cell types. The secretion of CCL2 was reduced by Canagliflozin in all cell types whereas its mRNA levels were reduced only in TPC-1. IL-6 was reduced in all cell types, while CXCL10 increased. More interestingly the CXCL8 and CCL2-induced TC cell migration as well as HUVEC proliferation was inhibited by Canagliflozin in both cell types.Conclusion: Canagliflozin exerts anti-cancer effects not only by reducing TC viability or colonies formation, but also by modulating two pro-tumorigenic chemokines resulting in reduced TC cells migration. These results expand the spectrum of canagliflozin-promoted anti-cancer effects
Digenic DUOX1 and DUOX2 mutations in cases with congenital hypothyroidism
No full textContext: The DUOX2 enzyme generates hydrogen peroxide (H2O2), a crucial electron acceptor for the TPO-catalyzed iodination and coupling reactions mediating thyroid hormone biosynthesis. DUOX2 mutations result in dyshormonogenetic Congenital Hypothyroidism (CH) which may be phenotypically heterogeneous, leading to the hypothesis that CH severity may be influenced by environmental factors (eg dietary iodine) and oligogenic modifiers (eg variants in the homologous NADPH-oxidase DUOX1). However, loss of function mutations in DUOX1 have not hitherto been described and its role in thyroid biology remains undefined. Case Description: We previously described a Proband and her brother (P1, P2) with unusually severe CH associated with a DUOX2 homozygous nonsense mutation (p.R434*); P1, P2: TSH >100 µU/mL (reference range, RR: 0.5-6.3), P1: Free T4 (FT4) C) resulting in aberrant splicing and a protein truncation (p.Val607Aspfs*43) which segregates with CH in this kindred. Conclusion: This is the first report of digenic mutations in DUOX1 and DUOX2 in association with CH and we hypothesize that the inability of DUOX1 to compensate for DUOX2 deficiency in this kindred may underlie the severe CH phenotype. Our studies provide evidence for a novel digenic basis for CH and support the notion that oligogenicity as well as environmental modulators may underlie phenotypic variability in genetically-ascertained CH
Oxidative Stress Correlates with More Aggressive Features in Thyroid Cancer
No full textOxidative stress (OS) can have an impact in the pathogenesis and in the progression of thyroid cancer. We investigated the levels of reactive oxygen species (ROS) in 50 malignant and benign thyroid lesions and 41 normal tissues, and correlated them with the thyroid differentiation score-TDS and the clinico-pathologic features. NOX4 expression, GPx activity and the genetic pattern of tumors were evaluated. In malignant and benign lesions, ROS generation and NOX4 protein expression were higher than in normal tissues. Follicular (FTCs) and anaplastic/poorly differentiated cancers had increased OS relative to papillary tumors (PTCs). Moreover, OS in FTCs was higher than in follicular adenomas. Mutated PTCs showed increased OS compared with non-mutated PTCs. In malignant tumors, OS was inversely correlated with TDS, and directly correlated with tumor stage and ATA risk. GPx activity was increased in tumors compared with normal tissues, and inversely correlated to OS. In conclusion, our data indicate that thyroid tumors are exposed to higher OS compared with normal tissues, while showing a compensative increased GPx activity. OS correlates with tumor aggressiveness and mutations in the MEK-ERK pathway in PTC. The inverse correlation between OS and TDS suggests that ROS may repress genes involved in thyroid differentiation
