Peroxiredoxins (PRDXs) are a ubiquitously expressed family of small (22–27 kDa) non-seleno peroxidases that catalyze the peroxide reduction of H2O2, organic hydroperoxides and peroxynitrite. They are highly involved in the control of various physiological functions, including cell growth, differentiation, apoptosis, embryonic development, lipid metabolism, the immune response, as well as cellular homeostasis. Although the protective role of PRDXs in cardiovascular and neurological diseases is well established, their role in cancer remains controversial. Increasing evidence suggests the involvement of PRDXs in carcinogenesis and in the development of drug resistance. Numerous types of cancer cells, in fact, are characterized by an increase in reactive oxygen species (ROS) production, and often exhibit an altered redox environment compared with normal cells. The present review focuses on the complex association between oxidant balance and cancer, and it provides a brief account of the involvement of PRDXs in tumorigenesis and in the development of chemoresistance.

Phosphatidylinositol 3-kinase (PI3K) is necessary for thyroid stimulating hormone (TSH)-induced cell cycle progression. To determine the molecular mechanism linking PI3K to TSH, we have identified a serine residue in p85a PI3K phosphorylated by protein kinase A (PKA) in vitro and in vivo. Expression of an alanine mutant (p85A) abolished cyclic AMP/TSH-induced cell cycle progression and was lethal in thyroid cells . The aspartic version of the p85a PI3K (p85D) inhibited apoptosis following TSH withdrawal. The p85a PI3K wild type not the p85A bound PKA regulatory subunit RIIb in cells stimulated with cAMP or TSH. The binding of the aspartic version of p85a PI3K to RIIb was independent of cAMP or TSH stimulation. Similarly, binding of PI3K to p21Ras and activation of AKT, a downstream PI3K target, were severely impaired in cells expressing the p85A mutant. Finally, we found that the catalytic activity of PI3K was stimulated by TSH in cells expressing the wildtype p85a PI3K but not in cells expressing p85A. This latter mutant did not affect the epidermal growth factorstimulated PI3K activity. We suggest that (1) TSHcAMP-induced PKA phosphorylates p85a PI3K at serine 83, (2) phosphorylated p85a PI3K binds RIIb-PKA and targets PKAII to the membrane, and (3) PI3K activity and p21Ras binding to PI3K increase and activate PI3K downstream targets. This pathway is essential for the transmission of TSH-cAMP growth signals.

No abstract

No abstract

Normal epithelial thyroid cells in culture are inhibited by TGF-β1. Instead, transformed thyroid cell lines are frequently resistant to its growth inhibitory effect. Loss of TGF-β responsiveness could be due to a reduced expression of TGF-β receptors, as shown in transformed rat thyroid cell lines and in human thyroid tumors, or to alterations of other genes controlling TGF-β signal transduction pathway. However, in thyroid neoplasia, a complex pattern of alterations occurring during transformation and progression has been identified. Functionally, TGF-β1 acts as a tumor suppressor in the early stage of transformation or as a tumor promoter in advanced cancer. This peculiar pleiotropic behaviour of TGF-β may result from cross-talk with signalling pathways mediated by other growth factors, among which EGF-like ligands play an important role. This paper reports evidences on TGF-β1 and EGF systems in thyroid tumors and on the cross-talk between these growth factors in thyroid cancer.

It has been demonstrated that transforming growth factor-b (TGFb) and other members of TGFb superfamily play an important role in thyroid proliferative diseases. The deficiencies of SMAD4 are responsible to accelerate the malignant progression of neoplastic lesions in several types of tumors. Therefore, the objective of the present study was to determine the functional role of reduced expression of SMAD4 in human papillary thyroid carcinogenesis. For this purpose, we examined the TGFb response in two cell lines, TPC-1 and BCPAP. Our data demonstrated for the first time that these cells showed a strong reduction in the level of SMAD4 protein, which was responsible for an alteration of TGFb signaling and for some of the TGFb-mediated biological effects. The overexpression of SMAD4, restoring TGFb transduction, determined a significant increase of antiproliferative response to TGFb, and reduced the invasive behavior of these cells. Therefore, our data indicated that reduction of SMAD4 may play a significant role in thyroid carcinogenesis.

The introduction of multigene panel testing for hereditary breast/ovarian cancer screening has greatly improved efficiency, speed, and costs. However, its clinical utility is still debated, mostly due to the lack of conclusive evidences on the impact of newly discovered genetic variants on cancer risk and lack of evidence‐based guidelines for the clinical management of their carriers. In this pilot study, we aimed to test whether a systematic and multiparametric characterization of newly discovered mutations could enhance the clinical utility of multigene panel sequencing. Out of a pool of 367 breast/ovarian cancer families Sanger‐sequenced for BRCA1 and BRCA2 gene mutations, we selected a cohort of 20 BRCA1/2‐negative families to be subjected to the BROCA‐Cancer Risk Panel massive parallel sequencing. As a strategy for the systematic characterization of newly discovered genetic variants, we collected blood and cancer tissue samples and established lymphoblastoid cell lines from all available individuals in these families, to perform segregation analysis, loss‐of‐heterozygosity and further molecular studies. We identified loss‐of‐function mutations in 6 out 20 high‐risk families, 5 of which occurred on BRCA1,CHEK2 and ATM and are esteemed to be risk‐relevant. In contrast, a novel RAD50 truncating mutation is most likely unrelated to breast cancer. Our data suggest that integrating multigene panel testing with a pre‐organized, multiparametric characterization of newly discovered genetic variants improves the identification of risk‐relevant alleles impacting on the clinical management of their carriers.

Many clinical studies highlight the dichotomous role of PRDXs in human cancers, where they can exhibit strong tumor-suppressive or tumor-promoting functions. Recent evidence suggests that lower expression of PRDXs correlates with cancer progression in colorectal cancer (CRC) or in esophageal squamous carcinoma. In the thyroid, increased levels of PRDX1 has been described in follicular adenomas and carcinomas, as well as in thyroiditis, while reduced levels of PRDX6 has been found in follicular adenomas. We studied the expression of PRDX1 and PRDX6, in a series of thyroid tissue samples, covering different thyroid diseases, including 13 papillary thyroid carcinomas (PTCs). Our results show that PRDX1 and PRDX6 are significantly reduced in all PTCs compared to normal tissues, to non-neoplastic tissue (MNG) or follicular neoplasms. This reduction is strongly evident in PTCs harboring BRAF V600E (31% of our cases). Using TPC-1 and BCPAP and FRTL-5 cell lines, we demonstrate for the first time that the presence of BRAF V600E is responsible of the hypoexpression of PRDX1 and PRDX6 both at mRNA and protein levels. Finally, independently of BRAF status, we observe an interesting correlation between the tumor size, the presence of lymph node metastasis and the lowest PRDX1 and PRDX6 levels. Therefore, these data indicate that PRDX1 and PRDX6 expression not only may play a key role in papillary thyroid carcinogenesis via a BRAF V600E-dependent mechanism, but their determination could be considered as potential tumor marker for indicating tumor progression in PTCs, independently of BRAF status.