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Borbone E.,Instituto Of Endocrinologia Ed Oncologia Sperimentale | Borbone E.,Naples Oncogenomic Center | Berlingieri M.T.,Instituto Of Endocrinologia Ed Oncologia Sperimentale | De Bellis F.,The Second University of Naples | And 7 more authors.
Oncogene | Year: 2010

Anaplastic thyroid carcinoma (ATC) is considered one of the most aggressive malignancies, having a poor prognosis and being refractory to conventional chemotherapy and radiotherapy. Alteration in histone deacetylase (HDAC) activity has been reported in cancer, thus encouraging the development of HDAC inhibitors, whose antitumor action has been shown in both solid and hematological malignancies. However, the molecular basis for their tumor selectivity is unknown. To find an innovative therapy for the treatment of ATCs, we studied the effects of deacetylase inhibitors on thyroid tumorigenesis models. We show that HDACs 1 and 2 are overexpressed in ATCs compared with normal cells or benign tumors and that HDAC inhibitors induce apoptosis selectively in the fully transformed thyroid cells. Our results indicate that these phenomena are mediated by a novel action of HDAC inhibitors that reduces tumor necrosis factor-related apoptosis-inducing ligand protein degradation by affecting the ubiquitin-dependent pathway. Indeed, the combined treatment with HDAC and proteasome inhibitors results in synergistic apoptosis. These results strongly encourage the preclinical application of the combination deacetylase-proteasome inhibitors for the treatment of ATC. © 2010 Macmillan Publishers Limited All rights reserved.


Incoronato M.,Fondazione IRCCS SDN | Urso L.,Fondazione IRCCS SDN | Portela A.,08908 LHospitalet | Laukkanen M.O.,Fondazione IRCCS SDN | And 7 more authors.
PLoS ONE | Year: 2011

Many studies have shown that microRNA expression in cancer may be regulated by epigenetic events. Recently, we found that in lung cancer miR-212 was strongly down-regulated. However, mechanisms involved in the regulation of miR-212 expression are unknown. Therefore, we addressed this point by investigating the molecular mechanisms of miR-212 silencing in lung cancer. We identified histone modifications rather than DNA hypermethylation as epigenetic events that regulate miR-212 levels in NSCLC. Moreover, we found that miR-212 silencing in vivo is closely associated with the severity of the disease. © 2011 Incoronato et al.


Leone V.,National Research Council Italy | Leone V.,Naples Oncogenomic Center | D'Angelo D.,National Research Council Italy | Rubio I.,University of Sao Paulo | And 9 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2011

Context: Micro-RNA have emerged as an important class of short endogenous RNA that act as posttranscriptional regulators of gene expression and are constantly deregulated in human cancer. MiR-1 has been found down-regulated in lung, colon, and prostate cancer. Objectives: In this study, we investigated the possible role of miR-1 in thyroid carcinogenesis. Design: We have analyzed miR-1 expression in a panel of thyroid neoplasias including benign and malignant lesions and searched for miR-1 targets. Results: Our results show that miR-1 expression is drastically down-regulated in thyroid adenomas and carcinomas in comparison with normal thyroid tissue. Interestingly, miR-1 down-regulation was also found in thyroid hyperproliferative nonneoplastic lesions such as goiters. We identified the CCND2, coding for the cyclin D2 (CCND2) protein that favors the G1/S transition, CXCR4, and SDF-1α genes, coding for the receptor for the stromal cell derived factor-1 (SDF-1)/CXCL12 chemokine and its ligand SDF-1/CXCL12, respectively, as miR-1 targets. An inverse correlation was found between miR-1 expression and CXC chemokine receptor 4 (CXCR4) and SDF-1α protein levels in papillary and anaplastic thyroid carcinomas. Consistent with a role of the CCND2 protein in cell proliferation and CXCR4 and SDF-1α proteins in cell invasion and metastasis, functional studies demonstrate that miR-1 is able to inhibit thyroid carcinoma cell proliferation and migration. Conclusions: These results indicate the involvement of miR-1 in thyroid cell proliferation and migration, validating a role of miR-1 down-regulation in thyroid carcinogenesis. Copyright © 2011 by The Endocrine Society.


Fedele M.,University of Naples Federico II | Fedele M.,Naples Oncogenomic Center | Fusco A.,University of Naples Federico II | Fusco A.,Naples Oncogenomic Center
Biochimica et Biophysica Acta - Gene Regulatory Mechanisms | Year: 2010

Long-standing studies have clearly established that the architectural chromatinic proteins High Mobility Group A (HMGA) are among the most widely expressed cancer-associated proteins. Indeed, their overexpression represents a constant feature of human malignancies, and correlates with a poor prognosis. Moreover, HMGA dysregulation, as a result of specific chromosomal rearrangements, occurs in a broad variety of common benign mesenchymal tumors, making HMGA genes among the most commonly rearranged genes in human neoplasms. Nevertheless, recent data propose a critical role of HMGA overexpression also in the generation of pituitary adenomas. Here, we review the involvement of HMGA proteins in cancer, analyzing the mechanisms underlying their crucial role in tumorigenesis, and, finally, discuss the potentiality of a cancer treatment based on HMGA targeting. © 2009 Elsevier B.V. All rights reserved.


Pallante P.,University of Naples Federico II | Pallante P.,Naples Oncogenomic Center | Visone R.,University of Naples Federico II | Croce C.M.,Ohio State University | And 2 more authors.
Endocrine-Related Cancer | Year: 2010

Carcinoma of the thyroid gland is an uncommon cancer, but one of the most frequent malignancies of the endocrine system. Most thyroid cancers are derived from the follicular cells. Follicular carcinoma is considered more malignant than papillary thyroid carcinoma (PTC), and anaplastic thyroid cancer (ATC) is one of the most lethal human cancers. Even though several genetic lesions have been already described in human thyroid cancer, particularly in the papillary histotype, the mechanisms underlying the development of these neoplasias are still far from being completely elucidated. Some years ago, several studies were undertaken to analyze the expression of microRNAs (miRNAs or miRs) in thyroid carcinoma to evaluate a possible role of their deregulation in the process of carcinogenesis. These studies showed an aberrant microRNA expression profile that distinguishes unequivocally among PTC, ATC, and normal thyroid tissue. Here, other than summarizing the current findings on microRNA expression in human thyroid carcinomas, we discuss the mechanisms by which microRNA deregulation may play a role in thyroid carcinogenesis, and the possible use of microRNA knowledge in the diagnosis and therapy of thyroid neoplasms. © 2010 Society for Endocrinology Printed in Great Britain.


Amente S.,University of Naples Federico II | Amente S.,Naples Oncogenomic Center | Bertoni A.,University of Naples Federico II | Morano A.,University of Naples Federico II | And 5 more authors.
Oncogene | Year: 2010

Myc is a transcription factor that significantly contributes to cancer progression by modulating the expression of important genes through binding to a DNA sequence, CACGTG, called E-box. We find that on Myc binding to chromatin, the lysine-demethylating enzyme, LSD1, triggers a transient demethylation of lysine 4 in the histone H3. In addition, we demonstrate that Myc binds and recruits LSD1 to the E-box chromatin and the formation of this complex is stimulated by cAMP-PKA. Demethylation by LSD1 produces H2O 2, which locally oxidizes guanine and induces the recruitment of 8-oxoguanine-DNA glycosylase (OGG1) and of the nuclease Ape1 on the E-box chromatin. Inhibition of oxidation or silencing of LSD1, OGG1 or Ape1 significantly reduce transcription and inhibit mRNA accumulation of Myc-target genes. Collectively, these data highlight the role of transient LSD1-mediated demethylation of H3K4 leading to local DNA oxidation as driving force in the assembly of the Myc-induced transcription initiation complex. © 2010 Macmillan Publishers Limited All rights reserved.


Palmieri D.,University of Naples Federico II | Palmieri D.,Ohio State University | Valentino T.,University of Naples Federico II | D'Angelo D.,University of Naples Federico II | And 7 more authors.
Oncogene | Year: 2011

DNA-damaging therapies represent a keystone in cancer treatment. Unfortunately, many tumors often relapse because of a group of cancer cells, which are resistant to conventional therapies. High-mobility group A (HMGA) proteins has a key role in cell transformation, and their overexpression is a common feature of human malignant neoplasias, representing a poor prognostic index often correlated to anti-cancer drug resistance. Our previous results demonstrated that HMGA1 is a substrate of ataxia-telangiectasia mutated (ATM), the main cellular sensor of genotoxic stress. Here we also report thatHMGA2, the other member of the HMGA family, is a novel substrate of ATM. Interestingly, we found that HMGA proteins positively regulate ATM gene expression. Moreover, induction of ATM kinase activity by DNA-damaging agents enhances HMGA-dependent transcriptional activation of ATM promoter, suggesting that ATM expression is modulated by a DNA-damage- and HMGA-dependent positive feedback loop. Finally, inhibition of HMGA expression in mouse embryonic fibroblasts and in cancer cells strongly reduces ATM protein levels, impairing the cellular DNA-damage response and enhancing the sensitivity to DNA-damaging agents. These findings indicate this novel HMGA-ATM pathway as a new potential target to improve the effectiveness of conventional anti-neoplastic treatments on the genotoxic-drug resistant cancer cells. © 2011 Macmillan Publishers Limited All rights reserved.


Leone V.,University of Naples Federico II | Leone V.,Naples Oncogenomic Center | D'Angelo D.,University of Naples Federico II | Pallante P.,University of Naples Federico II | And 4 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2012

Context: MicroRNA (miRNA or miR) have emerged as an important class of short endogenous RNA that act as post-transcriptional regulators of gene expression and have a critical role in cell proliferation and differentiation. Objectives: The aim of this study was to elucidate the role of miRNA in the proliferation of differentiated thyroid cells that require TSH for their growth. Design: To elucidate the role of miRNA in thyroid cell proliferation, we have analyzed the miRNA expression profile of PC Cl 3 cells before and after the stimulation by TSH. Results: We report the identification of two specific miRNA (miR-23b and miR-29b) whose upregulation by TSH is required for thyroid cell growth. We identified mothers against decapentaplegic homolog 3 (Smad3), a member of the TGF-β pathway that has an inhibitor role in thyroid follicular cell proliferation as a target of miR-23b and miR-29b. Functional studies demonstrated that the overexpression of miR-23b and miR-29b promotes thyroid cell growth. Interestingly, an increased expression of both these miRNA was also detected in experimental and human goiters. Conclusions: These findings support the idea that the regulation of miRNA expression synergizes with the traditional proliferation pathways in promoting cell growth. Copyright © 2012 by The Endocrine Society.


Palmieri D.,National Research Council Italy | D'Angelo D.,National Research Council Italy | Valentino T.,National Research Council Italy | De Martino I.,National Research Council Italy | And 9 more authors.
Oncogene | Year: 2012

Previous studies have demonstrated that high mobility group A proteins have a critical role on the onset of human pituitary adenomas. Indeed, both high mobility group A (HMGA) genes are overexpressed in pituitary adenomas, and consistently transgenic mice overexpressing either the Hmga1 or the Hmga2 gene develop mixed growth hormone/prolactin (GH-PRL)-secreting pituitary adenomas. Trisomy of chromosome 12, where HMGA2 is located, and/or amplification of the HMGA2 gene locus account for the HMGA2 overexpression in most human prolactinomas. Conversely, HMGA1 overexpression is not associated to any rearrangement or amplification of the HMGA1 locus. We have first identified micro RNAs (miRNAs) able to target both HMGA1 and HMGA2 messenger RNAs. Then, all of these miRNAs have been found downregulated in pituitary adenomas of different histotypes, compared with normal pituitary. Interestingly, their downregulation was also observed in nonfunctioning pituitary adenomas where HMGA2 overexpression is not associated to any alteration of the HMGA2 locus. Functional studies show that all these HMGA-targeting miRNAs inhibit the proliferation of the rat pituitary adenoma cell line GH3. Therefore, these results indicate that the downregulation of the miRNAs able to target the HMGA genes could contribute to increase HMGA protein levels in human pituitary adenomas, and then to pituitary tumorigenesis. © 2012 Macmillan Publishers Limited. All rights reserved.


Esposito F.,CNR Institute of Neuroscience | Tornincasa M.,CNR Institute of Neuroscience | Federico A.,CNR Institute of Neuroscience | Chiappetta G.,Instituto Nazionale dei Tumori | And 3 more authors.
Cell Death and Disease | Year: 2012

The high-mobility group A (HMGA) proteins are a family of non-histone chromatin factors, encoded by the HMGA1 and HMGA2 genes. Several studies demonstrate that HMGA proteins have a critical role in neoplastic transformation, and their overexpression is mainly associated with a highly malignant phenotype, also representing a poor prognostic index. Even though a cytoplasmic localization of these proteins has been previously reported in some highly malignant neoplasias, a clear role for this localization has not been defined. Here, we first confirm the localization of the HMGA1 proteins in the cytoplasm of cancer cells, and then we report a novel mechanism through which HMGA1 inhibits p53-mitochondrial apoptosis by counteracting the binding of p53 to the anti-apoptotic factor Bcl-2. Indeed, we demonstrate a physical and functional interaction between HMGA1 and Bcl-2 proteins. This interaction occurs at mitochondria interfering with the ability of p53 protein to bind Bcl-2, thus counteracting p53-mediated mitochondrial apoptosis. This effect is associated with the inhibition of cytochrome c release and activation of caspases. Consistent with this mechanism, a strong correlation between HMGA1 cytoplasmic localization and a more aggressive histotype of thyroid, breast and colon carcinomas has been observed. Therefore, cytoplasmic localization of HMGA1 proteins in malignant tissues is a novel mechanism of inactivation of p53 apoptotic function. © 2012 Macmillan Publishers Limited.

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