The Experts below are selected from a list of 6297 Experts worldwide ranked by ideXlab platform
Alfredo Fusco - One of the best experts on this subject based on the ideXlab platform.
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Emerging Role of USP8, HMGA, and Non-Coding RNAs in Pituitary Tumorigenesis.
Cancers, 2019Co-Authors: Daniela D'angelo, Marco De Martino, Claudio Arra, Alfredo FuscoAbstract:Two novel molecular mechanisms with a driver role in pituitary tumorigenesis have been recently identified. They are (a) mutations in the Ubiquitin-Specific Protease 8 (USP8) gene in corticotroph tumors and (b) overexpression of the HMGA1 and HMGA2 genes in most of the pituitary tumors. Moreover, deregulated expression of the non-coding RNAs has been very frequently observed in this neoplasia. The aim of this review is to better elucidate the role, the mechanisms, and the possible clinical impact of these novel alterations in the development of pituitary neoplasia.
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overexpression of HMGA1 figures as a potential prognostic factor in endometrioid endometrial carcinoma eec
Genes, 2019Co-Authors: Antonio Palumbo, Marco De Martino, Alfredo Fusco, Francesco Esposito, Floriana Forzati, Vanessa Paiva Leite De Sousa, Fabio Carvalho De Barros Moreira, Tatiana De Almeida Simao, Luiz Eurico Nasciutti, Luis Felipe Ribeiro PintoAbstract:Endometrioid endometrial carcinomas (EEC) are the most common malignant gynecologic tumors. Despite the increase in EEC molecular knowledge, the identification of new biomarkers involved in disease’s development and/or progression would represent an improvement in its course. High-mobility group A protein (HMGA) family members are frequently overexpressed in a wide range of malignancies, correlating with a poor prognosis. Thus, the aim of this study was to analyze HMGA1 and HMGA2 expression pattern and their potential role as EEC biomarkers. HMGA1 and HMGA2 expression was initially evaluated in a series of 46 EEC tumors (stages IA to IV), and the findings were then validated in The Cancer Genome Atlas (TCGA) EEC cohort, comprising 381 EEC tumors (stages IA to IV). Our results reveal that HMGA1 and HMGA2 mRNA and protein are overexpressed in ECC, but only HMGA1 expression is associated with increased histological grade and tumor size. Moreover, HMGA1 but not HMGA2 overexpression was identified as a negative prognostic factor to EEC patients. Finally, a positive correlation between expression of HMGA1 pseudogenes—HMGA1-P6 and HMGA1-P7—and HMGA1 itself was detected, suggesting HMGA1 pseudogenes may play a role in HMGA1 expression regulation in EEC. Thus, these results indicate that HMGA1 overexpression possesses a potential role as a prognostic biomarker for EEC.
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HMGA1 -pseudogenes and cancer
Oncotarget, 2016Co-Authors: Marco De Martino, Alfredo Fusco, Claudio Arra, Floriana Forzati, Francesco EspositoAbstract:// Marco De Martino 1 , Floriana Forzati 1 , Claudio Arra 2 , Alfredo Fusco 1 and Francesco Esposito 1 1 Istituto di Endocrinologia ed Oncologia Sperimentale del CNR c/o Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Scuola di Medicina e Chirurgia di Napoli, Universita degli Studi di Napoli “Federico II”, Naples, Italy 2 Istituto Nazionale dei Tumori, Fondazione Pascale, Naples, Italy Correspondence to: Francesco Esposito, email: // Alfredo Fusco, email: // Keywords : pseudogenes, HMGA, cancer, ceRNA Received : November 02, 2015 Accepted : February 05, 2016 Published : February 16, 2016 Abstract Pseudogenes are DNA sequences with high homology to the corresponding functional gene, but, because of the accumulation of various mutations, they have lost their initial functions to code for proteins. Consequently, pseudogenes have been considered until few years ago dysfunctional relatives of the corresponding ancestral genes, and then useless in the course of genome evolution. However, several studies have recently established that pseudogenes are owners of key biological functions. Indeed, some pseudogenes control the expression of functional genes by competitively binding to the miRNAs, some of them generate small interference RNAs to negatively modulate the expression of functional genes, and some of them even encode functional mutated proteins. Here, we concentrate our attention on the pseudogenes of the HMGA1 gene, that codes for the HMGA1a and HMGA1b proteins having a critical role in development and cancer progression. In this review, we analyze the family of HMGA1 pseudogenes through three aspects: classification, characterization, and their possible function and involvement in cancer.
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HMGA1 pseudogene expression is induced in human pituitary tumors
Cell Cycle, 2015Co-Authors: Francesco Esposito, Marco De Martino, Daniela Dangelo, Paula Mussnich, M L Jaffrainrea, J. Trouillas, Filippo Fraggetta, Gerald Raverot, Alfredo FuscoAbstract:Numerous studies have established that High Mobility Group A (HMGA) proteins play a pivotal role on the onset of human pituitary tumors. They are overexpressed in pituitary tumors, and, consistently, transgenic mice overexpressing either the HMGA1 or the Hmga2 gene develop pituitary tumors. In contrast with HMGA2, HMGA1 overexpression is not related to any rearrangement or amplification of the HMGA1 locus in these tumors. We have recently identified 2 HMGA1 pseudogenes, HMGA1P6 and HMGA1P7, acting as competitive endogenous RNA decoys for HMGA1 and other cancer related genes. Here, we show that HMGA1 pseudogene expression significantly correlates with HMGA1 mRNA levels in growth hormone and nonfunctioning pituitary adenomas likely inhibiting the repression of HMGA1 through microRNAs action. According to our functional studies, these HMGA1 pseudogenes enhance the proliferation and migration of the mouse pituitary tumor cell line, at least in part, through their upregulation. Our results point out that the o...
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HMGA1 pseudogene expression is induced in human pituitary tumors
Cell Cycle, 2015Co-Authors: Francesco Esposito, Marco De Martino, Daniela Dangelo, Paula Mussnich, M L Jaffrainrea, J. Trouillas, Filippo Fraggetta, Gerald Raverot, Alfredo FuscoAbstract:Numerous studies have established that High Mobility Group A (HMGA) proteins play a pivotal role on the onset of human pituitary tumors. They are overexpressed in pituitary tumors, and, consistently, transgenic mice overexpressing either the HMGA1 or the Hmga2 gene develop pituitary tumors. In contrast with HMGA2, HMGA1 overexpression is not related to any rearrangement or amplification of the HMGA1 locus in these tumors. We have recently identified 2 HMGA1 pseudogenes, HMGA1P6 and HMGA1P7, acting as competitive endogenous RNA decoys for HMGA1 and other cancer related genes. Here, we show that HMGA1 pseudogene expression significantly correlates with HMGA1 mRNA levels in growth hormone and nonfunctioning pituitary adenomas likely inhibiting the repression of HMGA1 through microRNAs action. According to our functional studies, these HMGA1 pseudogenes enhance the proliferation and migration of the mouse pituitary tumor cell line, at least in part, through their upregulation. Our results point out that the overexpression of HMGA1P6 and HMGA1P7 could contribute to increase HMGA1 levels in human pituitary tumors, and then to pituitary tumorigenesis.
Francesco Esposito - One of the best experts on this subject based on the ideXlab platform.
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overexpression of HMGA1 figures as a potential prognostic factor in endometrioid endometrial carcinoma eec
Genes, 2019Co-Authors: Antonio Palumbo, Marco De Martino, Alfredo Fusco, Francesco Esposito, Floriana Forzati, Vanessa Paiva Leite De Sousa, Fabio Carvalho De Barros Moreira, Tatiana De Almeida Simao, Luiz Eurico Nasciutti, Luis Felipe Ribeiro PintoAbstract:Endometrioid endometrial carcinomas (EEC) are the most common malignant gynecologic tumors. Despite the increase in EEC molecular knowledge, the identification of new biomarkers involved in disease’s development and/or progression would represent an improvement in its course. High-mobility group A protein (HMGA) family members are frequently overexpressed in a wide range of malignancies, correlating with a poor prognosis. Thus, the aim of this study was to analyze HMGA1 and HMGA2 expression pattern and their potential role as EEC biomarkers. HMGA1 and HMGA2 expression was initially evaluated in a series of 46 EEC tumors (stages IA to IV), and the findings were then validated in The Cancer Genome Atlas (TCGA) EEC cohort, comprising 381 EEC tumors (stages IA to IV). Our results reveal that HMGA1 and HMGA2 mRNA and protein are overexpressed in ECC, but only HMGA1 expression is associated with increased histological grade and tumor size. Moreover, HMGA1 but not HMGA2 overexpression was identified as a negative prognostic factor to EEC patients. Finally, a positive correlation between expression of HMGA1 pseudogenes—HMGA1-P6 and HMGA1-P7—and HMGA1 itself was detected, suggesting HMGA1 pseudogenes may play a role in HMGA1 expression regulation in EEC. Thus, these results indicate that HMGA1 overexpression possesses a potential role as a prognostic biomarker for EEC.
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HMGA2, but not HMGA1, is overexpressed in human larynx carcinomas
Histopathology, 2018Co-Authors: Antonio Palumbo, Marco De Martino, Filippo Fraggetta, Francesco Esposito, Luiz Eurico Nasciutti, Pedro Nicolau Neto, Priscila Valverde Fernandes, Izabella Costa Santos, Fernando Luiz Dias, Nathalia Meireles Da CostaAbstract:AIMS Malignant tumours from the upper aerodigestive tract are grouped collectively in the class of head and neck squamous cell carcinoma (HNSCC). The head and neck tumours were responsible for more than 500 000 cancer cases in 2012, accounting for the sixth highest incidence rate and mortality worldwide among all tumour types. Laryngeal squamous cell carcinoma (LSCC) possesses the second highest incidence rate among all HNSCC. Despite significant advances in surgery and radiotherapy during the last few decades, no treatment has been shown to achieve a satisfactory therapeutic outcome and the mortality rate of LSCC is still high, with a 5-year survival rate of 64%. Therefore, further investigations are required to identify the pathogenesis of LSCC. METHODS AND RESULTS In order to search for new LSCC biomarkers, we have analysed the expression of the HMGA family members, HMGA1 and HMGA2, by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and immunohistochemistry. HMGA proteins are usually absent in the healthy adult tissues. In contrast, their constitutive expression is a feature of several neoplasias, being associated with a highly malignant phenotype and reduced survival. Here, we report HMGA2 overexpression in larynx carcinomas. Conversely, HMGA1 does not show any differences in its expression between normal and carcinoma tissues. Interestingly, HMGA2 overexpression appears associated with that of two HMGA1-pseudogenes, HMGA1P6 and HMGA1P7, acting as a sponge for HMGA1- and HMGA2-targeting microRNAs and involved in several human cancers. CONCLUSIONS Therefore, HMGA2 overexpression appears to be a strong feature of larynx carcinoma, supporting its detection as a valid tool for the diagnosis of these malignancies.
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HMGA1 -pseudogenes and cancer
Oncotarget, 2016Co-Authors: Marco De Martino, Alfredo Fusco, Claudio Arra, Floriana Forzati, Francesco EspositoAbstract:// Marco De Martino 1 , Floriana Forzati 1 , Claudio Arra 2 , Alfredo Fusco 1 and Francesco Esposito 1 1 Istituto di Endocrinologia ed Oncologia Sperimentale del CNR c/o Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Scuola di Medicina e Chirurgia di Napoli, Universita degli Studi di Napoli “Federico II”, Naples, Italy 2 Istituto Nazionale dei Tumori, Fondazione Pascale, Naples, Italy Correspondence to: Francesco Esposito, email: // Alfredo Fusco, email: // Keywords : pseudogenes, HMGA, cancer, ceRNA Received : November 02, 2015 Accepted : February 05, 2016 Published : February 16, 2016 Abstract Pseudogenes are DNA sequences with high homology to the corresponding functional gene, but, because of the accumulation of various mutations, they have lost their initial functions to code for proteins. Consequently, pseudogenes have been considered until few years ago dysfunctional relatives of the corresponding ancestral genes, and then useless in the course of genome evolution. However, several studies have recently established that pseudogenes are owners of key biological functions. Indeed, some pseudogenes control the expression of functional genes by competitively binding to the miRNAs, some of them generate small interference RNAs to negatively modulate the expression of functional genes, and some of them even encode functional mutated proteins. Here, we concentrate our attention on the pseudogenes of the HMGA1 gene, that codes for the HMGA1a and HMGA1b proteins having a critical role in development and cancer progression. In this review, we analyze the family of HMGA1 pseudogenes through three aspects: classification, characterization, and their possible function and involvement in cancer.
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HMGA1 pseudogene expression is induced in human pituitary tumors
Cell Cycle, 2015Co-Authors: Francesco Esposito, Marco De Martino, Daniela Dangelo, Paula Mussnich, M L Jaffrainrea, J. Trouillas, Filippo Fraggetta, Gerald Raverot, Alfredo FuscoAbstract:Numerous studies have established that High Mobility Group A (HMGA) proteins play a pivotal role on the onset of human pituitary tumors. They are overexpressed in pituitary tumors, and, consistently, transgenic mice overexpressing either the HMGA1 or the Hmga2 gene develop pituitary tumors. In contrast with HMGA2, HMGA1 overexpression is not related to any rearrangement or amplification of the HMGA1 locus in these tumors. We have recently identified 2 HMGA1 pseudogenes, HMGA1P6 and HMGA1P7, acting as competitive endogenous RNA decoys for HMGA1 and other cancer related genes. Here, we show that HMGA1 pseudogene expression significantly correlates with HMGA1 mRNA levels in growth hormone and nonfunctioning pituitary adenomas likely inhibiting the repression of HMGA1 through microRNAs action. According to our functional studies, these HMGA1 pseudogenes enhance the proliferation and migration of the mouse pituitary tumor cell line, at least in part, through their upregulation. Our results point out that the o...
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HMGA1 pseudogene expression is induced in human pituitary tumors
Cell Cycle, 2015Co-Authors: Francesco Esposito, Marco De Martino, Daniela Dangelo, Paula Mussnich, M L Jaffrainrea, J. Trouillas, Filippo Fraggetta, Gerald Raverot, Alfredo FuscoAbstract:Numerous studies have established that High Mobility Group A (HMGA) proteins play a pivotal role on the onset of human pituitary tumors. They are overexpressed in pituitary tumors, and, consistently, transgenic mice overexpressing either the HMGA1 or the Hmga2 gene develop pituitary tumors. In contrast with HMGA2, HMGA1 overexpression is not related to any rearrangement or amplification of the HMGA1 locus in these tumors. We have recently identified 2 HMGA1 pseudogenes, HMGA1P6 and HMGA1P7, acting as competitive endogenous RNA decoys for HMGA1 and other cancer related genes. Here, we show that HMGA1 pseudogene expression significantly correlates with HMGA1 mRNA levels in growth hormone and nonfunctioning pituitary adenomas likely inhibiting the repression of HMGA1 through microRNAs action. According to our functional studies, these HMGA1 pseudogenes enhance the proliferation and migration of the mouse pituitary tumor cell line, at least in part, through their upregulation. Our results point out that the overexpression of HMGA1P6 and HMGA1P7 could contribute to increase HMGA1 levels in human pituitary tumors, and then to pituitary tumorigenesis.
Marco De Martino - One of the best experts on this subject based on the ideXlab platform.
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Emerging Role of USP8, HMGA, and Non-Coding RNAs in Pituitary Tumorigenesis.
Cancers, 2019Co-Authors: Daniela D'angelo, Marco De Martino, Claudio Arra, Alfredo FuscoAbstract:Two novel molecular mechanisms with a driver role in pituitary tumorigenesis have been recently identified. They are (a) mutations in the Ubiquitin-Specific Protease 8 (USP8) gene in corticotroph tumors and (b) overexpression of the HMGA1 and HMGA2 genes in most of the pituitary tumors. Moreover, deregulated expression of the non-coding RNAs has been very frequently observed in this neoplasia. The aim of this review is to better elucidate the role, the mechanisms, and the possible clinical impact of these novel alterations in the development of pituitary neoplasia.
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overexpression of HMGA1 figures as a potential prognostic factor in endometrioid endometrial carcinoma eec
Genes, 2019Co-Authors: Antonio Palumbo, Marco De Martino, Alfredo Fusco, Francesco Esposito, Floriana Forzati, Vanessa Paiva Leite De Sousa, Fabio Carvalho De Barros Moreira, Tatiana De Almeida Simao, Luiz Eurico Nasciutti, Luis Felipe Ribeiro PintoAbstract:Endometrioid endometrial carcinomas (EEC) are the most common malignant gynecologic tumors. Despite the increase in EEC molecular knowledge, the identification of new biomarkers involved in disease’s development and/or progression would represent an improvement in its course. High-mobility group A protein (HMGA) family members are frequently overexpressed in a wide range of malignancies, correlating with a poor prognosis. Thus, the aim of this study was to analyze HMGA1 and HMGA2 expression pattern and their potential role as EEC biomarkers. HMGA1 and HMGA2 expression was initially evaluated in a series of 46 EEC tumors (stages IA to IV), and the findings were then validated in The Cancer Genome Atlas (TCGA) EEC cohort, comprising 381 EEC tumors (stages IA to IV). Our results reveal that HMGA1 and HMGA2 mRNA and protein are overexpressed in ECC, but only HMGA1 expression is associated with increased histological grade and tumor size. Moreover, HMGA1 but not HMGA2 overexpression was identified as a negative prognostic factor to EEC patients. Finally, a positive correlation between expression of HMGA1 pseudogenes—HMGA1-P6 and HMGA1-P7—and HMGA1 itself was detected, suggesting HMGA1 pseudogenes may play a role in HMGA1 expression regulation in EEC. Thus, these results indicate that HMGA1 overexpression possesses a potential role as a prognostic biomarker for EEC.
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HMGA2, but not HMGA1, is overexpressed in human larynx carcinomas
Histopathology, 2018Co-Authors: Antonio Palumbo, Marco De Martino, Filippo Fraggetta, Francesco Esposito, Luiz Eurico Nasciutti, Pedro Nicolau Neto, Priscila Valverde Fernandes, Izabella Costa Santos, Fernando Luiz Dias, Nathalia Meireles Da CostaAbstract:AIMS Malignant tumours from the upper aerodigestive tract are grouped collectively in the class of head and neck squamous cell carcinoma (HNSCC). The head and neck tumours were responsible for more than 500 000 cancer cases in 2012, accounting for the sixth highest incidence rate and mortality worldwide among all tumour types. Laryngeal squamous cell carcinoma (LSCC) possesses the second highest incidence rate among all HNSCC. Despite significant advances in surgery and radiotherapy during the last few decades, no treatment has been shown to achieve a satisfactory therapeutic outcome and the mortality rate of LSCC is still high, with a 5-year survival rate of 64%. Therefore, further investigations are required to identify the pathogenesis of LSCC. METHODS AND RESULTS In order to search for new LSCC biomarkers, we have analysed the expression of the HMGA family members, HMGA1 and HMGA2, by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and immunohistochemistry. HMGA proteins are usually absent in the healthy adult tissues. In contrast, their constitutive expression is a feature of several neoplasias, being associated with a highly malignant phenotype and reduced survival. Here, we report HMGA2 overexpression in larynx carcinomas. Conversely, HMGA1 does not show any differences in its expression between normal and carcinoma tissues. Interestingly, HMGA2 overexpression appears associated with that of two HMGA1-pseudogenes, HMGA1P6 and HMGA1P7, acting as a sponge for HMGA1- and HMGA2-targeting microRNAs and involved in several human cancers. CONCLUSIONS Therefore, HMGA2 overexpression appears to be a strong feature of larynx carcinoma, supporting its detection as a valid tool for the diagnosis of these malignancies.
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HMGA1 -pseudogenes and cancer
Oncotarget, 2016Co-Authors: Marco De Martino, Alfredo Fusco, Claudio Arra, Floriana Forzati, Francesco EspositoAbstract:// Marco De Martino 1 , Floriana Forzati 1 , Claudio Arra 2 , Alfredo Fusco 1 and Francesco Esposito 1 1 Istituto di Endocrinologia ed Oncologia Sperimentale del CNR c/o Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Scuola di Medicina e Chirurgia di Napoli, Universita degli Studi di Napoli “Federico II”, Naples, Italy 2 Istituto Nazionale dei Tumori, Fondazione Pascale, Naples, Italy Correspondence to: Francesco Esposito, email: // Alfredo Fusco, email: // Keywords : pseudogenes, HMGA, cancer, ceRNA Received : November 02, 2015 Accepted : February 05, 2016 Published : February 16, 2016 Abstract Pseudogenes are DNA sequences with high homology to the corresponding functional gene, but, because of the accumulation of various mutations, they have lost their initial functions to code for proteins. Consequently, pseudogenes have been considered until few years ago dysfunctional relatives of the corresponding ancestral genes, and then useless in the course of genome evolution. However, several studies have recently established that pseudogenes are owners of key biological functions. Indeed, some pseudogenes control the expression of functional genes by competitively binding to the miRNAs, some of them generate small interference RNAs to negatively modulate the expression of functional genes, and some of them even encode functional mutated proteins. Here, we concentrate our attention on the pseudogenes of the HMGA1 gene, that codes for the HMGA1a and HMGA1b proteins having a critical role in development and cancer progression. In this review, we analyze the family of HMGA1 pseudogenes through three aspects: classification, characterization, and their possible function and involvement in cancer.
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HMGA1 pseudogene expression is induced in human pituitary tumors
Cell Cycle, 2015Co-Authors: Francesco Esposito, Marco De Martino, Daniela Dangelo, Paula Mussnich, M L Jaffrainrea, J. Trouillas, Filippo Fraggetta, Gerald Raverot, Alfredo FuscoAbstract:Numerous studies have established that High Mobility Group A (HMGA) proteins play a pivotal role on the onset of human pituitary tumors. They are overexpressed in pituitary tumors, and, consistently, transgenic mice overexpressing either the HMGA1 or the Hmga2 gene develop pituitary tumors. In contrast with HMGA2, HMGA1 overexpression is not related to any rearrangement or amplification of the HMGA1 locus in these tumors. We have recently identified 2 HMGA1 pseudogenes, HMGA1P6 and HMGA1P7, acting as competitive endogenous RNA decoys for HMGA1 and other cancer related genes. Here, we show that HMGA1 pseudogene expression significantly correlates with HMGA1 mRNA levels in growth hormone and nonfunctioning pituitary adenomas likely inhibiting the repression of HMGA1 through microRNAs action. According to our functional studies, these HMGA1 pseudogenes enhance the proliferation and migration of the mouse pituitary tumor cell line, at least in part, through their upregulation. Our results point out that the o...
Monica Fedele - One of the best experts on this subject based on the ideXlab platform.
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HMGA2 cooperates with either p27kip1 deficiency or Cdk4R24C mutation in pituitary tumorigenesis
2018Co-Authors: Monica Fedele, Orlando Paciello, Davide De Biase, Mario Monaco, Gennaro Chiappetta, Michela Vitiello, Antonio Barbieri, Domenica Rea, Antonio Luciano, Serenella PapparellaAbstract:We have previously reported a critical role of HMGA proteins in pituitary tumorigenesis since either the HMGA1 or Hmga2 gene overexpression/activation induces the development of mixed growth hormone/prolactin cell pituitary adenomas by activating the E2F transcription factor 1, and then enhancing the G1/S transition of the cell cycle. Consistently, amplification and overexpression of the HMGA2 gene was found in human pituitary prolactinomas. Since impairment of the cell cycle control represents a feature of experimental and human pituitary adenomas, we have investigated the possible synergism between the alterations of other cell cycle regulators, such as p27 deficiency or Cdk4R24C mutation, with Hmga2 overexpression in pituitary tumorigenesis. Therefore, we crossed the Hmga2/T mice, overexpressing the truncated/active form of the Hmga2 gene, either with the knockout mice for p27kip1, or with the knockin mice for the Cdk4R24C mutation, both developing pituitary adenomas. Increased incidence and decreased latency in the development of pituitary lesions appeared in double mutant Hmga2/T;Cdk4R24C mice, and increased features of invasiveness and atypia were observed in pituitary tumors of both Hmga2/T;p27-ko and Hmga2/T;Cdk4R24C double mutant mice as compared with single mutant compounds. Interestingly, most of these mice develop pituitary adenomas with high Ki67 index, extrasellar expansion and brain tissue infiltration, representing good mouse models for human aggressive pituitary adenomas. Taken together, the results reported here indicate a cooperation between HMGA2 overexpression and either p27kip1 or CDK4 impairment in promoting pituitary tumor development and progression.
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HMGA1 hmga2 double knock out mice display a superpygmy phenotype
Biology Open, 2014Co-Authors: Antonella Federico, Francesco Esposito, Monica Fedele, Dario Palmieri, Giovanna Maria Pierantoni, Claudio Arra, Antonio Barbieri, Floriana Forzati, Giuseppe Palma, Ivana De MartinoAbstract:The HMGA1 and HMGA2 genes code for proteins belonging to the High Mobility Group A family. Several genes are negatively or positively regulated by both these proteins, but a number of genes are specifically regulated by only one of them. Indeed, knock-out of the HMGA1 and Hmga2 genes leads to different phenotypes: cardiac hypertrophy and type 2 diabetes in the former case, and a large reduction in body size and amount of fat tissue in the latter case. Therefore, to better elucidate the functions of the Hmga genes, we crossed HMGA1-null mice with mice null for Hmga2. The HMGA1 2/2 /Hmga2 2/2 mice showed reduced vitality and a very small size (75% smaller than the wild-type mice); they were even smaller than pygmy Hmga2-null mice. The drastic reduction in E2F1 activity, and consequently in the expression of the E2F-dependent genes involved in cell cycle regulation, likely accounts for some phenotypic features of the HMGA1 2/2 /Hmga2 2/2 mice.
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expression of a truncated HMGA1b gene induces gigantism lipomatosis and b cell lymphomas in mice
European Journal of Cancer, 2011Co-Authors: Monica Fedele, Francesco Esposito, Dario Palmieri, Andres J Kleinszanto, Rosa Visone, Ivana De Martino, Claudio Arra, Teresa Valentino, Andrea CiarmielloAbstract:HMGA1 gene rearrangements have been frequently described in human lipomas. In vitro studies suggest that HMGA1 proteins have a negative role in the control of adipocyte cell growth, and that HMGA1 gene truncation acts in a dominant-negative fashion. Therefore, to define better the role of the HMGA1 alterations in the generation of human lipomas, we generated mice carrying an HMGA1b truncated (HMGA1b/T) gene. These mice develop a giant phenotype together with a drastic expansion of the retroperitoneal and subcutaneous white adipose tissue. We show that the activation of the E2F pathway likely accounts, at least in part, for this phenotype. Interestingly, the HMGA1b/T mice also develop B-cell lymphomas similar to that occurring in HMGA1-knockout mice, supporting a dominant-negative role of the HMGA1b/T mutant also in vivo.
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hmga2 a pituitary tumour subtype specific oncogene
Molecular and Cellular Endocrinology, 2010Co-Authors: Monica Fedele, Dario Palmieri, Alfredo FuscoAbstract:The high mobility group AT-hook (HMGA) proteins, a family of DNA architectural factors, are highly expressed during embryogenesis and play a crucial role in several different biological processes, as well as in tumorigenesis of a wide range of tissues, including pituitary. Indeed, HMGA2 has been found rearranged and amplified in human prolactinomas, and transgenic mice overexpressing either HMGA1 or Hmga2 develop pituitary adenomas secreting prolactin and growth hormone. Here, we overview HMGA proteins in human tumours, focusing on pituitary adenomas and the mechanisms by which the HMGA proteins are involved in their onset and development. Different HMGA-dependent potential drives of pituitary oncogenesis are discussed as future research directions in the field.
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transgenic mice overexpressing the wild type form of the HMGA1 gene develop mixed growth hormone prolactin cell pituitary adenomas and natural killer cell lymphomas
Oncogene, 2005Co-Authors: Monica Fedele, Sabrina Battista, Francesca Pentimalli, Gustavo Baldassarre, Andres J Kleinszanto, Lawrence C Kenyon, Rosa Visone, Ivana De Martino, Andrea Ciarmiello, Claudio ArraAbstract:Overexpression of HMGA1 proteins is a constant feature of human carcinomas. Moreover, rearrangements of this gene have been detected in several human benign tumors of mesenchymal origin. To define the role of these proteins in cell transformation in vivo, we have generated transgenic mice overexpressing ubiquitously the HMGA1 gene. These mice developed mixed growth hormone/prolactin cell pituitary adenomas and natural killer (NK)-T/NK cell lymphomas. The HMGA1-induced expression of IL-2 and IL-15 proteins and their receptors may account for the onset of these lymphomas. At odds with mice overexpressing a wild-type or a truncated HMGA2 protein, adrenal medullar hyperplasia and pancreatic islet cell hyperplasia frequently occurred and no increase in body size and weight was observed in HMGA1 mice. Taken together, these data indicate an oncogenic role of the HMGA1 gene also in vivo.
Claudio Arra - One of the best experts on this subject based on the ideXlab platform.
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Emerging Role of USP8, HMGA, and Non-Coding RNAs in Pituitary Tumorigenesis.
Cancers, 2019Co-Authors: Daniela D'angelo, Marco De Martino, Claudio Arra, Alfredo FuscoAbstract:Two novel molecular mechanisms with a driver role in pituitary tumorigenesis have been recently identified. They are (a) mutations in the Ubiquitin-Specific Protease 8 (USP8) gene in corticotroph tumors and (b) overexpression of the HMGA1 and HMGA2 genes in most of the pituitary tumors. Moreover, deregulated expression of the non-coding RNAs has been very frequently observed in this neoplasia. The aim of this review is to better elucidate the role, the mechanisms, and the possible clinical impact of these novel alterations in the development of pituitary neoplasia.
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HMGA1 -pseudogenes and cancer
Oncotarget, 2016Co-Authors: Marco De Martino, Alfredo Fusco, Claudio Arra, Floriana Forzati, Francesco EspositoAbstract:// Marco De Martino 1 , Floriana Forzati 1 , Claudio Arra 2 , Alfredo Fusco 1 and Francesco Esposito 1 1 Istituto di Endocrinologia ed Oncologia Sperimentale del CNR c/o Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Scuola di Medicina e Chirurgia di Napoli, Universita degli Studi di Napoli “Federico II”, Naples, Italy 2 Istituto Nazionale dei Tumori, Fondazione Pascale, Naples, Italy Correspondence to: Francesco Esposito, email: // Alfredo Fusco, email: // Keywords : pseudogenes, HMGA, cancer, ceRNA Received : November 02, 2015 Accepted : February 05, 2016 Published : February 16, 2016 Abstract Pseudogenes are DNA sequences with high homology to the corresponding functional gene, but, because of the accumulation of various mutations, they have lost their initial functions to code for proteins. Consequently, pseudogenes have been considered until few years ago dysfunctional relatives of the corresponding ancestral genes, and then useless in the course of genome evolution. However, several studies have recently established that pseudogenes are owners of key biological functions. Indeed, some pseudogenes control the expression of functional genes by competitively binding to the miRNAs, some of them generate small interference RNAs to negatively modulate the expression of functional genes, and some of them even encode functional mutated proteins. Here, we concentrate our attention on the pseudogenes of the HMGA1 gene, that codes for the HMGA1a and HMGA1b proteins having a critical role in development and cancer progression. In this review, we analyze the family of HMGA1 pseudogenes through three aspects: classification, characterization, and their possible function and involvement in cancer.
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HMGA1 pseudogenes as candidate proto oncogenic competitive endogenous rnas
Oncotarget, 2014Co-Authors: Francesco Esposito, Marco De Martino, Giovanna Maria Pierantoni, Claudio Arra, Antonella Federico, Floriana Forzati, Maria Grazia Petti, Mara Tornincasa, Alfredo FuscoAbstract:The High Mobility Group A (HMGA) are nuclear proteins that participate in the organization of nucleoprotein complexes involved in chromatin structure, replication and gene transcription. HMGA overexpression is a feature of human cancer and plays a causal role in cell transformation. Since non-coding RNAs and pseudogenes are now recognized to be important in physiology and disease, we investigated HMGA1 pseudogenes in cancer settings using bioinformatics analysis. Here we report the identification and characterization of two HMGA1 non-coding pseudogenes, HMGA1P6 and HMGA1P7. We show that their overexpression increases the levels of HMGA1 and other cancer-related proteins by inhibiting the suppression of their synthesis mediated by microRNAs. Consistently, embryonic fibroblasts from HMGA1P7-overexpressing transgenic mice displayed a higher growth rate and reduced susceptibility to senescence. Moreover, HMGA1P6 and HMGA1P7 were overexpressed in human anaplastic thyroid carcinomas, which are highly aggressive, but not in differentiated papillary carcinomas, which are less aggressive. Lastly, the expression of the HMGA1 pseudogenes was significantly correlated with HMGA1 protein levels thereby implicating HMGA1P overexpression in cancer progression. In conclusion, HMGA1P6 and HMGA1P7 are potential proto-oncogenic competitive endogenous RNAs.
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HMGA1 hmga2 double knock out mice display a superpygmy phenotype
Biology Open, 2014Co-Authors: Antonella Federico, Francesco Esposito, Monica Fedele, Dario Palmieri, Giovanna Maria Pierantoni, Claudio Arra, Antonio Barbieri, Floriana Forzati, Giuseppe Palma, Ivana De MartinoAbstract:The HMGA1 and HMGA2 genes code for proteins belonging to the High Mobility Group A family. Several genes are negatively or positively regulated by both these proteins, but a number of genes are specifically regulated by only one of them. Indeed, knock-out of the HMGA1 and Hmga2 genes leads to different phenotypes: cardiac hypertrophy and type 2 diabetes in the former case, and a large reduction in body size and amount of fat tissue in the latter case. Therefore, to better elucidate the functions of the Hmga genes, we crossed HMGA1-null mice with mice null for Hmga2. The HMGA1 2/2 /Hmga2 2/2 mice showed reduced vitality and a very small size (75% smaller than the wild-type mice); they were even smaller than pygmy Hmga2-null mice. The drastic reduction in E2F1 activity, and consequently in the expression of the E2F-dependent genes involved in cell cycle regulation, likely accounts for some phenotypic features of the HMGA1 2/2 /Hmga2 2/2 mice.
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expression of a truncated HMGA1b gene induces gigantism lipomatosis and b cell lymphomas in mice
European Journal of Cancer, 2011Co-Authors: Monica Fedele, Francesco Esposito, Dario Palmieri, Andres J Kleinszanto, Rosa Visone, Ivana De Martino, Claudio Arra, Teresa Valentino, Andrea CiarmielloAbstract:HMGA1 gene rearrangements have been frequently described in human lipomas. In vitro studies suggest that HMGA1 proteins have a negative role in the control of adipocyte cell growth, and that HMGA1 gene truncation acts in a dominant-negative fashion. Therefore, to define better the role of the HMGA1 alterations in the generation of human lipomas, we generated mice carrying an HMGA1b truncated (HMGA1b/T) gene. These mice develop a giant phenotype together with a drastic expansion of the retroperitoneal and subcutaneous white adipose tissue. We show that the activation of the E2F pathway likely accounts, at least in part, for this phenotype. Interestingly, the HMGA1b/T mice also develop B-cell lymphomas similar to that occurring in HMGA1-knockout mice, supporting a dominant-negative role of the HMGA1b/T mutant also in vivo.