Publications by authors named "Alfredo Fusco"

287 Publications

Critical role of the high mobility group A proteins in hematological malignancies.

Hematol Oncol 2021 Oct 12. Epub 2021 Oct 12.

Department of Molecular Medicine and Medical Biotechnology (DMMBM), National Research Council (CNR), Institute for Experimental Endocrinology and Oncology (IEOS) "G. Salvatore", University of Naples "Federico II", Naples, Italy.

The high mobility group A (HMGA) protein family is composed of three non-histone chromatin remodeling proteins that act as architectural transcriptional factors. Indeed, although HMGA proteins lack transcriptional activity per se, they bind the minor groove of DNA at AT-rich sequences, and, interacting with the transcription machinery, are able to modify chromatin modeling, thus regulating the expression of several genes. HMGA proteins have been deeply involved in embryogenesis process, and a large volume of studies has pointed out their key role in human cancer. Here, we review the studies on the role of the HMGA proteins in human hematological malignancies: they are overexpressed in most of the cases and their expression correlates with a reduced survival. In some cases, such as in acute lymphoblastic leukemia and acute myelogenous leukemia, HMGA2 gene rearrangements have been also described. Finally, recent studies evidence a synergism between HMGA and EZH2 in diffuse B-cell lymphomas, suggesting an innovative therapy for this disease based on the inhibition of the function of both these proteins.
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http://dx.doi.org/10.1002/hon.2934DOI Listing
October 2021

Publisher Correction: HMGA1-pseudogene7 transgenic mice develop B cell lymphomas.

Sci Rep 2021 Jun 11;11(1):12741. Epub 2021 Jun 11.

Istituto di Endocrinologia ed Oncologia Sperimentale - CNR c/o Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli "Federico II", Naples, Italy.

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http://dx.doi.org/10.1038/s41598-021-92173-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8196011PMC
June 2021

HMGA1 induces EZH2 overexpression in human B-cell lymphomas.

Am J Cancer Res 2021 15;11(5):2174-2187. Epub 2021 May 15.

Institute of Endocrinology and Experimental Oncology-CNR c/o Department of Molecular Medicine and Medical Biotechnology, University of Naples "Federico II" Naples, Italy.

EZH2 is an enzymatic subunit of PRC2, an epigenetic regulator that triggers the methylation of the histone H3 lysine 27 silencing the transcription of several genes. EZH2 has a critical role in cancer progression, since its overexpression has been associated with increased cancer cell invasiveness, drug resistance and poor patient survival. However, the mechanisms accounting for EZH2 overexpression in cancer remain still unclear. Intriguingly, also HMGA protein overexpression is a feature of many human malignancies and correlates with the presence of metastases and a poor outcome. The HMGA proteins, including HMGA1 and HMGA2, belong to the architectural transcription factors that play a key role in the organization of chromatin structure. Here, we report a statistically significant correlation between HMGA1 and EZH2 expression in human lymphomas. We demonstrate that HMGA1 is able to bind promoter and induce its activity. Consistently, silencing of expression results in the downregulation of the levels leading to a decreased proliferation and migration rate of human lymphoma cell lines. Therefore, these data identify HMGA1 as an activator, suggesting a novel molecular mechanism contributing to EZH2 overexpression in human malignancies and a synergism of these proteins in cancer progression.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8167683PMC
May 2021

MPPED2 is downregulated in glioblastoma, and its restoration inhibits proliferation and increases the sensitivity to temozolomide of glioblastoma cells.

Cell Cycle 2021 04 18;20(7):716-729. Epub 2021 Mar 18.

Institute for Experimental Endocrinology and Oncology (IEOS) "G. Salvatore", National Research Council (CNR), Naples, Italy.

Glioblastoma (GBM) is the most aggressive and lethal neoplasia of the central nervous system in adults. Based on the molecular signature genes, GBM has been classified in proneural, neural, mesenchymal and classical subtypes. The Metallophosphoesterase-domain-containing protein 2 () gene encodes a metallophosphodiesterase protein highly conserved throughout the evolution. MPPED2 downregulation, likely due to its promoter hypermethylation, has been found in several malignant neoplasias and correlated with a poor prognosis. In this study, we aimed to investigate the expression and the functional role of MPPED2 in GBM. TCGA and Gravendeel databases were employed to explore the expression levels in this type of tumor. We have found that expression is downregulated in GBM patients, showing a positive correlation with survival. Moreover, TCGA and Gravendeel data also revealed that expression negatively correlates with the most aggressive mesenchymal subtype. Additionally, the restoration of expression in U251 and GLI36 GBM cell lines decreases cell growth, migration and enhanced the sensitivity to the temozolomide, inducing apoptotic cell death, of GBM cells. These findings suggest that the restoration of MPPED2 function can be taken into consideration for an innovative GBM therapy.
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http://dx.doi.org/10.1080/15384101.2021.1901042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8078659PMC
April 2021

Identification of HMGA2 inhibitors by AlphaScreen-based ultra-high-throughput screening assays.

Sci Rep 2020 11 2;10(1):18850. Epub 2020 Nov 2.

Biomolecular Sciences Institute, Florida International University, Miami, FL, 33199, USA.

The mammalian high mobility group protein AT-hook 2 (HMGA2) is a multi-functional DNA-binding protein that plays important roles in tumorigenesis and adipogenesis. Previous results showed that HMGA2 is a potential therapeutic target of anticancer and anti-obesity drugs by inhibiting its DNA-binding activities. Here we report the development of a miniaturized, automated AlphaScreen ultra-high-throughput screening assay to identify inhibitors targeting HMGA2-DNA interactions. After screening the LOPAC1280 compound library, we identified several compounds that strongly inhibit HMGA2-DNA interactions including suramin, a century-old, negatively charged antiparasitic drug. Our results show that the inhibition is likely through suramin binding to the "AT-hook" DNA-binding motifs and therefore preventing HMGA2 from binding to the minor groove of AT-rich DNA sequences. Since HMGA1 proteins also carry multiple "AT-hook" DNA-binding motifs, suramin is expected to inhibit HMGA1-DNA interactions as well. Biochemical and biophysical studies show that charge-charge interactions and hydrogen bonding between the suramin sulfonated groups and Arg/Lys residues play critical roles in the binding of suramin to the "AT-hook" DNA-binding motifs. Furthermore, our results suggest that HMGA2 may be one of suramin's cellular targets.
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http://dx.doi.org/10.1038/s41598-020-75890-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606612PMC
November 2020

The shows oncogenic activity .

Cell Cycle 2020 11 10;19(22):2955-2959. Epub 2020 Oct 10.

Istituto di Endocrinologia ed Oncologia Sperimentale - CNR C/o Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università Degli Studi di Napoli "Federico II" , Naples, Italy.

We have recently reported that transgenic mice overexpressing the develop hematological neoplasia marked by monoclonal B-cell populations, and diagnosed as Diffuse Large B-cell Lymphoma. These findings prove the oncogenic role .
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http://dx.doi.org/10.1080/15384101.2020.1829825DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7714516PMC
November 2020

Interplay between HMGA and TP53 in cell cycle control along tumor progression.

Cell Mol Life Sci 2021 Feb 12;78(3):817-831. Epub 2020 Sep 12.

Laboratório de Interações Celulares, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro Prédio de Ciências da Saúde-Cidade Universitária, Ilha do Fundão, A. Carlos Chagas, 373-Bloco F, Sala 26, 21941-902, Rio de Janeiro, RJ, Brazil.

The high mobility group A (HMGA) proteins are found to be aberrantly expressed in several tumors. Studies (in vitro and in vivo) have shown that HMGA protein overexpression has a causative role in carcinogenesis process. HMGA proteins regulate cell cycle progression through distinct mechanisms which strongly influence its normal dynamics along malignant transformation. Tumor protein p53 (TP53) is the most frequently altered gene in cancer. The loss of its activity is recognized as the fall of a barrier that enables neoplastic transformation. Among the different functions, TP53 signaling pathway is tightly involved in control of cell cycle, with cell cycle arrest being the main biological outcome observed upon p53 activation, which prevents accumulation of damaged DNA, as well as genomic instability. Therefore, the interaction and opposing effects of HMGA and p53 proteins on regulation of cell cycle in normal and tumor cells are discussed in this review. HMGA proteins and p53 may reciprocally regulate the expression and/or activity of each other, leading to the counteraction of their regulation mechanisms at different stages of the cell cycle. The existence of a functional crosstalk between these proteins in the control of cell cycle could open the possibility of targeting HMGA and p53 in combination with other therapeutic strategies, particularly those that target cell cycle regulation, to improve the management and prognosis of cancer patients.
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http://dx.doi.org/10.1007/s00018-020-03634-4DOI Listing
February 2021

Characterization of transgenic mouse embryonic fibroblasts.

Cell Cycle 2020 09 13;19(18):2281-2285. Epub 2020 Aug 13.

Istituto di Endocrinologia Ed Oncologia Sperimentale del CNR C/o Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università Degli Studi Di Napoli "Federico II" , Naples, Italy.

Latest studies have shown that deregulated pseudogene transcripts contribute to cancer working as competing endogenous RNAs. Our research group has recently demonstrated that the overexpression of two pseudogenes, and , has a critical role in cancer progression. These pseudogenes work sustaining the expression of HMGA1 and other cancer-related genes. We generated a mouse model overexpressing to better study the -pseudogene function in a more physiological context. Here, we show the proliferation rate and the susceptibility to senescence of mouse embryonic fibroblasts obtained from -overexpressing mice to better characterize the HMGA1-pseudogene function. Indeed, our study reports that mouse embryonic fibroblasts (MEFs) derived from mice express higher HMGA1 mRNA and protein levels. Moreover, these cells grow faster and senesce later than wild-type sustaining the oncogenic role of ceRNA crosstalk mediated by .
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http://dx.doi.org/10.1080/15384101.2020.1807080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7513866PMC
September 2020

HMGA1-Regulating microRNAs Let-7a and miR-26a are Downregulated in Human Seminomas.

Int J Mol Sci 2020 Apr 24;21(8). Epub 2020 Apr 24.

Department of Psychology, University of Campania "L. Vanvitelli", 81100 Caserta, Italy.

Background: Recent studies have underlined HMGA protein's key role in the onset of testicular germ cell tumors, where HMGA1 is differently expressed with respect to the state of differentiation, suggesting its fine regulation as master regulator in testicular tumorigenesis. Several studies have highlighted that the transcript is strictly regulated by a set of inhibitory microRNAs. Thus, the aim of this study is to test whether HMGA1 overexpression in human seminomas may be induced by the deregulation of miR-26a and Let-7a-two -targeting microRNAs.

Methods: mRNA and Let-7a and miR-26a levels were measured in a seminoma dataset available in the Cancer Genome Atlas database and confirmed in a subset of seminomas by qRT-PCR and western blot. A TCam-2 seminoma cell line was then transfected with Let-7a and miR-26a and tested for proliferation and motility abilities.

Results: an inverse correlation was found between the expression of miR-26a and Let-7a and expression levels in seminomas samples, suggesting a critical role of these microRNAs in levels regulation. Accordingly, functional studies showed that miR-26a and Let-7a inhibited the proliferation, migration and invasion capabilities of the human seminoma derived cell line TCam-2.

Conclusions: these data strongly support that the upregulation of HMGA1 levels occurring in seminoma is-at least in part-due to the downregulation of -targeting microRNAs.
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http://dx.doi.org/10.3390/ijms21083014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7215726PMC
April 2020

HMGA1-pseudogene7 transgenic mice develop B cell lymphomas.

Sci Rep 2020 04 27;10(1):7057. Epub 2020 Apr 27.

Istituto di Endocrinologia ed Oncologia Sperimentale - CNR c/o Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli "Federico II", Naples, Italy.

We have recently identified and characterized two pseudogenes (HMGA1P6 and HMGA1P7) of the HMGA1 gene, which has a critical role in malignant cell transformation and cancer progression. HMGA1P6 and HMGAP17 act as microRNA decoy for HMGA1 and other cancer-related genes upregulating their protein levels. We have previously shown that they are upregulated in several human carcinomas, and their expression positively correlates with a poor prognosis and an advanced cancer stage. To evaluate in vivo oncogenic activity of HMGA1 pseudogenes, we have generated a HMGA1P7 transgenic mouse line overexpressing this pseudogene. By a mean age of 12 months, about 50% of the transgenic mice developed splenomegaly and accumulation of lymphoid cells in several body compartments. For these mice FACS and immunohistochemical analyses suggested the diagnosis of B-cell lymphoma that was further supported by clonality analyses and RNA expression profile of the pathological tissues of the HMGA1P7 transgenic tissues. Therefore, these results clearly demonstrate the oncogenic activity of HMGA1 pseudogenes in vivo.
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http://dx.doi.org/10.1038/s41598-020-62974-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7184748PMC
April 2020

The Long Non-Coding RNA () Is Downregulated in Anaplastic Thyroid Carcinomas Where It Acts as a Tumor Suppressor by Reducing EZH2 Activity.

Cancers (Basel) 2020 Jan 17;12(1). Epub 2020 Jan 17.

Institute for Experimental Endocrinology and Oncology (IEOS) "G. Salvatore", National Research Council (CNR), via S. Pansini, 5-80131 Naples, Italy.

Anaplastic thyroid carcinoma (ATC) represents one the most aggressive neoplasias in humans, and, nowadays, limited advances have been made to extend the survival and reduce the mortality of ATC. Thus, the identification of molecular mechanism underlying its progression is needed. Here, we evaluated the long non-coding RNA (lncRNA) expression profile of nine ATC in comparison with five normal thyroid tissues by a lncRNA microarray. By this analysis, we identified 19 upregulated and 28 downregulated lncRNAs with a fold change >1.1 or <-1.1 and -value < 0.05, in ATC samples. Some of them were subsequently validated by qRT-PCR. Then, we investigated the role of the lncRNA (), drastically and specifically downregulated in ATC. The restoration of reduces proliferation and migration rates of ATC-derived cell lines indicating that its downregulation contributes to thyroid cancer progression. Our results suggest that exerts its anti-oncogenic role by impairing Enhancer of Zeste Homolog 2 (EZH2) oncogenic activity since we demonstrated that interacts with it in thyroid cancer cell lines, reducing EZH2 protein levels and its binding on the promoter, relieving E-cadherin from the negative regulation by EZH2. Consistently, EZH2 is overexpressed in ATC, but not in differentiated thyroid carcinomas. The results reported here define a tumor suppressor role for in undifferentiated thyroid neoplasias, further highlighting the pivotal role of lncRNAs in thyroid carcinogenesis.
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http://dx.doi.org/10.3390/cancers12010235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7017000PMC
January 2020

RPSAP52 lncRNA Inhibits p21Waf1/CIP Expression by Interacting With the RNA Binding Protein HuR.

Oncol Res 2020 Mar 12;28(2):191-201. Epub 2019 Dec 12.

Istituto per l'Endocrinologia e l'Oncologia Sperimentale (IEOS) "G. Salvatore," Consiglio Nazionale delle Ricerche (CNR) c/o Dipartimento di Medicina Molecolare e Biotecnologie Mediche (DMMBM), Università degli Studi di Napoli "Federico II,"NaplesItaly.

Long noncoding RNAs have been recently demonstrated to have an important role in fundamental biological processes, and their deregulated expression has been found in several human neoplasias. Our group has recently reported a drastic overexpression of the long noncoding RNA (lncRNA) RPSAP52 (ribosomal protein SA pseudogene 52) in pituitary adenomas. We have shown that this lncRNA increased cell proliferation by upregulating the expression of the chromatinic proteins HMGA1 and HMGA2, functioning as a competing endogenous RNA (ceRNA) through competitively binding to microRNA-15a (miR-15a), miR-15b, and miR-16. The aim of this work was to identify further mechanisms by which RPSAP52 overexpression could contribute to the development of pituitary adenomas. We investigated the involvement of RPSAP52 in the modulation of the expression of cell cycle-related genes, such as p21Waf1/CIP, whose deregulation plays a critical role in pituitary cell transformation. We report that RPSAP52, interacting with the RNA binding protein HuR (human antigen R), favors the delocalization of miR-15a, miR-15b, and miR-16 on the cyclin-dependent kinase inhibitor p21Waf1/CIP1 that, accordingly, results in downregulation in pituitary adenomas. A RNA immunoprecipitation sequencing (RIPseq) analysis performed on cells overexpressing RPSAP52 identified 40 messenger RNAs (mRNAs) enriched in Argonaute 2 (AGO2) immunoprecipitated samples. Among them, we focused on GAS8 (growth arrest-specific protein 8) gene. Consistently, GAS8 expression was downregulated in all the analyzed pituitary adenomas with respect to normal pituitary and in RPSAP52-overepressing cells, supporting the role of RPSAP52 in addressing genes involved in growth inhibition and cell cycle arrest to miRNA-induced degradation. This study unveils another RPSAP52-mediated molecular mechanism in pituitary tumorigenesis.
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http://dx.doi.org/10.3727/096504019X15761465603129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851518PMC
March 2020

Double knock-out of Hmga1 and Hipk2 genes causes perinatal death associated to respiratory distress and thyroid abnormalities in mice.

Cell Death Dis 2019 10 3;10(10):747. Epub 2019 Oct 3.

Department of Molecular Medicine and Medical Biotechnology, University of Naples, Naples, Italy.

The serine-threonine kinase homeodomain-interacting protein kinase 2 (HIPK2) modulates important cellular functions during development, acting as a signal integrator of a wide variety of stress signals, and as a regulator of transcription factors and cofactors. We have previously demonstrated that HIPK2 binds and phosphorylates High-Mobility Group A1 (HMGA1), an architectural chromatinic protein ubiquitously expressed in embryonic tissues, decreasing its binding affinity to DNA. To better define the functional role of HIPK2 and HMGA1 interaction in vivo, we generated mice in which both genes are disrupted. About 50% of these Hmga1/Hipk2 double knock-out (DKO) mice die within 12 h of life (P1) for respiratory failure. The DKO mice present an altered lung morphology, likely owing to a drastic reduction in the expression of surfactant proteins, that are required for lung development. Consistently, we report that both HMGA1 and HIPK2 proteins positively regulate the transcriptional activity of the genes encoding the surfactant proteins. Moreover, these mice display an altered expression of thyroid differentiation markers, reasonably because of a drastic reduction in the expression of the thyroid-specific transcription factors PAX8 and FOXE1, which we demonstrate here to be positively regulated by HMGA1 and HIPK2. Therefore, these data indicate a critical role of HIPK2/HMGA1 cooperation in lung and thyroid development and function, suggesting the potential involvement of their impairment in the pathogenesis of human lung and thyroid diseases.
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http://dx.doi.org/10.1038/s41419-019-1975-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6776533PMC
October 2019

A ceRNA Circuitry Involving the Long Noncoding RNA Klhl14-AS, Pax8, and Bcl2 Drives Thyroid Carcinogenesis.

Cancer Res 2019 Nov 26;79(22):5746-5757. Epub 2019 Sep 26.

Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy.

is a long noncoding RNA expressed since early specification of thyroid bud and is the most enriched gene in the mouse thyroid primordium at E10.5. Here, we studied its involvement in thyroid carcinogenesis by analyzing its expression in cancer tissues and different models of neoplastic transformation. Compared with normal thyroid tissue and cells, was significantly downregulated in human thyroid carcinoma tissue specimens, particularly the anaplastic histotype, thyroid cancer cell lines, and rodent models of thyroid cancer. Downregulating the expression of in normal thyroid cells decreased the expression of thyroid differentiation markers and cell death and increased cell viability. These effects were mediated by the binding of to two miRNAs, and , which silenced and , both essential players of thyroid differentiation. and were upregulated in human thyroid cancer and thyroid cancer experimental models and their effects on and were rescued by overexpression, confirming as a ceRNA for both and . This work connects deregulation of differentiation with increased proliferation and survival in thyroid neoplastic cells and highlights a novel ceRNA circuitry involving key regulators of thyroid physiology. SIGNIFICANCE: This study describes a new ceRNA with potential tumor suppression activity and helps us better understand the regulatory mechanisms during thyroid differentiation and carcinogenesis.
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http://dx.doi.org/10.1158/0008-5472.CAN-19-0039DOI Listing
November 2019

HMGA and Cancer: A Review on Patent Literatures.

Recent Pat Anticancer Drug Discov 2019 ;14(3):258-267

Istituto di Endocrinologia e Oncologia Sperimentale-CNR c/o Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Universita degli Studi di Napoli "Federico II", via Pansini 5, Naples 80131, Italy.

Background: The high mobility group A proteins modulate the transcription of numerous genes by interacting with transcription factors and/or altering the structure of chromatin. These proteins are involved in both benign and malignant neoplasias as a result of several pathways. A large amount of benign human mesenchymal tumors has rearrangements of HMGA genes. On the contrary, malignant tumors show unarranged HMGA overexpression that is frequently and causally related to neoplastic cell transformation. Here, we review the function of the HMGA proteins in human neoplastic disorders, the pathways by which they contribute to carcinogenesis and the new patents focused on targeting HMGA proteins.

Objective: Current review was conducted to check the involvement of HMGA as a druggable target in cancer treatment.

Methods: We reviewed the most recent patents focused on targeting HMGA in cancer treatment analyzing patent literature published during the last years, including the World Intellectual Property Organization (WIPO®), United States Patent Trademark Office (USPTO®), Espacenet®, and Google Patents.

Results: HMGA proteins are intriguing targets for cancer therapy and are objects of different patents based on the use of DNA aptamers, inhibitors, oncolytic viruses, antisense molecules able to block their oncogenic functions.

Conclusion: Powerful strategies able to selectively interfere with HMGA expression and function could represent a helpful approach in the development of new anti-cancer therapies.
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http://dx.doi.org/10.2174/1574892814666190919152001DOI Listing
May 2020

Emerging Role of USP8, HMGA, and Non-Coding RNAs in Pituitary Tumorigenesis.

Cancers (Basel) 2019 Sep 4;11(9). Epub 2019 Sep 4.

Istituto di Endocrinologia ed Oncologia Sperimentale-Consiglio Nazionale delle Ricerche (CNR) c/o Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli "Federico II", 80131 Naples, Italy.

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 and 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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http://dx.doi.org/10.3390/cancers11091302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6770943PMC
September 2019

The () Gene Acts as Tumor Suppressor in Breast Cancer.

Cancers (Basel) 2019 Jun 8;11(6). Epub 2019 Jun 8.

Institute for Experimental Endocrinology and Oncology (IEOS) "G. Salvatore", National Research Council (CNR), Via Sergio Pansini 5, 80131 Naples, Italy.

: We have recently reported the downregulation of the gene and its cognate long non-coding RNA, , in papillary thyroid carcinomas. Functional studies supported a tumor suppressor role of both these genes in thyroid carcinogenesis. We then decided to investigate their role in breast carcinogenesis. : In order to verify expression, 45 human breast carcinoma samples have been investigated by quantitative real-time polymerase chain reaction (qRT-PCR). Then, has been transfected in several human breast carcinoma cell lines, analyzing its role in cell proliferation, migration and invasion. To study the regulation of expression the methylation of its promoter was investigated by targeted bisulfite sequencing. : expression was decreased in breast cancer samples, and this was confirmed by the analysis of data available in The Cancer Genome Atlas (TCGA). Interestingly, the hypermethylation of promoter likely accounted for its downregulation in breast cancer. Additionally, was also found downregulated in breast cancer tissues and, intriguingly, its expression decreased the hypermethylation of the promoter by inhibiting DNA methyltransferase 1 (DNMT1). Furthermore, the restoration of expression reduced cell proliferation, migration and invasion capability of breast carcinoma cell lines. : Taken together, these results propose downregulation as a critical event in breast carcinogenesis.
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http://dx.doi.org/10.3390/cancers11060797DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6627064PMC
June 2019

HMGA1 negatively regulates NUMB expression at transcriptional and post transcriptional level in glioblastoma stem cells.

Cell Cycle 2019 07 22;18(13):1446-1457. Epub 2019 May 22.

a Istituto di Endocrinologia ed Oncologia Sperimentale - CNR c/o Dipartimento di Medicina Molecolare e Biotecnologie Mediche , Università degli Studi di Napoli "Federico II" , Naples , Italy.

Glioblastoma (GBM) is a lethal, fast-growing brain cancer, affecting 2-3 per 100,000 adults per year. It arises from multipotent neural stem cells which have reduced their ability to divide asymmetrically and hence divide symmetrically, generating increasing number of cancer stem cells, fostering tumor growth. We have previously demonstrated that the architectural transcription factor HMGA1 is highly expressed in brain tumor stem cells (BTSCs) and that its silencing increases stem cell quiescence, reduces self-renewal and sphere-forming efficiency in serial passages, suggesting a shift from symmetric to asymmetric division. Since NUMB expression is fundamental for the fulfillment of asymmetric division in stem cells, and is lost or reduced in many tumors, including GBM, we have investigated the ability of HMGA1 to regulate NUMB expression. Here, we show that HMGA1 negatively regulates NUMB expression at transcriptional level, by binding its promoter and counteracting c/EBP-β and at posttranscriptional level, by regulating the expression of MSI1 and of miR-146a. Finally, we report that HMGA1 knockdown-induced NUMB upregulation leads to the downregulation of the NOTCH1 pathway. Therefore, the data reported here indicate that HMGA1 negatively regulates NUMB expression in BTSCs, further supporting HMGA1 targeting as innovative and effective anti-cancer therapy.
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http://dx.doi.org/10.1080/15384101.2019.1618541DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6592240PMC
July 2019

Overexpression of Figures as a Potential Prognostic Factor in Endometrioid Endometrial Carcinoma (EEC).

Genes (Basel) 2019 05 15;10(5). Epub 2019 May 15.

Programa de Carcinogênese Molecular, Instituto Nacional de Câncer-INCA, Rua André Cavalcanti, 37 - Centro, Rio de Janeiro, RJ 20231-050, Brazil.

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 expression is associated with increased histological grade and tumor size. Moreover, but not overexpression was identified as a negative prognostic factor to EEC patients. Finally, a positive correlation between expression of pseudogenes- and -and HMGA1 itself was detected, suggesting HMGA1 pseudogenes may play a role in HMGA1 expression regulation in EEC. Thus, these results indicate that overexpression possesses a potential role as a prognostic biomarker for EEC.
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http://dx.doi.org/10.3390/genes10050372DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562754PMC
May 2019

RPSAP52 lncRNA is overexpressed in pituitary tumors and promotes cell proliferation by acting as miRNA sponge for HMGA proteins.

J Mol Med (Berl) 2019 07 10;97(7):1019-1032. Epub 2019 May 10.

Istituto per l'Endocrinologia e l'Oncologia Sperimentale (IEOS) "G. Salvatore", Consiglio Nazionale delle Ricerche (CNR) c/o Dipartimento di Medicina Molecolare e Biotecnologie Mediche (DMMBM), Università degli Studi di Napoli "Federico II", Via Pansini 5, 80131, Naples, Italy.

Long non-coding RNAs (lncRNAs) are emerging as fundamental players in cancer biology. Indeed, they are deregulated in several neoplasias and have been associated with cancer progression, tumor recurrence, and resistance to treatment, thus representing potential biomarkers for cancer diagnosis, prognosis, and therapy. In this study, we aimed to identify lncRNAs associated with pituitary tumorigenesis. We have analyzed the lncRNA expression profile of a panel of gonadotroph pituitary adenomas in comparison with normal pituitaries. Then, we focused on RPSAP52, a novel lncRNA antisense for the HMGA2 gene, whose overexpression plays a critical role in the development of pituitary adenomas. We report that RPSAP52 expression is highly upregulated in gonadotroph and prolactin-secreting pituitary adenomas, where it correlates with that of HMGA2, compared with normal pituitary tissues. Conversely, its expression showed a variable behavior in somatotroph adenomas. We also demonstrate that RPSAP52 enhances HMGA2 protein expression in a ceRNA-dependent way acting as sponge for miR-15a, miR-15b, and miR-16, which have been already described to be able to target HMGA2. Interestingly, RPSAP52 also positively modulates HMGA1, the other member of the High-Mobility Group A family. Moreover, functional studies indicate that RPSAP52 promotes cell growth by enhancing the G1-S transition of the cell cycle. The results reported here reveal a novel mechanism, based on the overexpression of the lncRNA RPSAP52, which contributes to pituitary tumorigenesis, and propose this lncRNA as a novel player in the development of these tumors. KEY MESSAGES: RPSAP52 is overexpressed in pituitary adenomas. RPSAP52 increases HMGA protein levels. A ceRNA mechanism is proposed for the increased HMGA1/2 expression.
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http://dx.doi.org/10.1007/s00109-019-01789-7DOI Listing
July 2019

Oncogenic Properties of the Antisense lncRNA in - and -Driven Papillary Thyroid Carcinomas.

Cancer Res 2019 05 12;79(9):2124-2135. Epub 2019 Mar 12.

Institute of Genetics and Biophysics "Adriano Buzzati-Traverso," CNR, Naples, Italy.

rearrangements as well as and mutations drive differential pathway activation in papillary thyroid carcinomas, leading to different tumor phenotypes and prognoses. Although The Cancer Genome Atlas Consortium has identified tumor subgroups based on protein-coding gene signatures, neither expression of long noncoding RNAs (lncRNA) nor their correlation with specific tumor-driving mutations and rearrangements have been systematically assessed. Here, we reanalyzed our RNA-sequencing data using a discovery approach to identify lncRNAs and define tumor subtype-specific signatures of annotated lncRNAs. Among them, we identified (Correlated-to-), a natural antisense transcript that was highly expressed in carcinomas harboring mutation or gene rearrangements (i.e., -like tumors) and induced the downstream MAPK pathway. In papillary thyroid carcinomas, was part of a coexpression network including different oncogenes belonging to the MAPK pathway, and its expression highly correlated with expression. Depletion of resulted in reduced expression of genes within this network, including the oncogene. repression inhibited viability and proliferation of tumor cells harboring somatic mutation or oncogene rearrangement and dramatically reduced motility and invasiveness of tumor cells. Moreover, silencing markedly increased sensitivity to vemurafenib, a common inhibitor of mutated B-raf. Collectively, our results suggest as a new target to improve drug-based cancer therapies, especially in -mutated and -addicted papillary thyroid carcinomas. SIGNIFICANCE: These results highlight the oncogenic role of lncRNA in thyroid and indicate it as a potential new target to overcome vemurafenib resistance in -mutated and MET-addicted carcinomas.
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http://dx.doi.org/10.1158/0008-5472.CAN-18-2520DOI Listing
May 2019

The complex CBX7-PRMT1 has a critical role in regulating E-cadherin gene expression and cell migration.

Biochim Biophys Acta Gene Regul Mech 2019 04 28;1862(4):509-521. Epub 2019 Feb 28.

Istituto di Endocrinologia ed Oncologia Sperimentale - CNR c/o Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli "Federico II", Naples, Italy. Electronic address:

The Chromobox protein homolog 7 (CBX7) belongs to the Polycomb Group (PcG) family, and, as part of the Polycomb repressive complex (PRC1), contributes to maintain transcriptional gene repression. Loss of CBX7 expression has been reported in several human malignant neoplasias, where it often correlates with an advanced cancer state and poor survival, proposing CBX7 as a candidate tumor-suppressor gene in cancer progression. Indeed, CBX7 is able to positively or negatively regulate the expression of genes involved in cell proliferation and cancer progression, such as E-cadherin, cyclin E, osteopontin, EGR1. To understand the molecular mechanisms that underlie the involvement of CBX7 in cancer progression, we designed a functional proteomic experiment based on CHIP-MS to identify novel CBX7 protein partners. Among the identified CBX7-interacting proteins we focused our attention on the Protein Arginine Methyltransferase 1 (PRMT1) whose critical role in epithelial-mesenchymal transition (EMT), cancer cell migration and invasion has been already reported. We confirmed the interaction between CBX7 and PRMT1 and demonstrated that this interaction is crucial for PRMT1 enzymatic activity both in vitro and in vivo and for the regulation of E-cadherin expression, an important hallmark of EMT. These results suggest a general mechanism by which CBX7 interacting with histone modification enzymes like HDAC2 and PRMT1 enhances E-cadherin expression. Therefore, disruption of this equilibrium may induce impairment of E-cadherin expression and increased cell migration eventually leading to EMT and, then, cancer progression.
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http://dx.doi.org/10.1016/j.bbagrm.2019.02.006DOI Listing
April 2019
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