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1.
Hematol Oncol ; 2021 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-34637548

RESUMO

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.

3.
Am J Cancer Res ; 11(5): 2174-2187, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34094676

RESUMO

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 EZH2 promoter and induce its activity. Consistently, silencing of HMGA1 expression results in the downregulation of the EZH2 levels leading to a decreased proliferation and migration rate of human lymphoma cell lines. Therefore, these data identify HMGA1 as an EZH2 activator, suggesting a novel molecular mechanism contributing to EZH2 overexpression in human malignancies and a synergism of these proteins in cancer progression.

4.
Cell Cycle ; 20(7): 716-729, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33734003

RESUMO

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 (MPPED2) 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 MPPED2 expression levels in this type of tumor. We have found that MPPED2 expression is downregulated in GBM patients, showing a positive correlation with survival. Moreover, TCGA and Gravendeel data also revealed that MPPED2 expression negatively correlates with the most aggressive mesenchymal subtype. Additionally, the restoration of MPPED2 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.

6.
Cell Mol Life Sci ; 78(3): 817-831, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32920697

RESUMO

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.


Assuntos
Pontos de Checagem do Ciclo Celular/fisiologia , Proteínas HMGA/metabolismo , Neoplasias/patologia , Proteína Supressora de Tumor p53/metabolismo , Dano ao DNA , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Instabilidade Genômica , Proteínas HMGA/genética , Humanos , Neoplasias/genética , Neoplasias/metabolismo , Transdução de Sinais , Proteína Supressora de Tumor p53/genética
7.
Sci Rep ; 10(1): 18850, 2020 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-33139812

RESUMO

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.


Assuntos
Proteínas de Ligação a DNA/antagonistas & inibidores , Proteína HMGA1a/antagonistas & inibidores , Proteína HMGA2/antagonistas & inibidores , Suramina/química , Adipogenia/efeitos dos fármacos , Motivos de Aminoácidos/efeitos dos fármacos , Sequência de Bases/efeitos dos fármacos , Sítios de Ligação/efeitos dos fármacos , Carcinogênese/efeitos dos fármacos , DNA/efeitos dos fármacos , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/genética , Proteína HMGA1a/química , Proteína HMGA1a/genética , Proteína HMGA2/química , Proteína HMGA2/genética , Ensaios de Triagem em Larga Escala , Humanos , Suramina/isolamento & purificação , Suramina/farmacologia
8.
Cell Cycle ; 19(22): 2955-2959, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33043837

RESUMO

We have recently reported that transgenic mice overexpressing the HMGA1-pseudogene7 develop hematological neoplasia marked by monoclonal B-cell populations, and diagnosed as Diffuse Large B-cell Lymphoma. These findings prove the HMGA1-pseudogene7 oncogenic role in vivo.

9.
Cell Cycle ; 19(18): 2281-2285, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32787507

RESUMO

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 HMGA1 pseudogenes, HMGA1P6 and HMGA1P7, 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 HMGA1P6 to better study the HMGA1-pseudogene function in a more physiological context. Here, we show the proliferation rate and the susceptibility to senescence of mouse embryonic fibroblasts obtained from HMGA1P6-overexpressing mice to better characterize the HMGA1-pseudogene function. Indeed, our study reports that mouse embryonic fibroblasts (MEFs) derived from HMGA1P6 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 HMGA1Ps.

11.
Int J Mol Sci ; 21(8)2020 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-32344629

RESUMO

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 HMGA1 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 HMGA1-targeting microRNAs. METHODS: HMGA1 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 HMGA1 expression levels in seminomas samples, suggesting a critical role of these microRNAs in HMGA1 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 HMGA1-targeting microRNAs.


Assuntos
Regulação Neoplásica da Expressão Gênica , Proteína HMGA1a/metabolismo , MicroRNAs/genética , Seminoma/genética , Seminoma/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Humanos , Masculino , Interferência de RNA , RNA Mensageiro/genética , Seminoma/patologia
12.
Sci Rep ; 10(1): 7057, 2020 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-32341372

RESUMO

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.


Assuntos
Proteína HMGA1a/metabolismo , Linfoma de Células B/metabolismo , Animais , Citometria de Fluxo , Proteína HMGA1a/genética , Imuno-Histoquímica , Linfócitos/metabolismo , Linfoma de Células B/genética , Camundongos , Camundongos Transgênicos , Células NIH 3T3 , Pseudogenes/genética , RNA-Seq
13.
Cancers (Basel) ; 12(1)2020 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-31963578

RESUMO

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 p-value < 0.05, in ATC samples. Some of them were subsequently validated by qRT-PCR. Then, we investigated the role of the lncRNA Prader Willi/Angelman region RNA5 (PAR5), drastically and specifically downregulated in ATC. The restoration of PAR5 reduces proliferation and migration rates of ATC-derived cell lines indicating that its downregulation contributes to thyroid cancer progression. Our results suggest that PAR5 exerts its anti-oncogenic role by impairing Enhancer of Zeste Homolog 2 (EZH2) oncogenic activity since we demonstrated that PAR5 interacts with it in thyroid cancer cell lines, reducing EZH2 protein levels and its binding on the E-cadherin 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 PAR5 in undifferentiated thyroid neoplasias, further highlighting the pivotal role of lncRNAs in thyroid carcinogenesis.

14.
Oncol Res ; 28(2): 191-201, 2020 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-31831098

RESUMO

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.


Assuntos
Inibidor de Quinase Dependente de Ciclina p21/genética , Proteína Semelhante a ELAV 1/genética , Neoplasias Hipofisárias/genética , RNA Longo não Codificante/genética , Proteínas Argonauta/genética , Carcinogênese/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Proteínas do Citoesqueleto/genética , Regulação Neoplásica da Expressão Gênica/genética , Proteína HMGA1a/genética , Proteína HMGA2/genética , Humanos , MicroRNAs/genética , Proteínas de Neoplasias/genética , Neoplasias Hipofisárias/patologia , RNA Mensageiro/genética , Proteínas de Ligação a RNA/genética
15.
Cell Death Dis ; 10(10): 747, 2019 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-31582725

RESUMO

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.


Assuntos
Proteína HMGA1a/genética , Proteínas Serina-Treonina Quinases/genética , Doenças Respiratórias/genética , Glândula Tireoide/anormalidades , Animais , Animais Recém-Nascidos , Desenvolvimento Embrionário , Deleção de Genes , Regulação da Expressão Gênica , Proteína HMGA1a/metabolismo , Células HeLa , Humanos , Pulmão/metabolismo , Pulmão/patologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Associadas a Surfactantes Pulmonares , Doenças Respiratórias/patologia , Glândula Tireoide/embriologia , Glândula Tireoide/patologia
16.
Cancers (Basel) ; 11(9)2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31487906

RESUMO

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.

17.
Cancer Res ; 79(22): 5746-5757, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31558562

RESUMO

Klhl14-AS 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, Klhl14-AS 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 Klhl14-AS 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 Klhl14-AS to two miRNAs, Mir182-5p and Mir20a-5p, which silenced Pax8 and Bcl2, both essential players of thyroid differentiation. MIR182-5p and MIR20a-5p were upregulated in human thyroid cancer and thyroid cancer experimental models and their effects on Pax8 and Bcl2 were rescued by Klhl14-AS overexpression, confirming Klhl14-AS as a ceRNA for both Pax8 and Bcl2. 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.


Assuntos
Carcinogênese/genética , Fator de Transcrição PAX8/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , RNA Longo não Codificante/genética , Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Animais , Biomarcadores Tumorais/genética , Carcinogênese/patologia , Morte Celular/genética , Diferenciação Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Sobrevivência Celular/genética , Regulação para Baixo/genética , Regulação Neoplásica da Expressão Gênica/genética , Células HeLa , Humanos , Camundongos , Camundongos Transgênicos , MicroRNAs/genética , Regulação para Cima/genética
18.
Recent Pat Anticancer Drug Discov ; 14(3): 258-267, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31538905

RESUMO

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.


Assuntos
Aptâmeros de Nucleotídeos/farmacologia , Proteínas HMGA/antagonistas & inibidores , Neoplasias/terapia , RNA Interferente Pequeno/farmacologia , Bases de Dados Factuais , Proteínas HMGA/genética , Proteínas HMGA/metabolismo , Humanos , Terapia de Alvo Molecular , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Terapia Viral Oncolítica , Patentes como Assunto , Fatores de Transcrição/metabolismo
19.
Cancers (Basel) ; 11(6)2019 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-31181813

RESUMO

Background: We have recently reported the downregulation of the Metallophosphoesterase-domain-containing protein 2 (MPPED2) gene and its cognate long non-coding RNA, MPPED2-AS1, 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. Methods: In order to verify MPPED2 expression, 45 human breast carcinoma samples have been investigated by quantitative real-time polymerase chain reaction (qRT-PCR). Then, MPPED2 has been transfected in several human breast carcinoma cell lines, analyzing its role in cell proliferation, migration and invasion. To study the regulation of MPPED2 expression the methylation of its promoter was investigated by targeted bisulfite sequencing. Results: MPPED2 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 MPPED2 promoter likely accounted for its downregulation in breast cancer. Additionally, MPPED2-AS1 was also found downregulated in breast cancer tissues and, intriguingly, its expression decreased the hypermethylation of the MPPED2 promoter by inhibiting DNA methyltransferase 1 (DNMT1). Furthermore, the restoration of MPPED2 expression reduced cell proliferation, migration and invasion capability of breast carcinoma cell lines. Conclusion: Taken together, these results propose MPPED2 downregulation as a critical event in breast carcinogenesis.

20.
Genes (Basel) ; 10(5)2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-31096664

RESUMO

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.


Assuntos
Carcinoma Endometrioide/genética , Neoplasias do Endométrio/genética , Proteína HMGA1a/genética , Proteína HMGA2/genética , Adulto , Biomarcadores Tumorais/biossíntese , Biomarcadores Tumorais/genética , Carcinoma Endometrioide/metabolismo , Neoplasias do Endométrio/metabolismo , Feminino , Proteína HMGA1a/biossíntese , Proteína HMGA2/biossíntese , Humanos , Pessoa de Meia-Idade , Prognóstico , Transcriptoma
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