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1.
Am J Hum Genet ; 108(2): 337-345, 2021 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-33434492

RESUMO

Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS) is associated with congenital absence of the uterus, cervix, and the upper part of the vagina; it is a sex-limited trait. Disrupted development of the Müllerian ducts (MD)/Wölffian ducts (WD) through multifactorial mechanisms has been proposed to underlie MRKHS. In this study, exome sequencing (ES) was performed on a Chinese discovery cohort (442 affected subjects and 941 female control subjects) and a replication MRKHS cohort (150 affected subjects of mixed ethnicity from North America, South America, and Europe). Phenotypic follow-up of the female reproductive system was performed on an additional cohort of PAX8-associated congenital hypothyroidism (CH) (n = 5, Chinese). By analyzing 19 candidate genes essential for MD/WD development, we identified 12 likely gene-disrupting (LGD) variants in 7 genes: PAX8 (n = 4), BMP4 (n = 2), BMP7 (n = 2), TBX6 (n = 1), HOXA10 (n = 1), EMX2 (n = 1), and WNT9B (n = 1), while LGD variants in these genes were not detected in control samples (p = 1.27E-06). Interestingly, a sex-limited penetrance with paternal inheritance was observed in multiple families. One additional PAX8 LGD variant from the replication cohort and two missense variants from both cohorts were revealed to cause loss-of-function of the protein. From the PAX8-associated CH cohort, we identified one individual presenting a syndromic condition characterized by CH and MRKHS (CH-MRKHS). Our study demonstrates the comprehensive utilization of knowledge from developmental biology toward elucidating genetic perturbations, i.e., rare pathogenic alleles involving the same loci, contributing to human birth defects.


Assuntos
Transtornos 46, XX do Desenvolvimento Sexual/genética , Anormalidades Congênitas/genética , Ductos Paramesonéfricos/anormalidades , Ductos Paramesonéfricos/crescimento & desenvolvimento , Mutação , Ductos Mesonéfricos/crescimento & desenvolvimento , Adulto , Proteína Morfogenética Óssea 4/genética , Proteína Morfogenética Óssea 7/genética , Códon sem Sentido , Feminino , Estudos de Associação Genética , Pleiotropia Genética , Proteínas Homeobox A10/genética , Proteínas de Homeodomínio/genética , Humanos , Fator de Transcrição PAX8/genética , Herança Paterna , Penetrância , Proteínas com Domínio T/genética , Fatores de Transcrição/genética , Proteínas Wnt/genética , Ductos Mesonéfricos/anormalidades
2.
PLoS Pathog ; 16(8): e1008778, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32841292

RESUMO

EBV-associated gastric cancer (EBVaGC) is characterized by high frequency of DNA methylation. In this study, we investigated how epigenetic alteration of host genome contributes to pathogenesis of EBVaGC through the analysis of transcriptomic and epigenomic datasets from NIH TCGA (The Cancer Genome Atlas) consortium. We identified that immune related genes (IRGs) is a group of host genes preferentially silenced in EBV-positive gastric cancers through DNA hypermethylation. Further functional characterizations of selected IRGs reveal their novel antiviral activity against not only EBV but also KSHV. In particular, we showed that metallothionein-1 (MT1) and homeobox A (HOXA) gene clusters are down-regulated via EBV-driven DNA hypermethylation. Several MT1 isoforms suppress EBV lytic replication and release of progeny virions as well as KSHV lytic reactivation, suggesting functional redundancy of these genes. In addition, single HOXA10 isoform exerts antiviral activity against both EBV and KSHV. We also confirmed the antiviral effect of other dysregulated IRGs, such as IRAK2 and MAL, in scenario of EBV and KSHV lytic reactivation. Collectively, our results demonstrated that epigenetic silencing of IRGs is a viral strategy to escape immune surveillance and promote viral propagation, which is overall beneficial to viral oncogenesis of human gamma-herpesviruses (EBV and KSHV), considering that these IRGs possess antiviral activities against these oncoviruses.


Assuntos
Biomarcadores/metabolismo , Epigênese Genética , Gammaherpesvirinae/isolamento & purificação , Regulação Viral da Expressão Gênica , Infecções por Herpesviridae/complicações , Interações Hospedeiro-Patógeno , Neoplasias Gástricas/genética , Biomarcadores/análise , Metilação de DNA , Gammaherpesvirinae/genética , Células HEK293 , Infecções por Herpesviridae/virologia , Proteínas Homeobox A10/genética , Humanos , Incidência , Metalotioneína/genética , Neoplasias Gástricas/epidemiologia , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/virologia , Ativação Viral , Replicação Viral
3.
Int J Mol Med ; 45(3): 836-846, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31985027

RESUMO

Circular RNAs have been reported to play a vital role in the development and progression of various types of cancer. However, the underlying molecular role of circular RNA CTDP1 (circCTDP1) in the tumorigenesis of nasopharyngeal carcinoma (NPC) remains unknown. In the present study, circCTDP1 expression was found to be markedly upregulated in NPC tissues and cell lines (SUNE1, SUNE2 and 6­10B cell lines). Knockdown of circCTDP1 resulted in inhibition of proliferation, migration and invasion, and promoted apoptosis of NPC cells. Moreover, circCTDP1 directly interacted with microRNA (miR)­320b based on bioinformatics prediction and dual luciferase assay, and transfection with an miR­320b inhibitor reversed the effects of circCTDP1 knockdown on NPC cells. Furthermore, circCTDP1/miR­320b promoted NPC progression by regulating the expression of homeobox A10 (HOXA10). In addition, it was demonstrated that HOXA10 may exert its oncogenic role in NPC by regulating the expression of transforming growth factor ß2 (TGFß2). Taken together, these results revealed a novel regulatory mechanism, which may provide an improved understanding of NPC tumorigenesis and be useful in the development of potential targets for NPC therapy.


Assuntos
Proteínas Homeobox A10/metabolismo , MicroRNAs/metabolismo , Carcinoma Nasofaríngeo/metabolismo , Neoplasias Nasofaríngeas/metabolismo , RNA Circular/metabolismo , RNA Longo não Codificante/metabolismo , Fator de Crescimento Transformador beta2/metabolismo , Adulto , Idoso , Animais , Western Blotting , Linhagem Celular , Movimento Celular/genética , Movimento Celular/fisiologia , Biologia Computacional , Progressão da Doença , Feminino , Citometria de Fluxo , Regulação Neoplásica da Expressão Gênica/genética , Células HEK293 , Proteínas Homeobox A10/genética , Humanos , Técnicas In Vitro , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/genética , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/genética , RNA Circular/genética , RNA Longo não Codificante/genética , Ratos , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Fator de Crescimento Transformador beta2/genética , Cicatrização/genética , Cicatrização/fisiologia
4.
Med Sci Monit ; 26: e919460, 2020 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-31927557

RESUMO

BACKGROUND Small nuclear ribonucleoproteins (snRNPs) complexes of protein and noncoding RNA accumulate in the cell nucleus and catalyze pre-mRNA splicing to form the spliceosome. This study aimed to investigate the role of the spliceosome, splicing factor 3b subunit 1 (SF3B1), in AGS and MKN28 human gastric cancer cells in vitro, including gene knockdown with small interfering RNA (siRNA), and the use of the selective mRNA splicing inhibitor of SF3B1, pladienolide B. MATERIAL AND METHODS In AGS and MKN28 human gastric cancer cells, SF3B1expression was inhibited with siRNA and pladienolide B. Following SF3B1 inhibition, the Cell Counting Kit-8 (CCK-8) assay measured cell proliferation, and flow cytometry was used to investigate cell apoptosis and cell cycle arrest. The downstream HOXA10 and AKT pathways were studied by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and Western blot. The presence of alternative splicing, or differential splicing, of single-gene coding for multiple proteins, was analyzed using The Cancer Genome Atlas (TCGA) SpliceSeq. RESULTS Inhibition of SF3B1 reduced the proliferation rate of AGS and MKN28 human gastric cancer cells by inducing apoptosis and G2/M phase arrest. SF3B1 knockdown resulted in reduced homeobox A10 (HOXA10) mRNA expression and expression of long noncoding RNA (lncRNA) isoforms of HOXA10 (exons 1 and 3) and HOXA10 (exons 2 and 3). SF3B1 inhibition increased PTEN levels and reduced AKT protein phosphorylation. CONCLUSIONS In AGS and MKN28 human gastric cancer cells in vitro, inhibition of SF3B1 reduced cell proliferation, induced apoptosis, and resulted in cell cycle arrest by regulating HOXA10 splicing.


Assuntos
Apoptose , Pontos de Checagem do Ciclo Celular , Proteínas Homeobox A10/metabolismo , Fosfoproteínas/metabolismo , Fatores de Processamento de RNA/metabolismo , Neoplasias Gástricas/patologia , Processamento Alternativo/genética , Apoptose/efeitos dos fármacos , Apoptose/genética , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Compostos de Epóxi/química , Compostos de Epóxi/farmacologia , Éxons/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proteínas Homeobox A10/genética , Humanos , Macrolídeos/química , Macrolídeos/farmacologia , Fosfoproteínas/genética , Fatores de Processamento de RNA/genética , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Neoplasias Gástricas/genética
5.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 51(1): 24-29, 2020 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-31950785

RESUMO

Objective: To investigate the effect of antisense oligodeoxynucleotides (ASODN) of Homeobox A1 gene ( HOXA1) on proliferation, apoptosis, invasion and migration of esophageal carcinoma cells. Methods: The expression of HOXA1 protein in normal esophageal epithelial cells Het-1A and esophageal cancer TE-1, EC9706 and Eca109 cells was detected by Western blot. Screening of highly expressed of HOXA1 protein esophageal squamous cell carcinoma cells for follow-up experiments. HOXA1 antisense oligonucleotide (ASODN) chains, sense oligodeoxynucleotides (SODN) chain, and nonsense oligodeoxy nucleotides (N-ODN) chain were designed. The screened esophageal squamous cell carcinoma cells with high expression were divided into HOXA1 ASODN group (5, 10, 15 µmol/L HOXA1 ASODN transfected Eca109 cells), control group (conventional culture medium, no cell transfection), SODN group (cells transfected with 15 µmol/L of SODN) and N-ODN group (cells transfected with 15 µmol/L N-ODN). Cell viability, apoptosis rate and invasion and migration ability were detected by methylthiazolyldiphenyl-tetrazolium bromide (MTT) method, flow cytometry, transwell chamber respectively; The expression of HOXA1, phosphorylation serine/threonine kinase (p-AKT), proliferating cell nuclear antigen (PCNA), matrix metalloproteinase 2 (MMP-2) and B-cell lymphoma2 (Bcl-2) associated X protein (Bax) protein was detected by Western blot. Results: Compared with normal esophageal epithelial cells Het-1A, the expression of HOXA1 protein in human esophageal squamous cell carcinoma cells TE-1, EC9706 and Eca109 was significantly higher ( P<0.05). The expression of HOXA1 protein was the highest in Eca109 cells, therefore, Eca109 cells were selected for follow-up experiments. The expression of HOXA1 protein in Eca109 cells transfected with HOXA1 ASODN was significantly decreased ( P<0.05). After transfection of Eca109 cells with HOXA1 ASODN, the viability of Eca109 cells decreased with the increase of concentration and time, the difference was significant compared with the control, SODN and N-ODN groups ( P<0.05). 15 µmol/L HOXA1 ASODN significantly inhibited cell viability. After 15 µmol/L HOXA1 ASODN was transfected into Eca109 cells, the invasion and migration abilities of cells were significantly decreased, the apoptosis rate was increased, the expressions of p-AKT, PCNA and MMP-2 were significantly decreased, and the expression of Bax was significantly increased ( P<0.05). Conclusion: Antisense oligodeoxynucleotides of HOXA1 gene can inhibit the proliferation, invasion and migration of esophageal cancer cells, and induce apoptosis. The mechanism is related to the inhibition of PI3K/AKT signaling pathway.


Assuntos
Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Proteínas Homeobox A10 , Oligonucleotídeos Antissenso , Apoptose/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias Esofágicas/fisiopatologia , Carcinoma de Células Escamosas do Esôfago/fisiopatologia , Proteínas Homeobox A10/genética , Humanos , Oligonucleotídeos Antissenso/farmacologia , Transfecção
6.
Blood Adv ; 3(24): 4252-4263, 2019 12 23.
Artigo em Inglês | MEDLINE | ID: mdl-31867596

RESUMO

HOX genes are highly conserved, and their precisely controlled expression is crucial for normal hematopoiesis. Accordingly, deregulation of HOX genes can cause leukemia. However, despite of intensive research on the coding HOX genes, the role of the numerous long noncoding RNAs (lncRNAs) within the HOX clusters during hematopoiesis and their contribution to leukemogenesis are incompletely understood. Here, we show that the lncRNA HOXA10-AS, located antisense to HOXA10 and mir-196b in the HOXA cluster, is highly expressed in hematopoietic stem cells (HSCs) as well as in KMT2A-rearranged and NPM1 mutated acute myeloid leukemias (AMLs). Using short hairpin RNA- and locked nucleic acid-conjugated chimeric antisense oligonucleotide (LNA-GapmeR)-mediated HOXA10-AS-knockdown and CRISPR/Cas9-mediated excision in vitro, we demonstrate that HOXA10-AS acts as an oncogene in KMT2A-rearranged AML. Moreover, HOXA10-AS knockdown severely impairs the leukemic growth of KMT2A-rearranged patient-derived xenografts in vivo, while high HOXA10-AS expression can serve as a marker of poor prognosis in AML patients. Lentiviral expression of HOXA10-AS blocks normal monocytic differentiation of human CD34+ hematopoietic stem and progenitor cells. Mechanistically, we show that HOXA10-AS localizes in the cytoplasm and acts in trans to induce NF-κB target genes. In total, our data imply that the normally HSC-specific HOXA10-AS is an oncogenic lncRNA in KMT2A-r AML. Thus, it may also represent a potential therapeutic target in KMT2A-rearranged AML.


Assuntos
Rearranjo Gênico , Histona-Lisina N-Metiltransferase/genética , Proteínas Homeobox A10/genética , Leucemia/genética , Proteína de Leucina Linfoide-Mieloide/genética , Células-Tronco Neoplásicas/metabolismo , RNA Antissenso , RNA Longo não Codificante , Animais , Modelos Animais de Doenças , Citometria de Fluxo , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Leucemia/diagnóstico , Leucemia/mortalidade , Leucemia/terapia , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Camundongos , NF-kappa B/metabolismo , Células-Tronco Neoplásicas/patologia , Prognóstico , Transcriptoma
7.
Biosci Rep ; 39(12)2019 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-31763673

RESUMO

PURPOSE: Dysregulation of microRNAs (miRNAs) contributes to tumor progression via the regulation of the expression of specific oncogenes and tumor suppressor genes. One such example, miR-27b-3p, has reportedly been involved in tumor progression in many types of cancer. The aim of the present study was to delve into the role and the underlying mechanism of miR-27b-3p in colorectal cancer (CRC) cells. METHODS: In the present study, we detected the expression level of miR-27b-3p by RT-PCR. The effect of miR-27b-3p overexpression on cell proliferation in CRC cells was evaluated by cell counting and Edu assays. Transwell migration and invasion assays were used to examine the effects of cell migration and invasion. Bioinformatics, luciferase reporter assay and western blot assay were performed to identify the target of miR-27b-3p. RESULTS: Here, we have demonstrated that although miR-27b-3p can affect cell morphology, it has no observable effect on the proliferation of CRC cells. However, it significantly promotes the migration and invasion of CRC cells. We discovered that HOXA10 was a newly identified target of miR-27b-3p in CRC cells, as confirmed by bioinformatics, western blots and dual luciferase reporter assay. Furthermore, the overexpression of miR-27b-3p or the suppression of HOXA10 can activate the integrin ß1 signaling pathway. In conclusion, our results reveal a new function of miR-27b-3p that demonstrates its ability to promote CRC cell migration and invasion by targeting the HOXA10/integrin ß1 cell signal axis. CONCLUSION: This may provide a mechanism to explain why miR-27b-3p promotes CRC cell migration and invasion.


Assuntos
Neoplasias Colorretais/genética , Proteínas Homeobox A10/genética , MicroRNAs/genética , Invasividade Neoplásica/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Neoplasias Colorretais/patologia , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Invasividade Neoplásica/patologia
8.
Gynecol Endocrinol ; 35(sup1): 31-34, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31532317

RESUMO

Objective: The objective of this study is to investigate the association between methylation levels of HOXA10 and HOXA11 promoters, clinical parameters, and implantation outcomes after in vitro fertilization-embryo transfer (IVT-ET) cycles in women with repeated implantation failures and tubal infertility. Methods: Endometrium samples were collected from 34 women during implantation window before IVF-ET cycle to assess methylation status of HOXA10 and HOXA11 promoters using bisulfite sequencing. All participants had a tubal factor of infertility and at least two implantation failures in the anamnesis. A logistic regression model was used to predict the implantation outcome depending on methylation status and clinical parameters. Results: The methylation of CpG-islands of HOXA10 and HOXA11 promoters was identified in 76.5 and 100% of participants, respectively. The median methylation levels did not differ significantly between the groups with different implantation outcomes, but a logistic regression model based on HOXA10 and HOXA11 methylation and clinical parameters allowed to classify the implantation outcomes with the total percentage of correct predictions of 85.19%. Conclusions: Abnormal methylation levels of the HOXA10 and HOXA11 promoters were found in the endometrium of women with tubal infertility and repeated implantation failures. The findings suggest that methylation status could be an important factor of implantation failure during IVF-ET cycles.


Assuntos
Metilação de DNA/fisiologia , Implantação do Embrião/genética , Perda do Embrião/genética , Proteínas Homeobox A10/genética , Proteínas de Homeodomínio/genética , Regiões Promotoras Genéticas , Aborto Habitual/genética , Aborto Habitual/patologia , Adolescente , Adulto , Biópsia , Estudos de Casos e Controles , Perda do Embrião/patologia , Transferência Embrionária/métodos , Endométrio/metabolismo , Endométrio/patologia , Feminino , Fertilização In Vitro/métodos , Humanos , Infertilidade Feminina/genética , Infertilidade Feminina/patologia , Infertilidade Feminina/terapia , Gravidez , Adulto Jovem
9.
Am J Pathol ; 189(11): 2154-2170, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31381886

RESUMO

Previous investigations have implicated long noncoding RNAs in lung adenocarcinoma, which is an aggressive disease with poor prognosis and high mortality. Through the alteration of lung adenocarcinoma-related long noncoding RNA and miRNA based on microarray analysis, our aim was to understand the role of LINC00466 and miR-144 in lung adenocarcinoma progression. The relationship among LINC00466, miR-144, and HOXA10 was also verified. Moreover, to examine whether the LINC00466/miR-144/HOXA10 axis contributed to the cellular processes in lung adenocarcinoma, A549 and XWLC-05 cells were transduced with siRNA LINC00466, siRNA HOXA10, or miR-144 mimic plasmids. Highly expressed LINC00466 and HOXA10 and lowly expressed miR-144 were eventually revealed in lung adenocarcinoma tissues. HOXA10 was down-regulated in response to the overexpression of miR-144, whereas inhibition of LINC00466 decreased its binding to miR-144, thereby up-regulating miR-144, which, in turn, halted the lung adenocarcinoma progression. LINC00466 silencing or miR-144 up-regulation exerted an inhibitory role in the tumorigenicity, invasion, migration, and proliferation, and it also promoted apoptosis of lung adenocarcinoma cells. Furthermore, tumor formation was inhibited by knockdown of LINC00466 or overexpression of miR-144. Taken together, LINC00466 could restrain the miR-144 expression to up-regulate HOXA10 and, therefore, promote lung adenocarcinoma.


Assuntos
Adenocarcinoma de Pulmão/genética , Transformação Celular Neoplásica/genética , Proteínas Homeobox A10/genética , Neoplasias Pulmonares/genética , MicroRNAs/fisiologia , RNA Longo não Codificante/fisiologia , Células A549 , Adenocarcinoma de Pulmão/patologia , Animais , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Nus , MicroRNAs/genética , Oncogenes/fisiologia , Transdução de Sinais/genética
10.
Cancer Med ; 8(12): 5651-5661, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31364281

RESUMO

Homeobox A10 (HOXA10) has been implicated critical for the promotion of carcinogenesis, but the underlying mechanism between HOXA10 and malignant gastric cancer (GC) phenotype remains elusive. In the present study, we analyzed and validated that HOXA10 and BCL2 expressions were elevated both at the mRNA and protein levels in GC tissues. Upregulated HOXA10 promoted GC cell proliferation with reduced apoptosis in vitro and accelerated GC tumor growth in vivo. Bioinformatics analysis and quantitative real-time polymerase chain reaction (qRT-PCR) experiment inferred that HOXA10 might upregulate the expression of BCL2. By performing western blot, chromatin immunoprecipitation and quantitative PCR (ChIP-qPCR), and rescue experiment, we found that HOXA10 might bind to BCL2 promoter region, induce its expression, and thus inhibit intrinsic apoptosis pathway. Moreover, higher expression of HOXA10 and BCL2 predicted poor overall survival (OS) in GC patients. In summary, our study indicated that HOXA10 was upregulated in GC, and that HOXA10 might promote cell proliferation by elevating BCL2 expression and inhibiting apoptosis.


Assuntos
Proteínas Homeobox A10/genética , Proteínas Homeobox A10/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Neoplasias Gástricas/patologia , Regulação para Cima , Animais , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Transplante de Neoplasias , Prognóstico , Regiões Promotoras Genéticas , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Análise de Sobrevida
12.
Endocr Relat Cancer ; 26(3): 279-292, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30667363

RESUMO

Homeobox A10 (HOXA10) is an important transcription factor that regulates the development of the prostate gland. However, it remains unknown whether it modulates prostate cancer (PCa) progression into castrate-resistant stages. In this study, we have applied RNA in situ hybridization assays to demonstrate that downregulation of HOXA10 expression is associated with castrate-resistant PCa. These findings are supported by public RNA-seq data showing that reduced HOXA10 expression is correlated with poor patient survival. We show that HOXA10 suppresses PCa cell proliferation, anchorage colony formation and xenograft growth independent to androgens. Using AmpliSeq transcriptome sequencing, we have found that gene groups associated with lipid metabolism and androgen receptor (AR) signaling are enriched in the HOXA10 transcriptome. Furthermore, we demonstrate that HOXA10 suppresses the transcription of the fatty acid synthase (FASN) gene by forming a protein complex with AR and prevents AR recruitment to the FASN gene promoter. These results lead us to conclude that downregulation of HOXA10 gene expression may enhance lipogenesis to promote PCa cell growth and tumor progression to castrate-resistant stage.


Assuntos
Regulação Neoplásica da Expressão Gênica , Proteínas Homeobox A10/genética , Proteínas Homeobox A10/metabolismo , Neoplasias de Próstata Resistentes à Castração/fisiopatologia , Receptores Androgênicos/metabolismo , Animais , Linhagem Celular Tumoral , Proliferação de Células , Progressão da Doença , Ácido Graxo Sintase Tipo I/genética , Ácido Graxo Sintase Tipo I/metabolismo , Expressão Gênica , Humanos , Metabolismo dos Lipídeos/genética , Masculino , Camundongos , Camundongos Nus , Regiões Promotoras Genéticas , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/metabolismo , Neoplasias de Próstata Resistentes à Castração/mortalidade , Ligação Proteica , Receptores Androgênicos/genética , Transdução de Sinais/genética , Análise de Sobrevida
13.
Prostate ; 79(5): 554-563, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30614022

RESUMO

BACKGROUND: HOX genes encode transcription factors that play key roles in modulating normal tissue morphogenesis, differentiation and homeostasis. Disruption of normal HOX gene expression occurs frequently in human cancers and is associated with both tumor promoting and suppressing activities. Among these is, HOXA10, a pleiotropic gene that is critical for normal prostate development. In this study we characterized HOXA10 expression in human and mouse PCa to gain insights into its clinical significance. METHODS: A meta-analysis of HOXA10 mRNA expression was carried out across several publicly available data sets. Expression of HOXA10 protein expression was assessed by immunohistochemistry (IHC) using human radical prostatectomy (RP) cases. We correlated HOXA10 expression to clinicopathological features and investigated its relationship to biochemical recurrence (BCR) after RP by the Kaplan-Meier method. HOXA10 mRNA and IHC protein expression was also examined in a mouse model of Pten-null PCa. RESULTS: A meta-analysis of HOXA10 gene expression indicated dysregulated expression of HOXA10 in human PCa. IHC profiling of HOXA10 revealed inverse correlations between HOXA10 expression and Gleason pattern, Gleason score, and pathological stage (P < 0.01). Patients with low expression profiles of HOXA10 were associated with a higher risk of BCR, (OR, 3.54; 95%CI, 1.21-16.14; P = 0.049) whereas patients with high HOXA10 expression experienced longer times to BCR (P = 0.045). However, HOXA10 was not an independent predictor of BCR (OR, 1.52; 95%CI, 0.42-5.54; P = 0.52). Evaluation of expression patterns of HOXA10 in mouse prostate tumors mimicked that of humans. CONCLUSIONS: Our findings show that HOXA10 expression is inversely associated with tumor differentiation and high HOXA10 expression is associated with improved BCR-free survival. This study provides human and mouse evidence to suggest tumor suppressive roles for HOXA10 in the context of prostate cancer.


Assuntos
Proteínas Homeobox A10/genética , Neoplasias da Próstata/genética , Idoso , Animais , Expressão Gênica , Proteínas Homeobox A10/biossíntese , Humanos , Imuno-Histoquímica , Masculino , Camundongos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , RNA Mensageiro/biossíntese , RNA Mensageiro/genética
14.
Reprod Sci ; 26(11): 1439-1448, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-30599813

RESUMO

To some extent, the use of metformin may improve endometrial receptivity and pregnancy outcomes of women with polycystic ovarian syndrome (PCOS) undergoing in vitro fertilization/intracytoplasmic sperm injection. However, the mechanism is not well-known. The endometrium of metformin-treated group (metformin-treated patients with PCOS) and the control group (non-metformin-treated patients with PCOS) were analyzed for the expression of homeobox A10 (HOXA10) and integrin beta-3 (ITGB3) and differential micro RNA (miRNA) expression profiles. On this basis, miRDB and Target Scan databases were used to predict and screen out that miR-491-3p and miR-1910-3p may target HOXA10 and ITGB3. Furthermore, we verified the effects of metformin on the expression of HOXA10 and ITGB3, and regulatory effects of miR-1910-3p and miR-491-3p on HOXA10 and ITGB3 using Ishikawa cell line. Metformin induced a significant dose-dependent upregulation of HOXA10 and ITGB3. The results from the microarray analyses showed there were 40 differentially expressed miRNAs between the 2 groups. Among them, miR-1910-3p and miR-491-3p were the 2 significantly downregulated miRNAs. Bioinformatics prediction indicated that HOXA10 and ITGB3 are potential target genes for miR-1910-3p and miR-491-3p. In Ishikawa cells transfected with miR-491-3p mimics, the expression of HOXA10 and ITGB3 on both messenger RNA (mRNA) and protein level were lower than those in control group (P < .001). Also, the expression of HOXA10 mRNA and protein was lower in Ishikawa cells transfected with miR-1910-3p mimics (P < .001). However, no significant changes in ITGB3 levels were observed in cells transfected with miR-1910-3p mimics (P > .05). Metformin likely improves endometrial receptivity through downregulating the expression of miR-491-3p and miR-1910-3p, thereby increasing the expression of HOXA10 and ITGB3 in the endometrium of PCOS women.


Assuntos
Fertilização In Vitro/métodos , Metformina/uso terapêutico , MicroRNAs/biossíntese , Síndrome do Ovário Policístico/tratamento farmacológico , Síndrome do Ovário Policístico/metabolismo , Injeções de Esperma Intracitoplásmicas/métodos , Adulto , Implantação do Embrião/efeitos dos fármacos , Implantação do Embrião/fisiologia , Endométrio/efeitos dos fármacos , Endométrio/metabolismo , Feminino , Expressão Gênica , Marcadores Genéticos/efeitos dos fármacos , Marcadores Genéticos/fisiologia , Proteínas Homeobox A10/biossíntese , Proteínas Homeobox A10/genética , Humanos , Infertilidade Feminina/tratamento farmacológico , Infertilidade Feminina/genética , Infertilidade Feminina/metabolismo , Integrina beta3/biossíntese , Integrina beta3/genética , Metformina/farmacologia , MicroRNAs/genética , Recuperação de Oócitos/métodos , Síndrome do Ovário Policístico/genética
15.
J Cell Biochem ; 120(3): 3423-3427, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30242886

RESUMO

OBJECTIVE: The aim of this study was to evaluate endometrial receptivity by measuring HOXA-10, HOXA-11, and LIF gene expressions in women with polycystic ovary syndrome. METHODS: A total of 48 women were included in this clinical study. Thepatients were allocated to two groups: study group consisted of 28 patients with myoma uteri and control group consisted of 20 patients without myoma uteri. Endometrial sampling was performed during the proliferative phase. The biopsies obtained from the patients with myoma uteri were taken from the place where the fibroids were localized. HOXA-10, HOXA-11, and LIF expressions were measured in the endometrial sampling material. Demographic data of the patients such as age, obstetric and gynecologic history, medical conditions, medications, surgical history, last menstrual period were recorded. Also, the number, size, localization, and type of the myoma were registered. RESULTS: The mean age of the patients was 42.07 and 38.17, respectively. HOXA-11 levels in the study and control groups were 0.004 ± 0.001 and 0.010 ± 0.001, respectively ( P < 0.90). Paradoxically, HOXA-10 levels were found to be higher in the study group than the control group, but the difference was not statistically significant ( P < 0.25). LIF levels were significantly lower in the study group ( P < 0.05). CONCLUSION: Our results showed that myoma uteri might lead to a decrease in implantation rate by diminishing LIF gene expressions. However, there were no differences between the two groups in terms of HOXA-10 and HOXA-11 levels.


Assuntos
Biomarcadores Tumorais/genética , Proteínas Homeobox A10/genética , Proteínas de Homeodomínio/genética , Fator Inibidor de Leucemia/genética , Mioma/genética , Neoplasias Uterinas/genética , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Mioma/patologia , Prognóstico , Neoplasias Uterinas/patologia
16.
Reprod Sci ; 26(6): 839-846, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30522400

RESUMO

Endometrial receptivity is a critical factor for embryo implantation. A decrease in endometrial homeobox A10 (HOXA10) expression is associated with hypermethylation of its promoter and lower endometrial receptivity in animals and humans. 5-Aza-2'-deoxycytidine (AZA) is a DNA methyltransferase inhibitor. However, whether demethylation of the HOXA10 gene could increase the receptivity of the human endometrium remains unknown. Homeobox A10 promoter methylation was analyzed using bisulfite genomic sequencing polymerase chain reaction. Quantitative real time polymerase chain reaction and Western blotting were used to analyze the expression of HOXA10 and its downstream target genes (integrin subunit ß 3 [ITGB3] and insulin growth factor binding protein 1 [IGFBP1]) in Ishikawa cells treated with or without AZA for 24 hours. Their protein expression was analyzed with or without HOXA10 siRNA treatment. The effect of AZA on embryo implantation was examined using a Jeg-3 spheroid-endometrial cell attachment assay. The percentage of methylated CpG islands in the HOXA10 promoter was 72.0% without AZA treatment. However, it was 38% and 35% in the 1 and 10 µM AZA treatment groups, respectively. 5-Aza-2'-deoxycytidine strongly induced the expression of HOXA10, ITGB3, and IGFBP1 messenger RNA and their protein expression. Homeobox A10 knockdown led to decreased expression of HOXA10, ITGB3, and IGFBP1, with or without AZA treatment. The attachment rate of Jeg-3 spheroids increased significantly from 82% (control) to 95% (AZA 1 µM) and 96% (AZA 10 µM) after AZA treatment. 5-Aza-2'-deoxycytidine could upregulate the expression of ITGB3 and IGFBP1 via HOXA10 upregulation, and upregulation of ITGB3 and IGFBP1 plays an important role in endometrial receptivity during implantation. 5-Aza-2'-deoxycytidine may improve endometrial receptivity by upregulating the expression of HOXA10.


Assuntos
Metilação de DNA/efeitos dos fármacos , Decitabina/farmacologia , Endométrio/efeitos dos fármacos , Proteínas Homeobox A10/genética , Regulação para Cima/efeitos dos fármacos , Adenocarcinoma , Linhagem Celular Tumoral , Coriocarcinoma , Ilhas de CpG/genética , Implantação do Embrião/efeitos dos fármacos , Implantação do Embrião/fisiologia , Neoplasias do Endométrio , Endométrio/fisiologia , Inibidores Enzimáticos , Feminino , Humanos , Regiões Promotoras Genéticas/efeitos dos fármacos , Regiões Promotoras Genéticas/genética , RNA Interferente Pequeno , Neoplasias Uterinas
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