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1.
Oncotarget ; 13: 291-306, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35136486

RESUMO

Long noncoding RNAs (lncRNAs) are known to regulate gene expression; however, in many cases, the mechanism of this regulation is unknown. One novel lncRNA relevant to inflammation and arachidonic acid (AA) metabolism is the p50-associated COX-2 extragenic RNA (PACER). We focused our research on the regulation of PACER in lung cancer. While the function of PACER is not entirely understood, PACER is known to play a role in inflammation-associated conditions. Our data suggest that PACER is critically involved in COX-2 transcription and dysregulation in lung cancer cells. Our analysis of The Cancer Genome Atlas (TCGA) expression data revealed that PACER expression is significantly higher in lung adenocarcinomas than normal lung tissues. Additionally, we discovered that elevated PACER expression strongly correlates with COX-2 expression in lung adenocarcinoma patients. Specific siRNA-mediated knockdown of PACER decreases COX-2 expression indicating a direct relationship. Additionally, we show that PACER expression is induced upon treatment with proinflammatory cytokines to mimic inflammation. Treatment with prostaglandin E2 (PGE2) induces both PACER and COX-2 expression, suggesting a PGE2-mediated feedback loop. Inhibition of COX-2 with celecoxib decreased PACER expression, confirming this self-regulatory process. Significant overlap between the COX-2 promotor and the PACER promotor led us to investigate their transcriptional regulatory mechanisms. Treatment with pharmacologic inhibitors of NF-κB or AP-1 showed a modest effect on both PACER and COX-2 expression but did not eliminate expression. These data suggest that the regulation of expression of both PACER and COX-2 is complex and intricately linked.


Assuntos
Neoplasias Pulmonares , RNA Longo não Codificante , Ácido Araquidônico/metabolismo , Celecoxib , Ciclo-Oxigenase 2/metabolismo , Citocinas/metabolismo , Dinoprostona/metabolismo , Humanos , Inflamação/metabolismo , Pulmão/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , NF-kappa B/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , RNA Interferente Pequeno/metabolismo , Fator de Transcrição AP-1/metabolismo
2.
RNA Biol ; 16(12): 1721-1732, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31425002

RESUMO

Non-small cell lung cancer (NSCLC) is a complex disease in need of new methods of therapeutic intervention. Recent interest has focused on using microRNAs (miRNAs) as a novel treatment method for various cancers. miRNAs negatively regulate gene expression post-transcriptionally, and have become attractive candidates for cancer treatment because they often simultaneously target multiple genes of similar biological function. One such miRNA is miR-146a-5p, which has been described as a tumor suppressive miRNA in NSCLC cell lines and tissues. In this study, we performed RNA-Sequencing (RNA-Seq) analysis following transfection of synthetic miR-146a-5p in an NSCLC cell line, A549, and validated our data with Gene Ontology and qRT-PCR analysis of known miR-146a-5p target genes. Our transcriptomic data revealed that miR-146a-5p exerts its tumor suppressive function beyond previously reported targeting of EGFR and NF-κB signaling. miR-146a-5p mimic transfection downregulated arachidonic acid metabolism genes, the RNA-binding protein HuR, and many HuR-stabilized pro-cancer mRNAs, including TGF-ß, HIF-1α, and various cyclins. miR-146a-5p transfection also reduced expression and cellular release of the chemokine CCL2, and this effect was mediated through the 3' untranslated region of its mRNA. Taken together, our work reveals that miR-146a-5p functions as a tumor suppressor in NSCLC by controlling various metabolic and signaling pathways through direct and indirect mechanisms.


Assuntos
Adenocarcinoma de Pulmão/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma de Células Escamosas/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/genética , MicroRNAs/genética , Transcriptoma , Células A549 , Adenocarcinoma de Pulmão/metabolismo , Adenocarcinoma de Pulmão/mortalidade , Adenocarcinoma de Pulmão/patologia , Animais , Ácido Araquidônico/antagonistas & inibidores , Ácido Araquidônico/metabolismo , Atlas como Assunto , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Ciclinas/genética , Ciclinas/metabolismo , Proteína Semelhante a ELAV 1/genética , Proteína Semelhante a ELAV 1/metabolismo , Perfilação da Expressão Gênica , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , MicroRNAs/metabolismo , Transdução de Sinais , Análise de Sobrevida , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo
3.
Sci Rep ; 9(1): 5405, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30931980

RESUMO

Elevated prostaglandin E2 (PGE2) levels are observed in colorectal cancer (CRC) patients, and this increase is associated with poor prognosis. Increased synthesis of PGE2 in CRC has been shown to occur through COX-2-dependent mechanisms; however, loss of the PGE2-catabolizing enzyme, 15-hydroxyprostaglandin dehydrogenase (15-PGDH, HPGD), in colonic tumors contributes to increased prostaglandin levels and poor patient survival. While loss of 15-PGDH can occur through transcriptional mechanisms, we demonstrate that 15-PGDH can be additionally regulated by a miRNA-mediated mechanism. We show that 15-PGDH and miR-21 are inversely correlated in CRC patients, with increased miR-21 levels associating with low 15-PGDH expression. 15-PGDH can be directly regulated by miR-21 through distinct sites in its 3' untranslated region (3'UTR), and miR-21 expression in CRC cells attenuates 15-PGDH and promotes increased PGE2 levels. Additionally, epithelial growth factor (EGF) signaling suppresses 15-PGDH expression while simultaneously enhancing miR-21 levels. miR-21 inhibition represses CRC cell proliferation, which is enhanced with EGF receptor (EGFR) inhibition. These findings present a novel regulatory mechanism of 15-PGDH by miR-21, and how dysregulated expression of miR-21 may contribute to loss of 15-PGDH expression and promote CRC progression via increased accumulation of PGE2.


Assuntos
Neoplasias do Colo/genética , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Hidroxiprostaglandina Desidrogenases/genética , MicroRNAs/genética , Regiões 3' não Traduzidas/genética , Sítios de Ligação/genética , Células CACO-2 , Proliferação de Células/genética , Neoplasias do Colo/enzimologia , Neoplasias do Colo/patologia , Neoplasias Colorretais/enzimologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Dinoprostona/metabolismo , Células HCT116 , Células HT29 , Células HeLa , Humanos , Hidroxiprostaglandina Desidrogenases/metabolismo
4.
Wiley Interdiscip Rev RNA ; 10(4): e1533, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30895717

RESUMO

Cancer as we know it is actually an umbrella term for over 100 very unique malignancies in various tissues throughout the human body. Each type, and even subtype of cancer, has different genetic, epigenetic, and other cellular events responsible for malignant development and metastasis. Recent work has indicated that microRNAs (miRNAs) play a major role in these processes, sometimes by promoting cancer growth and other times by suppressing tumorigenesis. miRNAs are small, noncoding RNAs that negatively regulate expression of specific target genes. This review goes into an in-depth look at the most recent finding regarding the significance of one particular miRNA, miR-146a-5p, and its involvement in cancer. Target gene validation and pathway analysis have provided mechanistic insight into this miRNA's purpose in assorted tissues. Additionally, this review outlines novel findings that suggest miR-146a-5p may be useful as a noninvasive biomarker and as a targeted therapeutic in several cancers. This article is categorized under: RNA in Disease and Development > RNA in Disease Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAs.


Assuntos
Carcinogênese , Transformação Celular Neoplásica , Regulação da Expressão Gênica , MicroRNAs/metabolismo , Neoplasias/fisiopatologia , Humanos
5.
Oncotarget ; 9(42): 26751-26769, 2018 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-29928483

RESUMO

Arachidonic acid (AA) can be converted into prostaglandins (PGs) or leukotrienes (LTs) by the enzymatic actions of cyclooxygenases (COX-1 and COX-2) or 5-lipoxygenase (5-LO), respectively. PGs and LTs are lipid signaling molecules that have been implicated in various diseases, including multiple cancers. 5-LO and its activating protein (FLAP) work together in the first two conversion steps of LT production. Previous work has suggested a role for LTs in cancer development and progression. MicroRNAs (miRNAs) are small RNA molecules that negatively regulate gene expression post-transcriptionally, and have previously been shown to be involved in cancer. Here, we show that high FLAP expression is associated with lower overall survival in lung adenocarcinoma patients, and FLAP protein is overexpressed in lung cancer cells compared to normal lung cells. Our lab has previously shown that miR-146a regulates COX-2 in lung cancer cells, and this miRNA is also predicted to target FLAP. Transient and stable transfections of miR-146a repress endogenous FLAP expression in lung cancer cells, and reporter assays show this regulation occurs through a direct interaction between the FLAP 3' untranslated region (UTR) and miR-146a. Restoration of miR-146a also results in decreased cancer cell Leukotriene B4 (LTB4) production. Additionally, methylation analysis indicates the miR-146a promoter is hypermethylated in lung cancer cell lines. Taken together, this study and previous work from our lab suggest miR-146a is an endogenous dual inhibitor of AA metabolism in lung cancer cells by regulating both PG and LT production through direct targeting of the COX-2 and FLAP 3' UTRs.

6.
Wiley Interdiscip Rev RNA ; 6(4): 351-67, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25832716

RESUMO

PTB-associated splicing factor (PSF) is an abundant and essential nucleic acid-binding protein that participates in a wide range of gene regulatory processes and cellular response pathways. At the protein level, PSF consists of multiple domains, many of which remain poorly characterized. Although grouped in a family with the proteins p54nrb/NONO and PSPC1 based on sequence homology, PSF contains additional protein sequence not included in other family members. Consistently, PSF has also been implicated in functions not ascribed to p54nrb/NONO or PSPC1. Here, we provide a review of the cellular activities in which PSF has been implicated and what is known regarding the mechanisms by which PSF functions in each case. We propose that the complex domain arrangement of PSF allows for its diversity of function and integration of activities. Finally, we discuss recent evidence that individual activities of PSF can be regulated independently from one another through the activity of domain-specific co-factors.


Assuntos
Proteínas de Ligação a RNA/metabolismo , Animais , Humanos , Fator de Processamento Associado a PTB , Estrutura Terciária de Proteína , Proteínas de Ligação a RNA/química
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