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1.
Mol Cancer ; 18(1): 149, 2019 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-31660951

RESUMO

In the published article [1], an error was noticed in Fig. 6B. The western blot results were reversed between the overexpression group and the knockdown group of circ-AKT3. The corrected and updated Fig. 6 is provided below. This error does not affect the findings or conclusions of the article.

2.
Mol Cancer ; 18(1): 131, 2019 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-31470874

RESUMO

BACKGROUND: The RTK/PI3K/AKT pathway plays key roles in the development and progression of many cancers, including GBM. As a regulatory molecule and a potential drug target, the oncogenic role of AKT has been substantially studied. Three isoforms of AKT have been identified, including AKT1, AKT2 and AKT3, but their individual functions in GBM remain controversial. Moreover, it is not known if there are more AKT alternative splicing variants. METHODS: High-throughput RNA sequencing and quantitative reverse transcription-PCR were used to identify the differentially expressed circRNAs in GBM samples and in paired normal tissues. High throughput RNA sequencing was used to identify circ-AKT3 regulated signaling pathways. Mass spectrometry, western blotting and immunofluorescence staining analyses were used to validate AKT3-174aa expression. The tumor suppressive role of AKT3-174aa was validated in vitro and in vivo. The competing interaction between AKT3-174aa and p-PDK1 was investigated by mass spectrometry and immunoprecipitation analyses. RESULTS: Circ-AKT3 is a previously uncharacterized AKT transcript variant. Circ-AKT3 is expressed at low levels in GBM tissues compared with the expression in paired adjacent normal brain tissues. Circ-AKT3 encodes a 174 amino acid (aa) novel protein, which we named AKT3-174aa, by utilizing overlapping start-stop codons. AKT3-174aa overexpression decreased the cell proliferation, radiation resistance and in vivo tumorigenicity of GBM cells, while the knockdown of circ-AKT3 enhanced the malignant phenotypes of astrocytoma cells. AKT3-174aa competitively interacts with phosphorylated PDK1, reduces AKT-thr308 phosphorylation, and plays a negative regulatory role in modulating the PI3K/AKT signal intensity. CONCLUSIONS: Our data indicate that the impaired circRNA expression of the AKT3 gene contributes to GBM tumorigenesis, and our data corroborate the hypothesis that restoring AKT3-174aa while inhibiting activated AKT may provide more benefits for certain GBM patients.

3.
Cancer Biol Med ; 16(1): 11-23, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31119043

RESUMO

As a newly discovered type of RNA, circular RNAs (circRNAs) are widespread throughout the eukaryotic genome. The expression of circRNAs is regulated by both cis-elements and trans-factors, and the expression pattern of circRNAs is cell type- and disease-specific. Similar to other types of non-coding RNAs, functions of circRNAs are also versatile. CircRNAs have been reported previously to function as microRNA (miRNA) sponges, protein sponges, coding RNAs or scaffolds for protein complexes. Recently, several circRNAs have been reported to play important roles in human malignancies, including glioma. Here, we reviewed several reports related to circRNAs and glioma, as well as the potential diagnostic and therapeutic applications of circRNAs in brain cancer. In general, some circRNAs, such as circSMARCA5 and circCFH, are found to be expressed in a glioma-specific pattern, these circRNAs may be used as tumor biomarkers. In addition, some circRNAs have been found to play oncogenic roles in glioma (e.g., circNFIX and circNT5E), whereas others have been reported to function as tumor suppressors (e.g., circFBXW7 and circSHPRH). Furthermore, circRNA is a good tool for protein expression because of its higher stability compared to linear RNAs. Thus, circRNAs may also be an ideal choice for gene/protein delivery in future brain cancer therapies. There are some challenges in circRNA research in glioma and other diseases. Research related to circRNAs in glioma is comparatively new and many mysteries remain to be solved.

4.
Nat Commun ; 9(1): 4475, 2018 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-30367041

RESUMO

Circular RNAs (circRNAs) are a large class of transcripts in the mammalian genome. Although the translation of circRNAs was reported, additional coding circRNAs and the functions of their translated products remain elusive. Here, we demonstrate that an endogenous circRNA generated from a long noncoding RNA encodes regulatory peptides. Through ribosome nascent-chain complex-bound RNA sequencing (RNC-seq), we discover several peptides potentially encoded by circRNAs. We identify an 87-amino-acid peptide encoded by the circular form of the long intergenic non-protein-coding RNA p53-induced transcript (LINC-PINT) that suppresses glioblastoma cell proliferation in vitro and in vivo. This peptide directly interacts with polymerase associated factor complex (PAF1c) and inhibits the transcriptional elongation of multiple oncogenes. The expression of this peptide and its corresponding circRNA are decreased in glioblastoma compared with the levels in normal tissues. Our results establish the existence of peptides encoded by circRNAs and demonstrate their potential functions in glioblastoma tumorigenesis.


Assuntos
Carcinogênese/genética , Regulação Neoplásica da Expressão Gênica/genética , Glioblastoma/genética , Peptídeos/metabolismo , RNA Longo não Codificante/genética , RNA/genética , Elongação da Transcrição Genética , Animais , Ciclo Celular/genética , Linhagem Celular , Proliferação de Células/genética , Feminino , Glioblastoma/química , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Transplante de Neoplasias , Proteínas Nucleares/metabolismo , Oncogenes/genética , Peptídeos/genética , RNA/metabolismo , RNA Longo não Codificante/metabolismo , Deleção de Sequência , Análise de Sobrevida , Distribuição Tecidual , Fatores de Transcrição
5.
Oncogene ; 37(13): 1805-1814, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29343848

RESUMO

Circular RNAs (circRNAs) are recognized as functional non-coding transcripts in eukaryotic cells. Recent evidence has indicated that even though circRNAs are generally expressed at low levels, they may be involved in many physiological or pathological processes, such as gene regulation, tissue development and carcinogenesis. Although the 'microRNA sponge' function is well characterized, most circRNAs do not contain perfect trapping sites for microRNAs, which suggests the possibility that circRNAs have functions that have not yet been defined. In this study, we show that a circRNA containing an open reading frame (ORF) driven by the internal ribosome entry site (IRES) can translate a functional protein. The circular form of the SNF2 histone linker PHD RING helicase (SHPRH) gene encodes a novel protein that we termed SHPRH-146aa. Circular SHPRH (circ-SHPRH) uses overlapping genetic codes to generate a 'UGA' stop codon, which results in the translation of the 17 kDa SHPRH-146aa. Both circ-SHPRH and SHPRH-146aa are abundantly expressed in normal human brains and are down-regulated in glioblastoma. The overexpression of SHPRH-146aa in U251 and U373 glioblastoma cells reduces their malignant behavior and tumorigenicity in vitro and in vivo. Mechanistically, SHPRH-146aa protects full-length SHPRH from degradation by the ubiquitin proteasome. Stabilized SHPRH sequentially ubiquitinates proliferating cell nuclear antigen (PCNA) as an E3 ligase, leading to inhibited cell proliferation and tumorigenicity. Our findings provide a novel perspective regarding circRNA function in physiological and pathological processes. Specifically, SHPRH-146aa generated from overlapping genetic codes of circ-SHPRH is a tumor suppressor in human glioblastoma.


Assuntos
Neoplasias Encefálicas/genética , Carcinogênese/genética , DNA Helicases/genética , Genes Supressores de Tumor , Glioma/genética , RNA/genética , Ubiquitina-Proteína Ligases/genética , Neoplasias Encefálicas/patologia , Proliferação de Células/genética , DNA Helicases/metabolismo , Glioblastoma/genética , Glioblastoma/patologia , Glioma/patologia , Células HEK293 , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Análise de Sequência de RNA , Células Tumorais Cultivadas , Ubiquitina-Proteína Ligases/metabolismo
6.
J Natl Cancer Inst ; 110(3)2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-28903484

RESUMO

Background: Circular RNAs (circRNAs) are RNA transcripts that are widespread in the eukaryotic genome. Recent evidence indicates that circRNAs play important roles in tissue development, gene regulation, and carcinogenesis. However, whether circRNAs encode functional proteins remains elusive, although translation of several circRNAs was recently reported. Methods: CircRNA deep sequencing was performed by using 10 pathologically diagnosed glioblastoma samples and their paired adjacent normal brain tissues. Northern blotting, Sanger sequencing, antibody, and liquid chromatograph Tandem Mass Spectrometer were used to confirm the existence of circ-FBXW7 and its encoded protein in in two cell lines. Lentivirus-transfected stable U251 and U373 cells were used to assess the biological functions of the novel protein invitro and invivo (five mice per group). Clinical implications of circ-FBXW7 were assessed in 38 pathologically diagnosed glioblastoma samples and their paired periphery normal brain tissues by using quantitative polymerase chain reaction (two-sided log-rank test). Results: Circ-FBXW7 is abundantly expressed in the normal human brain (reads per kilobase per million mapped reads [RPKM] = 9.31). The spanning junction open reading frame in circ-FBXW7 driven by internal ribosome entry site encodes a novel 21-kDa protein, which we termed FBXW7-185aa. Upregulation of FBXW7-185aa in cancer cells inhibited proliferation and cell cycle acceleration, while knockdown of FBXW7-185aa promoted malignant phenotypes invitro and invivo. FBXW7-185aa reduced the half-life of c-Myc by antagonizing USP28-induced c-Myc stabilization. Moreover, circ-FBXW7 and FBXW7-185aa levels were reduced in glioblastoma clinical samples compared with their paired tumor-adjacent tissues (P < .001). Circ-FBXW7 expression positively associated with glioblastoma patient overall survival (P = .03). Conclusions: Endogenous circRNA encodes a functional protein in human cells, and circ-FBXW7 and FBXW7-185aa have potential prognostic implications in brain cancer.


Assuntos
Neoplasias Encefálicas/genética , Proteínas de Ciclo Celular/genética , Transformação Celular Neoplásica/genética , Proteínas F-Box/genética , Glioblastoma/genética , RNA/análise , Ubiquitina-Proteína Ligases/genética , Animais , Encéfalo/metabolismo , Neoplasias Encefálicas/química , Ciclo Celular/genética , Proteínas de Ciclo Celular/análise , Linhagem Celular Tumoral , Proliferação de Células/genética , Proteínas F-Box/análise , Proteína 7 com Repetições F-Box-WD , Feminino , Glioblastoma/química , Meia-Vida , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Transplante de Neoplasias , Fases de Leitura Aberta , Proteínas Proto-Oncogênicas c-myc/metabolismo , Análise de Sequência de RNA , Taxa de Sobrevida , Ubiquitina Tiolesterase/metabolismo , Ubiquitina-Proteína Ligases/análise , Regulação para Cima
7.
Cell Cycle ; 16(18): 1705-1718, 2017 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-28767320

RESUMO

Ubiquitin-conjugating enzyme E2C (UBE2C) is characterized as a crucial molecule in cancer cell growth that plays an essential role in the development of gliomas, but the detailed mechanisms have not been fully elucidated. In this study, we found that Forkhead box transcription factor M1 (FoxM1) overexpression increased UBE2C expression, whereas FoxM1 suppression inhibited UBE2C expression in glioma cells. In addition, high FoxM1/UBE2C expression was significantly correlated with poor prognosis in glioma. We subsequently demonstrated that UBE2C was a direct transcriptional target of FoxM1, and site-directed mutations markedly down-regulated UBE2C promoter activity. Moreover, UBE2C siRNA (si-UBE2C) significantly induced glioma cell autophagy and increased both mCherry-LC3 punctate fluorescence and LC3B-II/LC3-I expression. Notably, the si-UBE2C-induced decrease in cell viability was markedly inhibited by the autophagy inhibitor bafilomycin A1. The silencing of UBE2C resulted in a distinct inhibition of the PI3K-Akt-mTOR pathway, which functions in the negative modulation of autophagy. Collectively, our findings provide clinical and molecular evidence that FoxM1 promotes glioma progression by enhancing UBE2C transcription and that the inhibition of UBE2C partially induces autophagic glioma cell death. Thus, targeting the FoxM1-UBE2C axis has therapeutic potential in the treatment of gliomas.


Assuntos
Autofagia , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Proteína Forkhead Box M1/metabolismo , Glioma/metabolismo , Glioma/patologia , Neuroproteção , Enzimas de Conjugação de Ubiquitina/metabolismo , Adolescente , Adulto , Apoptose/efeitos dos fármacos , Autofagia/genética , Linhagem Celular Tumoral , Sobrevivência Celular/genética , Biologia Computacional , Feminino , Técnicas de Silenciamento de Genes , Inativação Gênica , Humanos , Estimativa de Kaplan-Meier , Macrolídeos/farmacologia , Masculino , Regiões Promotoras Genéticas , Ligação Proteica , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo
8.
Cancer Biol Ther ; 17(8): 790-8, 2016 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-27260617

RESUMO

Hypoxia is a general event in solid tumor growth. Therefore, induced cellular responses by hypoxia are important for tumorigenesis and tumor growth. MicroRNAs (miRNAs) have recently emerged as important regulators of hypoxia induced cellular responses. Here we report that miR-147a is a novel and crucial hypoxia induced miRNA. HIF-1α up-regulates the expression of miR-147a, and miR-147a in turn stabilizes and accumulates HIF-1α protein via directly targeting HIF-3α, a dominant negative regulator of HIF-1α. Subsequent studies in xenograft mouse model reveal that miR-147a is capable of inhibiting tumor growth. Collectively, these data demonstrate a positive feedback loop between HIF-1α, miR-147a and HIF-3α, which provide a new insight into the mechanism of miR-147a induced cell proliferation arrest under hypoxia.


Assuntos
Hipóxia Celular/fisiologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , MicroRNAs/metabolismo , Sequência de Aminoácidos , Animais , Apoptose/fisiologia , Proliferação de Células/fisiologia , Células HeLa , Xenoenxertos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/biossíntese , Transfecção , Regulação para Cima
9.
Cancer Biol Ther ; 16(6): 941-8, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25945419

RESUMO

It has been reported that persistent or excessive autophagy promotes cancer cell death during chemotherapy, either by enhancing the induction of apoptosis or mediating autophagic cell death. Here, we show that miR-15a and miR-16 are potent inducers of autophagy. Rictor, a component of mTORC2 complex, is directly targeted by miR-15a/16. Overexpression of miR-15a/16 or depletion of endogenous Rictor attenuates the phosphorylation of mTORC1 and p70S6K, inhibits cell proliferation and G1/S cell cycle transition in human cervical carcinoma HeLa cells. Moreover, miR-15a/16 dramatically enhances anticancer drug camptothecin (CPT)-induced autophagy and apoptotic cell death in HeLa cells. Collectively, these data demonstrate that miR-15a/16 induced autophagy contribute partly to their inhibition of cell proliferation and enhanced chemotherapeutic efficacy of CPT.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Autofagia/genética , Camptotecina/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , MicroRNAs/genética , Regiões 3' não Traduzidas , Sequência de Bases , Sítios de Ligação , Proteínas de Transporte/genética , Linhagem Celular Tumoral , Proliferação de Células , Técnicas de Silenciamento de Genes , Células HeLa , Humanos , Interferência de RNA , Proteína Companheira de mTOR Insensível à Rapamicina
10.
Biochem Biophys Res Commun ; 457(1): 37-42, 2015 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-25529446

RESUMO

Previous studies showed that miR-378a plays important roles in adipogenesis and obesity; however, the precise mechanisms of action remain unknown. Here, we found that miR-378a-3p expression is up-regulated in adipose tissues of high fat diet-induced obese mice, as well as during the differentiation of 3T3-L1 preadipocytes. Mir-378a-3p induced adipogenesis by targeting mitogen-activated protein kinase 1 (MAPK1). Overexpression of miR-378a-3p or silencing MAPK1 reduced MAPK1 expression and enhanced adipogenesis, whereas blockage of endogenous miR-378a-3p had the opposite effect, suggesting that miR-378a-3p promotes the adipogenesis of 3T3-L1 cells by targeting MAPK1.


Assuntos
Adipogenia , MicroRNAs/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Células 3T3-L1 , Adipogenia/genética , Animais , Sequência de Bases , Dieta Hiperlipídica , Masculino , Camundongos , MicroRNAs/genética , Modelos Biológicos , Dados de Sequência Molecular , Obesidade/genética , Obesidade/patologia , Regulação para Cima/genética
11.
Cell Commun Signal ; 12: 66, 2014 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-25304455

RESUMO

BACKGROUND: Accelerated cell cycle progression is the common feature of most cancers. MiRNAs can act as oncogenes or tumor suppressors by directly modulating cell cycle machinery. It has been shown that miR-188 is upregulated in UVB-irradiated mouse skin and human nasopharyngeal carcinoma CNE cells under hypoxic stress. However, little is known about the function of miR-188 in cell proliferation and growth control. RESULTS: Overexpression of miR-188 inhibits cell proliferation, tumor colony formation and G1/S cell cycle transition in human nasopharyngeal carcinoma CNE cells. Using bioinformatics approach, we identify a series of genes regulating G1/S transition as putative miR-188 targets. MiR-188 inhibits both mRNA and protein expression of CCND1, CCND3, CCNE1, CCNA2, CDK4 and CDK2, suppresses Rb phosphorylation and downregulates E2F transcriptional activity. The expression level of miR-188 also inversely correlates with the expression of miR-188 targets in human nasopharyngeal carcinoma (NPC) tissues. Moreover, studies in xenograft mouse model reveal that miR-188 is capable of inhibiting tumor initiation and progression by suppressing target genes expression and Rb phosphorylation. CONCLUSIONS: This study demonstrates that miR-188 exerts anticancer effects, via downregulation of multiple G1/S related cyclin/CDKs and Rb/E2F signaling pathway.


Assuntos
Quinases Ciclina-Dependentes/genética , Ciclinas/genética , Interfase/fisiologia , MicroRNAs/metabolismo , Animais , Linhagem Celular Tumoral , Proliferação de Células , Quinases Ciclina-Dependentes/metabolismo , Ciclinas/metabolismo , Fatores de Transcrição E2F/metabolismo , Humanos , Camundongos Nus , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Proteína do Retinoblastoma/metabolismo
12.
Autophagy ; 10(1): 70-9, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24262949

RESUMO

Hypoxia activates autophagy, an evolutionarily conserved cellular catabolic process. Dysfunction in the autophagy pathway has been implicated in an increasing number of human diseases, including cancer. Hypoxia induces upregulation of a specific set of microRNAs (miRNAs) in a variety of cell types. Here, we describe hypoxia-induced MIR155 as a potent inducer of autophagy. Enforced expression of MIR155 increases autophagic activity in human nasopharyngeal cancer and cervical cancer cells. Knocking down endogenous MIR155 inhibits hypoxia-induced autophagy. We demonstrated that MIR155 targets multiple players in MTOR signaling, including RHEB, RICTOR, and RPS6KB2. MIR155 suppresses target-gene expression by directly interacting with their 3' untranslated regions (UTRs), mutations of the binding sites abolish their MIR155 responsiveness. Furthermore, by downregulating MTOR signaling, MIR155 also attenuates cell proliferation and induces G 1/S cell cycle arrest. Collectively, these data present a new role for MIR155 as a key regulator of autophagy via dysregulation of MTOR pathway.


Assuntos
Autofagia/genética , MicroRNAs/genética , Transdução de Sinais/genética , Serina-Treonina Quinases TOR/metabolismo , Regiões 3' não Traduzidas/genética , Sequência de Bases , Ciclo Celular/genética , Hipóxia Celular/genética , Linhagem Celular Tumoral , Proliferação de Células , Regulação para Baixo/genética , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , MicroRNAs/metabolismo , Dados de Sequência Molecular , Proteínas de Neoplasias/metabolismo , Fagossomos/metabolismo , Regulação para Cima/genética
13.
PLoS One ; 8(3): e58639, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23516523

RESUMO

miR-181a has been presumed to target the 3'-untranslated regions (3'-UTR) of IL1a based on software predictions. miR-181a and IL1a have opposite expression levels in monocytes and macrophages in the inflammatory state. This led us to suspect that mir-181a has an important function in regulating inflammatory response by targeting IL1a. Fluorescence reporter assays showed that miR-181a effectively binds to the 3'-UTR of IL1a. The anti-inflammatory functions of miR-181a were investigated in lipopolysaccharides (LPS)-induced Raw264.7 and phorbol 12-myristate 13-acetate (PMA)/LPS-induced THP-1 cells. We found that miR-181a mimics significantly lowered IL1a expression levels in these cells and, interestingly, miR-181a inhibitors reversed this decrease. In addition, miR-181a mimics significantly inhibited increase in the levels of inflammatory factors (IL1b, IL6, and TNFa) in these cells. Furthermore, miR-181a mimics and inhibitors decreased and increased, respectively, production of reactive oxygen species in PMA/LPS-induced THP-1 cells. These results indicate that miR-181a regulates inflammatory responses by directly targeting the 3'-UTR of IL1a and down-regulating IL1a levels. Interestingly, we found that miR-181a inhibited production of inflammatory factors even in IL1a-induced THP-1 cells, suggesting that the anti-inflammatory effects of miR-181a possibly involves other targets in addition to IL1a. Thus, we provide the first evidence for anti-inflammatory effects of miR-181a mediated at least in part by down-regulating IL1a.


Assuntos
Macrófagos/metabolismo , MicroRNAs/metabolismo , Monócitos/metabolismo , Regiões 3' não Traduzidas/genética , Animais , Sequência de Bases , Sítios de Ligação , Linhagem Celular Tumoral , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Inflamação/genética , Inflamação/metabolismo , Interleucina-1alfa/deficiência , Interleucina-1alfa/genética , Interleucina-1alfa/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Camundongos , MicroRNAs/genética , Monócitos/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/genética , Espécies Reativas de Oxigênio/metabolismo , Acetato de Tetradecanoilforbol/farmacologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
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