RESUMO
microRNAs are small noncoding RNAs that regulate gene expression at the posttranscriptional level. Let-7d is a microRNA of the conserved let-7 family that is dysregulated in female malignancies including breast cancer, ovarian cancer, endometrial cancer, and cervical cancer. Moreover, a dysregulation is observed in endometriosis and pregnancy-associated diseases such as preeclampsia and fetal growth restriction. Let-7d expression is regulated by cytokines and steroids, involving transcriptional regulation by OCT4, MYC and p53, as well as posttranscriptional regulation via LIN28 and ADAR. By downregulating a wide range of relevant mRNA targets, let-7d affects cellular processes that drive disease progression such as cell proliferation, apoptosis (resistance), angiogenesis and immune cell function. In an oncological context, let-7d has a tumor-suppressive function, although some of its functions are context-dependent. Notably, its expression is associated with improved therapeutic responses to chemotherapy in breast and ovarian cancer. Studies in mouse models have furthermore revealed important roles in uterine development and function, with implications for obstetric diseases. Apart from a possible utility as a diagnostic blood-based biomarker, pharmacological modulation of let-7d emerges as a promising therapeutic concept in a variety of female disease conditions.
Assuntos
Regulação da Expressão Gênica , Doenças dos Genitais Femininos/genética , MicroRNAs/genética , Envelhecimento , Animais , Biomarcadores , Biomarcadores Tumorais , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Feminino , Fertilidade/genética , Regulação Neoplásica da Expressão Gênica , Genes Supressores de Tumor , Doenças dos Genitais Femininos/tratamento farmacológico , Neoplasias dos Genitais Femininos/tratamento farmacológico , Neoplasias dos Genitais Femininos/genética , Humanos , Camundongos , MicroRNAs/fisiologia , Terapia de Alvo Molecular , Gravidez , Complicações na Gravidez/genética , RNA Neoplásico/antagonistas & inibidores , RNA Neoplásico/genética , RNA Neoplásico/fisiologiaRESUMO
Glioma ranks first among the aggressive brain tumors all over the world. LncRNA LINC00689 has been confirmed to play key roles in the progression of cancers, and LINC00689 was upregulated in glioma. However, the biological function of LINC00689 in glioma is unclear. qRT-PCR was applied to detect the expressions of LINC00689 and miR-526b-3p in glioma cells. Dual-luciferase report was performed to examine the relation among LINC00689, miR-526b-3p, and insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1). Then, the growth, migration, and invasion of glioma cells were detected by colony formation, flow cytometry, and transwell assay, respectively. The expressions of p21, cleaved caspase 3, and MAPK signaling-related proteins in glioma cells were tested by western blotting. Finally, xenograft mice model was established to detect the effect of LINC00689 on tumor growth of glioma in vivo. LINC00689 was upregulated in glioma cells, while miR-526b-3p was downregulated. In addition, LINC00689 bound to miR-526b-3p, and IGFBP1 was targeted by miR-526b-3p. Moreover, LINC00689 knockdown or upregulation of miR-526b-3p inhibited the proliferation of glioma cells and induced the apoptosis. Consistently, the migration and invasion of glioma cells were notably reduced by LINC00689 shRNA/miR-526-3p mimics. miR-526b-3p inhibitor or IGF2BP1 upregulation could reverse the effect of LINC00689 knockdown or miR-526b-3p mimics. Finally, knockdown of LINC00689 inhibited the tumor growth of glioma in vivo through regulating miR-526b-3p/IGF2BP1/MAPK axis. In conclusion, silencing of LINC00689 could inhibit the tumorigenesis of glioma via mediation of miR-526b-3p/IGF2BP1 axis. LINC00689 may serve as a new target for the treatment of glioma.
Assuntos
Glioma/genética , MicroRNAs/fisiologia , Proteínas de Neoplasias/fisiologia , RNA Longo não Codificante/fisiologia , RNA Neoplásico/fisiologia , Proteínas de Ligação a RNA/fisiologia , Animais , Apoptose , Linhagem Celular Tumoral , Movimento Celular , Transformação Celular Neoplásica/genética , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Genes Reporter , Glioma/metabolismo , Glioma/patologia , Xenoenxertos , Humanos , Sistema de Sinalização das MAP Quinases , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/antagonistas & inibidores , Invasividade Neoplásica , TransfecçãoRESUMO
PURPOSE: To explore whether miR-573 can suppress pancreatic cancer cell proliferation, migration, and invasion by targeting TSPAN1. METHODS: The expression of miR-573 and TSPAN1 in pancreatic cancer tissues and cells lines was analyzed using RT-qPCR. The human pancreatic cancer cell line PANC1 was transfected with miR-573 mimic, pcDNA3.1-TSPAN1, or genOFFTM st-h-TSPAN1. The effects of miR-573 and TSPAN1 on cell proliferation, colony formation, migration, and invasion were analyzed by CCK8, colony formation, transwell migration, and invasion assay, respectively. Target genes of miR-573 were screened using bioinformatics tools and confirmed by dual-luciferase reporter assay and real-time PCR. The effects of miR-573 in vivo were observed using tumor xenografts. RESULTS: We found that miR-573 is downregulated and TSPAN1 is upregulated in pancreatic cancer tissues and cells lines. Function assays demonstrated that overexpression of miR-573 inhibited cell proliferation, colony formation, migration, and invasion of pancreatic cancer cells, as well as suppressing tumor growth in vivo. Target genes of miR-573 were predicted using bioinformatics tools and confirmed by dual-luciferase reporter assay and RT-qPCR or western blotting. Downregulation of TSPAN1 also inhibited cell proliferation, colony formation, migration, and invasion of pancreatic cancer cells. Furthermore, overexpression of TSPAN1 attenuated miR-573-induced inhibition of pancreatic cancer cell proliferation and migration. CONCLUSION: Our findings indicated that miR-573 suppresses pancreatic cancer cell proliferation, migration, and invasion through targeting TSPAN1. TSPAN1 targeted by miR-573 might be a potential therapeutic target for clinical treatment of pancreatic cancer.
Assuntos
MicroRNAs/fisiologia , Proteínas de Neoplasias/antagonistas & inibidores , Neoplasias Pancreáticas/patologia , RNA Neoplásico/fisiologia , Tetraspaninas/antagonistas & inibidores , Animais , Divisão Celular , Linhagem Celular Tumoral , Movimento Celular , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica/genética , Genes Reporter , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/biossíntese , MicroRNAs/genética , MicroRNAs/uso terapêutico , Invasividade Neoplásica , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , RNA Neoplásico/biossíntese , RNA Neoplásico/genética , Distribuição Aleatória , Reação em Cadeia da Polimerase em Tempo Real , Organismos Livres de Patógenos Específicos , Tetraspaninas/biossíntese , Tetraspaninas/genética , Ensaio Tumoral de Célula-Tronco , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Our recent research has revealed that passenger strands of certain microRNAs (miRNAs) function as tumor-suppressive miRNAs in cancer cells, e.g., miR-101-5p, miR-143-5p, miR-144-5p, miR-145-3p, and miR-150-3p. Thus, they are important in cancer pathogenesis. Analysis of the miRNA expression signature of breast cancer (BrCa) showed that the expression levels of two miRNAs derived from pre-miR-99a (miR-99a-5p and miR-99a-3p) were suppressed in cancerous tissues. The aim of this study was to identify oncogenic genes controlled by pre-miR-99a that are closely involved in the molecular pathogenesis of BrCa. A total of 113 genes were identified as targets of pre-miR-99a regulation (19 genes modulated by miR-99a-5p, and 95 genes regulated by miR-99a-3p) in BrCa cells. Notably, FAM64A was targeted by both of the miRNAs. Among these targets, high expression of 16 genes (C5orf22, YOD1, SLBP, F11R, C12orf49, SRPK1, ZNF250, ZNF695, CDK1, DNMT3B, TRIM25, MCM4, CDKN3, PRPS, FAM64A, and DESI2) significantly predicted reduced survival of BrCa patients based upon The Cancer Genome Atlas (TCGA) database. In this study, we focused on FAM64A and investigated the relationship between FAM64A expression and molecular pathogenesis of BrCa subtypes. The upregulation of FAM64A was confirmed in BrCa clinical specimens. Importantly, the expression of FAM64A significantly differed between patients with Luminal-A and Luminal-B subtypes. Our data strongly suggest that the aberrant expression of FAM64A is involved in the malignant transformation of BrCa. Our miRNA-based approaches (identification of tumor-suppressive miRNAs and their controlled targets) will provide novel information regarding the molecular pathogenesis of BrCa.
Assuntos
Neoplasias da Mama/genética , Estrogênios , Regulação Neoplásica da Expressão Gênica/genética , Genes Supressores de Tumor , Peptídeos e Proteínas de Sinalização Intracelular/genética , MicroRNAs/genética , Proteínas de Neoplasias/genética , Neoplasias Hormônio-Dependentes/genética , Proteínas Nucleares/genética , Oncogenes , Progesterona , RNA Neoplásico/genética , Aminopiridinas/administração & dosagem , Aminopiridinas/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzimidazóis/administração & dosagem , Benzimidazóis/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Regulação para Baixo , Feminino , Genes erbB-2 , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/biossíntese , Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , Estimativa de Kaplan-Meier , MicroRNAs/fisiologia , Pessoa de Meia-Idade , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/fisiologia , Neoplasias Hormônio-Dependentes/tratamento farmacológico , Neoplasias Hormônio-Dependentes/mortalidade , Neoplasias Hormônio-Dependentes/patologia , Proteínas Nucleares/biossíntese , Proteínas Nucleares/fisiologia , Piperazinas/administração & dosagem , Piperazinas/uso terapêutico , Prognóstico , Intervalo Livre de Progressão , Piridinas/administração & dosagem , Piridinas/uso terapêutico , Interferência de RNA , RNA Neoplásico/fisiologia , RNA Interferente Pequeno/genética , Resultado do TratamentoRESUMO
Acquired drug resistance is a major obstacle in cancer therapy. Recent studies revealed that reprogramming of tRNA modifications modulates cancer survival in response to chemotherapy. However, dynamic changes in tRNA modification were not elucidated. In this study, comparative analysis of the human cancer cell lines and their taxol resistant strains based on tRNA mapping was performed by using UHPLC-MS/MS. It was observed for the first time in all three cell lines that 4-demethylwyosine (imG-14) substitutes for hydroxywybutosine (OHyW) due to tRNA-wybutosine synthesizing enzyme-2 (TYW2) downregulation and becomes the predominant modification at the 37th position of tRNAphe in the taxol-resistant strains. Further analysis indicated that the increase in imG-14 levels is caused by downregulation of TYW2. The time courses of the increase in imG-14 and downregulation of TYW2 are consistent with each other as well as consistent with the time course of the development of taxol-resistance. Knockdown of TYW2 in HeLa cells caused both an accumulation of imG-14 and reduction in taxol potency. Taken together, low expression of TYW2 enzyme promotes the cancer survival and resistance to taxol therapy, implying a novel mechanism for taxol resistance. Reduction of imG-14 deposition offers an underlying rationale to overcome taxol resistance in cancer chemotherapy.
Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Paclitaxel/farmacologia , Processamento Pós-Transcricional do RNA/genética , RNA Neoplásico/química , RNA de Transferência de Fenilalanina/química , Células A549 , Sequência de Bases , Linhagem Celular Tumoral , Cromatografia Líquida de Alta Pressão , Regulação para Baixo , Resistencia a Medicamentos Antineoplásicos/fisiologia , Feminino , Regulação Enzimológica da Expressão Gênica , Técnicas de Silenciamento de Genes , Guanosina/análogos & derivados , Guanosina/química , Guanosina/metabolismo , Células HeLa , Humanos , Estrutura Molecular , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Conformação de Ácido Nucleico , Neoplasias Ovarianas/patologia , RNA Neoplásico/fisiologia , RNA de Transferência de Fenilalanina/fisiologia , Espectrometria de Massas em Tandem , Ensaio Tumoral de Célula-TroncoRESUMO
BACKGROUND: Cisplatin is the first-line chemotherapeutic drug for non-small cell lung cancer (NSCLC), and emerging evidences suggests that targeting circular RNAs (circRNAs) is an effective strategy to increase cisplatin-sensitivity in NSCLC, but the detailed mechanisms are still not fully delineated. METHODS: Cell proliferation, viability and apoptosis were examined by using the cell counting kit-8 (CCK-8) assay, trypan blue staining assay and Annexin V-FITC/PI double staining assay, respectively. The expression levels of cancer associated genes were measured by using the Real-Time qPCR and Western Blot analysis at transcriptional and translated levels. Dual-luciferase reporter gene system assay was conducted to validated the targeting sites among hsa_circRNA_103809, miR-377-3p and 3' untranslated region (3'UTR) of GOT1 mRNA. The expression status, including expression levels and localization, were determined by immunohistochemistry (IHC) assay in mice tumor tissues. RESULTS: Here we identified a novel hsa_circRNA_103809/miR-377-3p/GOT1 signaling cascade which contributes to cisplatin-resistance in NSCLC in vitro and in vivo. Mechanistically, parental cisplatin-sensitive NSCLC (CS-NSCLC) cells were subjected to continuous low-dose cisplatin treatment to generate cisplatin-resistant NSCLC (CR-NSCLC) cells, and we found that hsa_circRNA_103809 and GOT1 were upregulated, while miR-377-3p was downregulated in CR-NSCLC cells but not in CS-NSCLC cells. In addition, hsa_circRNA_103809 sponged miR-337-3p to upregulate GOT1 in CS-NSCLC cells, and knock-down of hsa_circRNA_103809 enhanced the inhibiting effects of cisplatin on cell proliferation and viability, and induced cell apoptosis in CR-NSCLC cells, which were reversed by downregulating miR-377-3p and overexpressing GOT1. Consistently, overexpression of hsa_circRNA_103809 increased cisplatin-resistance in CS-NSCLC cells by regulating the miR-377-3p/GOT1 axis. Finally, silencing of hsa_circRNA_103809 aggravated the inhibiting effects of cisplatin treatment on NSCLC cell growth in vivo. CONCLUSIONS: Analysis of data suggested that targeting the hsa_circRNA_103809/miR-377-3p/GOT1 pathway increased susceptibility of CR-NSCLC cells to cisplatin, and this study provided novel targets to improve the therapeutic efficacy of cisplatin for NSCLC treatment in clinic.
Assuntos
Aspartato Aminotransferase Citoplasmática/fisiologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Cisplatino/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , MicroRNAs/fisiologia , Proteínas de Neoplasias/fisiologia , RNA Circular/fisiologia , RNA Neoplásico/fisiologia , Regiões 3' não Traduzidas , Animais , Apoptose , Aspartato Aminotransferase Citoplasmática/genética , Divisão Celular , Linhagem Celular Tumoral , Técnicas de Silenciamento de Genes , Vetores Genéticos/farmacologia , Humanos , Camundongos , Camundongos Nus , MicroRNAs/genética , Proteínas de Neoplasias/genética , RNA Circular/antagonistas & inibidores , RNA Circular/genética , RNA Neoplásico/antagonistas & inibidores , RNA Neoplásico/genética , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/farmacologia , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Noncoding RNAs (ncRNAs) are a large segment of the transcriptome that do not have apparent protein-coding roles, but they have been verified to play important roles in diverse biological processes, including disease pathogenesis. With the development of innovative technologies, an increasing number of novel ncRNAs have been uncovered; information about their prominent tissue-specific expression patterns, various interaction networks, and subcellular locations will undoubtedly enhance our understanding of their potential functions. Here, we summarized the principles and innovative methods for identifications of novel ncRNAs that have potential functional roles in cancer biology. Moreover, this review also provides alternative ncRNA databases based on high-throughput sequencing or experimental validation, and it briefly describes the current strategy for the clinical translation of cancer-associated ncRNAs to be used in diagnosis.
Assuntos
RNA não Traduzido/fisiologia , Cromatina/genética , Bases de Dados Genéticas , Regulação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Análise em Microsséries , Modelos Genéticos , Neoplasias/genética , Neoplasias/metabolismo , Fases de Leitura Aberta/genética , Especificidade de Órgãos , Biossíntese de Proteínas , RNA Neoplásico/genética , RNA Neoplásico/fisiologia , RNA não Traduzido/classificação , RNA não Traduzido/genética , RNA não Traduzido/isolamento & purificação , RNA-Seq , Ribossomos/metabolismo , Análise de Célula Única , Frações Subcelulares/química , Transcrição GênicaRESUMO
Dysregulation of long non-coding RNAs (lncRNAs) has been implicated in many cancer developments. Previous studies showed that lncRNA LINC00941 was aberrantly expressed in oral squamous cell carcinoma (OSCC). However, its role in OSCC development remains elusive. In this study, we demonstrated that in OSCC cells, EP300 activates LINC00941 transcription through up-regulating its promoter H3K27ac modification. Up-regulated LINC00941 in turn activates CAPRIN2 expression by looping to CAPRIN2 promoter. Functional assays suggest that both LINC00941 and CAPRIN2 play pivotal roles in promoting OSCC cell proliferation and colony formation. In vivo assay further confirmed the role of LINC00941 in promoting OSCC cell tumour formation. Lastly, we showed that the role of LINC00941 and CAPRIN2 in OSCC progression was mediated through activating the canonical WNT/ß-catenin signaling pathway. Thus, LINC00941/CAPRIN2/ WNT/ß-catenin signaling pathway provides new therapeutic targets for OSCC treatment.
Assuntos
Carcinoma de Células Escamosas/patologia , Neoplasias Bucais/patologia , Proteínas de Neoplasias/fisiologia , RNA Longo não Codificante/metabolismo , RNA Neoplásico/fisiologia , Proteínas de Ligação a RNA/fisiologia , Via de Sinalização Wnt/fisiologia , Animais , Sistemas CRISPR-Cas , Carcinoma de Células Escamosas/genética , Divisão Celular , Células Cultivadas , DNA de Neoplasias/genética , DNA de Neoplasias/ultraestrutura , Progressão da Doença , Proteína p300 Associada a E1A/fisiologia , Regulação Neoplásica da Expressão Gênica , Genes Reporter , Código das Histonas , Queratinócitos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Bucais/genética , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Transplante de Neoplasias , Regiões Promotoras Genéticas/genética , RNA Guia de Cinetoplastídeos/administração & dosagem , RNA Guia de Cinetoplastídeos/genética , RNA Longo não Codificante/genética , RNA Neoplásico/biossíntese , RNA Neoplásico/genética , Proteínas de Ligação a RNA/biossíntese , Proteínas de Ligação a RNA/genética , Proteínas Recombinantes/metabolismo , Ensaio Tumoral de Célula-Tronco , Regulação para Cima , Via de Sinalização Wnt/genéticaRESUMO
Both inflammasomes and autophagy have important roles in the intracellular homeostasis, inflammation, and pathology; the dysregulation of these processes is often associated with the pathogenesis of numerous cancers. In addition, they can crosstalk with each other in multifaceted ways to influence various physiological and pathological responses, including cancer. Multiple molecular mechanisms connect the autophagy pathway to inflammasome activation and, through this, may influence the outcome of pro-tumor or anti-tumor responses depending on the cancer types, microenvironment, and the disease stage. In this review, we highlight the rapidly growing literature on the various mechanisms by which autophagy interacts with the inflammasome pathway, to encourage additional applications in the context of tumors. In addition, we provide insight into the mechanisms by which pathogen modulates the autophagy-inflammasome pathway to favor the infection-induced carcinogenesis. We also explore the challenges and opportunities of using multiple small molecules/agents to target the autophagy/inflammasome axis and their effects upon cancer treatment. Finally, we discuss the emerging clinical efforts assessing the potential usefulness of targeting approaches for either autophagy or inflammasome as anti-cancer strategies, although it remains underexplored in terms of their crosstalks.
Assuntos
Autofagia/fisiologia , Inflamassomos/fisiologia , Neoplasias/imunologia , Animais , Autofagia/efeitos dos fármacos , Ensaios Clínicos como Assunto , Homeostase , Humanos , Inflamassomos/efeitos dos fármacos , Membranas Intracelulares/fisiologia , Mitocôndrias/metabolismo , Mitofagia/efeitos dos fármacos , Mitofagia/fisiologia , Modelos Biológicos , Proteína 3 que Contém Domínio de Pirina da Família NLR/fisiologia , Proteínas de Neoplasias/fisiologia , Neoplasias/fisiopatologia , RNA de Cadeia Dupla/fisiologia , RNA Neoplásico/fisiologia , Espécies Reativas de Oxigênio/metabolismoRESUMO
Acute myeloid leukemia (AML) is a highly heterogeneous disease featured by the clonal accumulation of immature myeloid cells. Zinc finger Ebox binding homeobox 2 (ZEB2)antisense RNA 1 (AS1) has been verified to participate in the progression of several types of cancer, including AML. However, the potential mechanisms of ZEB2AS1 in AML have not yet been fully elucidated. The present study aimed to elucidate the role and regulatory mechanisms of ZEB2AS1 in AML. The expression of ZEB2AS1, microRNA1225p (miRNA/miR1225p) and pololike kinase 1 (PLK1) was detected by reverse transcriptionquantitative polymerase chain reaction (RTqPCR) in AML tissues or cells. Cell proliferation and apoptosis were examined by methyl thiazolyl tetrazolium (MTT) assay and apoptosis assay, respectively. The protein levels were examined by western blot analysis. The targeted sequence between miR1225p and ZEB2AS1 or PLK1 was predicted using an online database and verified by dualluciferase reporter assay. A mouse tumor xenograft model was established to confirm the effects of ZEB2AS1 on tumor growth in vivo. The results revealed that the expression levels of ZEB2AS1 and PLK1 were upregulated, while those of miR1225p were downregulated in AML tissues and cells. The knockdown of ZEB2AS1 inhibited proliferation and induced apoptosis in vitro, and inhibited tumor growth in vivo. By experimental verification, ZEB2AS1 was found to negatively regulate miR1225p expression and PLK1 was found to be a target gene of miR1225p. Furthermore, ZEB2AS1 was verified to regulate the expression of PLK1 by sponging miR1225p in AML cells. On the whole, the findings of the present study demonstrate that ZEB2AS1 promotes cell proliferation and inhibits apoptosis, at least partly by targeting PLK1 mediated by miR1225p in AML cells.
Assuntos
Proteínas de Ciclo Celular/antagonistas & inibidores , Leucemia Mieloide Aguda/genética , MicroRNAs/fisiologia , Proteínas de Neoplasias/fisiologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas/antagonistas & inibidores , RNA Longo não Codificante/fisiologia , RNA Neoplásico/fisiologia , Transdução de Sinais/fisiologia , Animais , Apoptose , Proteínas de Ciclo Celular/biossíntese , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/fisiologia , Divisão Celular , Linhagem Celular Tumoral , Criança , Pré-Escolar , Feminino , Técnicas de Silenciamento de Genes , Genes Reporter , Xenoenxertos , Humanos , Leucemia Mieloide Aguda/patologia , Masculino , Camundongos , Camundongos Nus , MicroRNAs/biossíntese , MicroRNAs/genética , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Proteínas Serina-Treonina Quinases/biossíntese , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/fisiologia , Proteínas Proto-Oncogênicas/biossíntese , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/fisiologia , RNA Longo não Codificante/biossíntese , RNA Longo não Codificante/genética , RNA Neoplásico/biossíntese , RNA Neoplásico/genética , Transdução de Sinais/genética , Quinase 1 Polo-LikeRESUMO
Glioblastoma is the most common primary tumor of the central nervous system that develops chemotherapy resistance. Previous studies showed that Allicin could inhibit multiple cancer cells including glioblastoma, but the function of Allicin in glioblastoma is still unclear. Our work aimed to investigate the underlying molecular mechanism. The results showed that miR-486-3p levels were greatly increased in glioblastoma during Allicin treatment. Overexpression of miR-486-3p increased chemosensitivity to temozolomide (TMZ) in vitro and in vivo. O6-methylguanine-DNA methyltransferase (MGMT) was identified as a direct target of miR-486-3p, and miR-486-3p overexpression prevented the protein translation of MGMT. Moreover, overexpression of MGMT restored miR-486-3p-induced chemosensitivity to TMZ. Taken together, our studies revealed that Allicin could upregulate miR-486-3p and enhance TMZ sensitivity in glioblastoma. The results suggested that in the future, Allicin can be used as an adjuvant therapy with TMZ to improve the prognosis of patients, and miR-486-3p may be a potential target for glioblastoma treatment to improve the curative effects.
Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Metilases de Modificação do DNA/antagonistas & inibidores , Enzimas Reparadoras do DNA/antagonistas & inibidores , Dissulfetos/farmacologia , Glioblastoma/tratamento farmacológico , MicroRNAs/fisiologia , Proteínas de Neoplasias/antagonistas & inibidores , RNA Neoplásico/fisiologia , Ácidos Sulfínicos/farmacologia , Temozolomida/uso terapêutico , Proteínas Supressoras de Tumor/antagonistas & inibidores , Adulto , Animais , Apoptose/efeitos dos fármacos , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Dissulfetos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Glioblastoma/patologia , Humanos , Camundongos , Camundongos Nus , MicroRNAs/biossíntese , MicroRNAs/genética , Proteínas de Neoplasias/genética , RNA Neoplásico/biossíntese , RNA Neoplásico/genética , Proteínas Recombinantes/efeitos dos fármacos , Organismos Livres de Patógenos Específicos , Ácidos Sulfínicos/uso terapêutico , Temozolomida/farmacologia , Proteínas Supressoras de Tumor/genética , Regulação para Cima/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. The alveolar subtype (ARMS) is clinically more aggressive, and characterized by an oncogenic fusion protein PAX3-FOXO1 that drives oncogenic cellular properties. Exosomes are small, secreted vesicles that affect paracrine signaling. We show that PAX3-FOXO1 transcript alters exosome content of C2C12 myoblasts, leading to pro-tumorigenic paracrine effects in recipient cells. Microarray analysis revealed alteration in miRNA content of exosomes, affecting cellular networks involved in cell metabolism, growth signaling, and cellular invasion. Overexpression and knockdown studies showed that miR-486-5p is an effector of PAX3-FOXO1, and mediates its paracrine effects in exosomes, including promoting recipient cell migration, invasion, and colony formation. Analysis of human RMS cells showed miR-486-5p is enriched in both cells and exosomes, and to a higher extent in ARMS subtypes. Analysis of human serum samples showed that miR-486-5p is enriched in exosomes of patients with RMS, and follow-up after chemotherapy showed decrease to control values. Our findings identify a novel role of both PAX3-FOXO1 and its downstream effector miR-486-5p in exosome-mediated oncogenic paracrine effects of RMS, and suggest its possible use as a biomarker.
Assuntos
Exossomos/genética , MicroRNAs/análise , Proteínas de Fusão Oncogênica/genética , Fatores de Transcrição Box Pareados/genética , RNA Neoplásico/fisiologia , Rabdomiossarcoma Alveolar/genética , Neoplasias de Tecidos Moles/genética , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais , Adesão Celular , Divisão Celular , Linhagem Celular , Exossomos/ultraestrutura , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/sangue , MicroRNAs/genética , MicroRNAs/fisiologia , Análise em Microsséries , Mioblastos , Invasividade Neoplásica , Comunicação Parácrina , RNA Neoplásico/sangue , RNA Neoplásico/genética , Proteínas Recombinantes/metabolismo , Rabdomiossarcoma Alveolar/tratamento farmacológico , Rabdomiossarcoma Alveolar/metabolismo , Neoplasias de Tecidos Moles/tratamento farmacológico , Neoplasias de Tecidos Moles/metabolismo , Transdução GenéticaRESUMO
Myeloid-derived suppressor cells (MDSCs) are a heterogeneous cell population with potent immunosuppressive functions. They play major roles in cancer and many of the pathologic conditions associated with inflammation. Long non-coding RNAs (lncRNAs) are untranslated functional RNA molecules. The lncRNAs are involved in the control of a wide variety of cellular processes and are dysregulated in different diseases. They can participate in the modulation of immune function and activity of inflammatory cells, including MDSCs. This mini review focuses on the emerging role of lncRNAs in MDSC activity. We summarize how lncRNAs modulate the generation, recruitment, and immunosuppressive functions of MDSCs and the underlying mechanisms.
Assuntos
Inflamação/imunologia , Células Supressoras Mieloides/imunologia , Neoplasias/imunologia , RNA Longo não Codificante/fisiologia , Animais , Proteína beta Intensificadora de Ligação a CCAAT/fisiologia , Linhagem da Célula , Epigênese Genética , Previsões , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Imunoterapia , Camundongos , Células Supressoras Mieloides/classificação , Neoplasias/genética , Neoplasias/terapia , Óxido Nítrico/metabolismo , Pseudogenes , RNA Longo não Codificante/genética , RNA Longo não Codificante/imunologia , RNA Neoplásico/imunologia , RNA Neoplásico/fisiologia , Espécies Reativas de Oxigênio/metabolismo , Evasão Tumoral , Microambiente TumoralRESUMO
LncRNAs play critical roles in various pathophysiological and biological processes, such as protein translation, RNA splicing, and epigenetic modification. Indeed, abundant evidences demonstrated that lncRNA act as competing endogenous RNAs (ceRNAs) to participate in tumorigenesis. However, little is known about the underlying function of lncRNA in nonhomologous end joining (NHEJ) pathway 1 (LINP1) in pediatric and adolescent acute myeloid leukemia (AML). The expression of LINP1 was examined in AML patient samples by qRT-PCR. Cell proliferation was examined by CCK-8 and Edu assays. ß-Galactosidase senescence assay, mGlucose uptake assay, lactate production assay, and Gene Ontology (GO) analysis were performed for functional analysis. We found that LINP1 was significantly overexpressed in AML patients at diagnosis, whereas downregulated after complete remission (CR). Furthermore, knockdown of LINP1 expression remarkably suppressed glucose uptake and AML cell maintenance. Mechanistically, LINP1 was found to inhibit the glucose metabolism by suppressing the expression of HNF4a. Both LINP1 and HNF4a knockdown reduced the expression levels of AMPK phosphorylation and WNT5A, indicating for the first time that LINP1 strengthened the HNF4a-AMPK/WNT5A signaling pathway involved in cell glucose metabolism modulation and AML cell survival. Taken together, our results indicated that LINP1 promotes the malignant phenotype of AML cells and stimulates glucose metabolism, which can be regarded as a potential prognostic marker and therapeutic target for AML.
Assuntos
Adenilato Quinase/fisiologia , Fator 4 Nuclear de Hepatócito/fisiologia , Leucemia Mieloide Aguda/genética , RNA Longo não Codificante/fisiologia , RNA Neoplásico/fisiologia , Transdução de Sinais/fisiologia , Proteína Wnt-5a/fisiologia , Adolescente , Animais , Medula Óssea/patologia , Divisão Celular , Criança , Regulação Leucêmica da Expressão Gênica , Técnicas de Silenciamento de Genes , Ontologia Genética , Glucose/metabolismo , Fator 4 Nuclear de Hepatócito/biossíntese , Fator 4 Nuclear de Hepatócito/genética , Humanos , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Transplante de Neoplasias , Púrpura Trombocitopênica Idiopática/metabolismo , Interferência de RNA , RNA Longo não Codificante/biossíntese , RNA Longo não Codificante/genética , RNA Neoplásico/biossíntese , RNA Neoplásico/genética , RNA Interferente Pequeno/genética , Distribuição Aleatória , Indução de Remissão , Transdução de Sinais/genética , Células THP-1RESUMO
Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide, with a high mortality rate. Its dismal prognosis is attributed to late diagnosis, high risk of recurrence and drug resistance. To improve the survival of patients with HCC, new approaches are required for early diagnosis, real-time monitoring and effective treatment. Exosomes are small membranous vesicles released by most cells that contain biological molecules and play a great role in intercellular communication under physiological or pathological conditions. In cancer, exosomes from tumor cells or non-tumor cells can be taken up by neighboring or distant target cells, and the cargoes in exosomes are functional to modulate the behaviors of tumors or reshape tumor microenvironment (TME). As essential components, non-coding RNAs (ncRNAs) are selectively enriched in exosomes, and exosomal ncRNAs participate in regulating specific aspects of tumor development, including tumorigenesis, tumor metastasis, angiogenesis, immunomodulation and drug resistance. Besides, dysregulated exosomal ncRNAs have emerged as potential biomarkers, and exosomes can serve as natural vehicles to deliver tumor-suppressed ncRNAs for treatment. In this review, we briefly summarize the biology of exosomes, the functions of exosomal ncRNAs in HCC development and their potential clinical applications, including as biomarkers and therapeutic tools.
Assuntos
Carcinoma Hepatocelular/genética , Exossomos/genética , Neoplasias Hepáticas/genética , RNA Neoplásico/fisiologia , RNA não Traduzido/fisiologia , Animais , Biomarcadores Tumorais/fisiologia , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/terapia , Sistemas de Liberação de Medicamentos , Exossomos/metabolismo , Regulação Neoplásica da Expressão Gênica , Terapia Genética/métodos , Humanos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/terapia , Terapia de Alvo Molecular/métodos , RNA Neoplásico/metabolismo , RNA não Traduzido/metabolismoRESUMO
MicroRNAs (miRNA) are small noncoding RNAs that regulate gene expression by targeting mRNAs in a sequence specific manner, thereby determining their degradation or inhibiting translation. They are involved in processes such as proliferation, differentiation and apoptosis by fine-tuning the expression of genes underlying such events. The expression of specific miRNAs is involved in hematopoietic differentiation and their deregulation contributes to the development of hematopoietic malignancies such as acute myeloid leukemia (AML). miR-130a is over-expressed in AML. Here we show that miR-130a is physiologically expressed in myeloblasts and down-regulated during monocyte differentiation. Gain- and loss-of-function experiments performed on CD34+â¯human hematopoietic stem cells confirmed that expression of miR-130a inhibits monocyte differentiation by interfering with the expression of key transcription factors HOXA10, IRF8, KLF4, MAFB and PU-1. The data obtained in this study highlight that the correct modulation of miR-130a is necessary for normal differentiation to occur and confirming that deregulation of this miRNA might underlie the differentiation block occurring in AML.
Assuntos
Regulação da Expressão Gênica , Células Precursoras de Granulócitos/metabolismo , Células-Tronco Hematopoéticas/metabolismo , MicroRNAs/fisiologia , Monócitos/citologia , Mielopoese/fisiologia , Proteínas de Neoplasias/fisiologia , Antígenos CD34/análise , Linhagem Celular Tumoral , Linhagem da Célula , Células Cultivadas , Ensaio de Unidades Formadoras de Colônias , Mutação com Ganho de Função , Células Precursoras de Granulócitos/citologia , Células-Tronco Hematopoéticas/citologia , Humanos , Fator 4 Semelhante a Kruppel , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Mutação com Perda de Função , MicroRNAs/antagonistas & inibidores , MicroRNAs/biossíntese , MicroRNAs/genética , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Ácidos Nucleicos Peptídicos/farmacologia , RNA Neoplásico/genética , RNA Neoplásico/fisiologia , Fatores de Transcrição/biossíntese , Fatores de Transcrição/genéticaRESUMO
Long non-coding RNAs (lncRNAs) are reported to play a significant role in various malignant tumors, yet their potential functions in gastric cancer are not clear. In this study, we found a novel lncRNA, named TONSL-AS1, was downregulated in gastric cancer tissues and cell lines compared with the normal. TONSL-AS1 inhibited cell migration, invasion and proliferation in SGC-7901, MGC-803â¯cells. Furthermore, TONSL-AS1 could suppress cell tumorigenesis in vivo. Mechanistically, TONSL-AS1's genomic neighboring gene TONSL, which was reported as a tumor suppress gene, was upregulated by TONSL. Additionally, the TONSL-AS1 was positively associated with TONSL in cancer tissues. Our study revealed that the tumor-inhibiting effect of TONSL-AS1 in gastric cancer cells was associated with TONSL. In general, our results indicated that TONSL-AS1 works as a tumor suppressor lncRNA, which may be a new therapeutic target for gastric cancer.
Assuntos
Regulação Neoplásica da Expressão Gênica/genética , Genes Supressores de Tumor , NF-kappa B/fisiologia , Proteínas de Neoplasias/fisiologia , RNA Neoplásico/fisiologia , Neoplasias Gástricas/genética , Adulto , Idoso , Animais , Carcinogênese , Adesão Celular , Divisão Celular , Linhagem Celular Tumoral , Movimento Celular , Progressão da Doença , Regulação para Baixo , Feminino , Genes Reporter , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , NF-kappa B/genética , Proteínas de Neoplasias/genética , Interferência de RNA , RNA Neoplásico/genética , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/farmacologia , Organismos Livres de Patógenos EspecíficosRESUMO
Emerging evidence indicates that long noncoding RNAs (LncRNAs) are new players in gene regulation but their mechanisms of action are mainly undocumented. In this study, we investigated LncRNA alterations that contribute to lung cancer by analyzing published microarray data in Gene Expression Obminus (GEO) and The Cancer Genome Atlas RNA (TCGA) sequencing data. Here, we reported that HAGLR (also called HOXD-AS1) was frequently down-regulated in lung adenocarcinoma (LUAD) tissues, and decreased HAGLR expression was clinically associated with shorter survival of LUAD patients. Preclinical studies using multiple LUAD cells and in vivo mouse model indicated that HAGLR could attenuate LUAD cell growth in vitro and in vivo. Mechanistically, HAGLR could physically interact with DNMT1, and recruit DNMT1 on E2F1 promoter to increase local DNA methylation. Overall, our study demonstrated that HAGLR promoted LUAD progression by recruiting DNMT1 to modulate the promoter methylation and expression of E2F1, which expanded potential therapeutic strategies for LUAD treatment.
Assuntos
Adenocarcinoma/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Fator de Transcrição E2F1/genética , Genes Supressores de Tumor , Proteínas de Neoplasias/genética , RNA Longo não Codificante/fisiologia , RNA Neoplásico/fisiologia , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , DNA (Citosina-5-)-Metiltransferase 1/fisiologia , Metilação de DNA , DNA de Neoplasias/genética , Fator de Transcrição E2F1/antagonistas & inibidores , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Humanos , Estimativa de Kaplan-Meier , Proteínas de Neoplasias/antagonistas & inibidores , Prognóstico , Regiões Promotoras Genéticas/genética , Mapeamento de Interação de Proteínas , Interferência de RNA , RNA Longo não Codificante/genética , RNA Neoplásico/genética , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/farmacologiaRESUMO
Scaffolding adaptor Gab2 is overexpressed in a subset of high-grade ovarian cancer. Our published work shows that Gab2 via PI3K enhances migratory behaviors and epithelial to mesenchymal transition (EMT) features of ovarian cancer cells in vitro. However, it is still unclear how Gab2/PI3K pathway reuglates EMT characteristics and whether Gab2 promotes the growth of ovarian cancer stem cell (CSC)-like population and metastatic growth. In this study, we examined the effects of Gab2 expression on CSC-like cell growth using Aldefluor and tumorshpere assays commonly used for assessing ovarian cancer cells with CSC properties. Gab2 overexpression increased the number of ALDH+ cells and tumorsphere formation in two different ovarian cancer cell lines OVCAR5 and OVCAR8, whereas knockdown of Gab2 decreased the number of ALDH+ cells and tumorsphere formation in Caov-3â¯cells. Furthermore, Gab2 promoted metastatic tumor growth of OVCAR5 in nude mice. Mechanistically, we uncovered that Gab2 via PI3K specifically inhibited miR-200c expression. miR-200c downregulation contributed to the Gab2-enhanced cell migratory behaviors, EMT properties, and the expansion of ALDH+ cells and tumorspheres. Furthermore, Gab2 promoted CD44 expression and cell migration/invasion through miR-200c downregulation. Our findings support a model that Gab2-PI3K pathway via miR-200c downregulation promotes CD44 expression, EMT characteristics, and CSC-like cell growth. Therapies involving miR-200c or targeting CD44 should help treat ovarian cancer with high Gab2 expression.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Regulação Neoplásica da Expressão Gênica , MicroRNAs/fisiologia , Proteínas de Neoplasias/fisiologia , Neoplasias Ovarianas/genética , RNA Neoplásico/fisiologia , Animais , Movimento Celular , Regulação para Baixo , Feminino , Xenoenxertos , Humanos , Receptores de Hialuronatos/antagonistas & inibidores , Receptores de Hialuronatos/biossíntese , Receptores de Hialuronatos/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/genética , Invasividade Neoplásica , Metástase Neoplásica , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Fosfatidilinositol 3-Quinases/fisiologia , Interferência de RNA , RNA Neoplásico/genética , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/farmacologiaRESUMO
The acquired chemoresistance during long term chemotherapy is one of the most important factors to limit the application of Doxorubicin (Dox) on clinical treatment of hepatocellular carcinoma (HCC) patients. Our present study found that Dox resistant HCC (HCC/Dox) cells had greater capability of in vitro migration and invasion compared to their parental cells. HCC/Dox cells exhibited mesenchymal characteristics, which was evidenced by the up regulation of fibronectin, vimentin while down regulation of E-Cadherin. Zeb1, one powerful epithelial mesenchymal transition related transcription factor (EMT-TF), was markedly upregulated in HCC/Dox cells. Targeted inhibition of Zeb1 via siRNA can suppress the cell migration and re-sensitized cells to Dox treatment. The upregulation of Zeb1 in HCC/Dox cells was due to the increasing protein and mRNA stability of Zeb1. In HCC/Dox cells, the down regulation of SIAH1 mediated the upregulation of protein stability of Zeb1, while decreased levels of miR-3129-5p was responsible for the increasing mRNA stability of Zeb1. Collectively, our data suggested that SIAH1 and miR-3129-5p induced upregulation of Zeb1 mediated the Dox resistance of HCC cells. Targeted inhibition of Zeb1 might be helpful to overcome of Dox resistance of HCC.