RESUMEN
MicroRNAs (miRNA) are small and conserved noncoding RNA molecules that regulate gene expression at the posttranscriptional level. These groups of RNAs are crucial in various cellular processes, especially in mediating disease pathogenesis, particularly cancer. The dysregulation of miRNAs was reported in many cancer types, including nasopharyngeal cancer (NPC), which is a malignant tumor of the nasopharynx. In this review, miRNAs involvement in crucial signaling pathways associated with NPC such as PTEN/PI3K/AKT, TGFß/SMAD, RAS/MAPK, Wnt/ß-catenin and pRB-E2F was investigated. miRNAs could function as tumor suppressor-miR or onco-miR in NPC profoundly influenced cell cycle, apoptosis, proliferation, migration, and metastasis. This comprehensive review of current literature provided a thorough profile of miRNAs and their interplay with the aforementioned signaling pathways in NPC. Understanding these molecular interactions could remarkably impact the diagnosis, prognosis, and therapeutic strategies for NPC.
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Carcinoma , MicroARNs , Neoplasias Nasofaríngeas , Humanos , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/metabolismo , MicroARNs/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , beta Catenina/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/patología , Transducción de Señal , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Línea Celular Tumoral , Movimiento Celular/genética , Fosfohidrolasa PTEN/genética , Fosfohidrolasa PTEN/metabolismoRESUMEN
Glioblastoma multiforme (GBM) is a highly aggressive brain tumor with a poor prognosis. The cleavage factor Im 25 (CFIm25), a crucial component of the CFIm complex, plays a key role in regulating the length of the mRNA 3'-UTR and has been implicated in various cancers, including GBM. This study sought to investigate the regulatory influence of specific microRNAs (miRNAs) on CFIm25 expression in GBM, a highly aggressive brain tumor. Bioinformatics analysis identified miRNA candidates targeting CFIm25 mRNA, and gene expression profiles from the NCBI database (GSE90603) were used for further analysis. Expression levels of CFIm25 and selected miRNAs were assessed using qRT-PCR in GBM clinical samples (n = 20) and non-malignant brain tissues (n = 5). Additionally, the MTT assay was performed to examine the effect of miRNA overexpression on U251 cell viability. Lentivectors expressing the identified miRNAs were employed to experimentally validate their regulatory role on CFIm25 in U251 cell lines, and Western blot analysis was conducted to determine CFIm25 protein levels. We observed significantly increased levels of miR-23, miR-24, and miR-27 expression, associated with a marked reduction in CFIm25 expression in GBM samples compared to non-malignant brain tissues. In particular, overexpression of miR-23, miR-24, and miR-27 in U251 cells resulted in CFIm25 downregulation at both the mRNA and protein levels, while their inhibition increased CFIm25 and reduced cell proliferation. These observations strongly implicate miR-23, miR-24, and miR-27 in regulating CFIm25 expression in GBM, emphasizing their potential as promising therapeutic targets for enhancing treatment responses in glioblastoma.
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MicroRNAs are small, noncoding molecules of about twenty-two nucleotides with crucial roles in both healthy and pathological cells. Their expression depends not only on genetic factors, but also on epigenetic mechanisms like genomic imprinting and inactivation of X chromosome in females that influence in a sex-dependent manner onset, progression, and response to therapy of different diseases like cancer. There is evidence of a correlation between miRNAs, sex, and cancer both in solid tumors and in hematological malignancies; as an example, in lymphomas, with a prevalence rate higher in men than women, miR-142 is "silenced" because of its hypermethylation by DNA methyltransferase-1 and it is blocked in its normal activity of regulating the migration of the cell. This condition corresponds in clinical practice with a more aggressive tumor. In addition, cancer treatment can have advantages from the evaluation of miRNAs expression; in fact, therapy with estrogens in hepatocellular carcinoma determines an upregulation of the oncosuppressors miR-26a, miR-92, and miR-122 and, consequently, apoptosis. The aim of this review is to present an exhaustive collection of scientific data about the possible role of sex differences on the expression of miRNAs and the mechanisms through which miRNAs influence cancerogenesis, autophagy, and apoptosis of cells from diverse types of tumors.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , MicroARNs , Humanos , Femenino , Masculino , MicroARNs/metabolismo , Caracteres Sexuales , Factores Sexuales , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Regulación Neoplásica de la Expresión GénicaRESUMEN
Colorectal cancer (CRC) is one of the most frequent cancers leading to death worldwide. Different signaling pathways such as the canonical Wnt signaling pathway have many effects on the development of CRC. MicroRNAs are small non-coding RNAs and different evidence represent their importance in the development of cancer via regulating the expression of their target genes. miRNAs can affect CRC progression as oncogenes or tumor suppressors. Dysregulation in miRNA expression can occur for various reasons, causes different abnormalities in the Wnt signaling pathway, and contributes to CRC development. Identifying the exact interactions between microRNAs and mRNAs or other non-coding RNAs assists in designing effective therapeutic, diagnostic, and prognostic approaches. In this review, we aim to focus on microRNAs that regulate CRC through modulating the Wnt pathway and then present the perspective outlook on the implication of miRNA in liquid biopsy for the management of patients with CRC.
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Neoplasias Colorrectales , MicroARNs , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Vía de Señalización Wnt/genética , Regulación Neoplásica de la Expresión Génica , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , ARN MensajeroRESUMEN
Exosomes are a novel class of intercellular signal modulators that contain a wide range of molecules and deliver information between cells and tissues. MicroRNAs (miRNAs), a type of regulatory non-coding RNA, are often incorporated into exosomes as signaling molecules. In this review, we discuss the expression of exosomal miRNAs from diverse origins such as tumor cells, solid tumor tissue, and biological fluids in various cancers (lung, breast, colorectal, liver, stomach, and pancreatic). We address the biological functions of exosome-derived miRNAs in processes such as tumor-cell proliferation, angiogenesis, metastasis, and chemoresistance in the tumor microenvironment. In particular, we discuss three oncogenic miRNAs, miR-21, miR-141, and miR-451, which occur within exosomes, in terms of gene regulation and intercellular communication. We consider therapeutic miRNA-based nanoparticles, which are widely expressed in tumors and show promise in drug therapy. The review assesses the wide-ranging evidence for using exosomal miRNAs as tumor markers in molecular diagnosis. Further, we consider the use of nanoparticle platforms to transport miRNAs, in the targeted treatment of disease and tumors.
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Progresión de la Enfermedad , Exosomas/genética , Regulación Neoplásica de la Expresión Génica , MicroARNs/genética , MicroARNs/uso terapéutico , Neoplasias/patología , Neoplasias/terapia , Neoplasias/genéticaRESUMEN
PURPOSE: MicroRNAs (miRNAs) are short (~ 22 nts) RNAs that regulate gene expression via binding to mRNA. MiRNAs promoting cancer are known as oncomiRs. Targeting oncomiRs is an emerging area of cancer therapy. OncomiR-21 and oncomiR-155 are highly upregulated in lymphoma cells, which are dependent on these oncomiRs for survival. Targeting specific miRNAs and determining their effect on cancer cell progression and metastasis have been the focus of various studies. Inhibiting a single miRNA can have a limited effect, as there may be other overexpressed miRNAs present that may promote tumor proliferation. Herein, we target miR-21 and miR-155 simultaneously using nanoparticles delivered two different classes of antimiRs: phosphorothioates (PS) and peptide nucleic acids (PNAs) and compared their efficacy in lymphoma cell lines. METHODS: Poly-Lactic-co-Glycolic acid (PLGA) nanoparticles (NPs) containing PS and PNA-based antimiR-21 and -155 were formulated, and comprehensive NP characterizations: morphology (scanning electron microscopy), size (differential light scattering), and surface charge (zeta potential) were performed. Cellular uptake analysis was performed using a confocal microscope and flow cytometry analysis. The oncomiR knockdown and the effect on downstream targets were confirmed by gene expression (real time-polymerase chain reaction) assay. RESULTS: We demonstrated that simultaneous targeting with NP delivered PS and PNA-based antimiRs resulted in significant knockdown of miR-21 and miR-155, as well as their downstream target genes followed by reduced cell viability ex vivo. CONCLUSIONS: This project demonstrated that targeting miRNA-155 and miR-21 simultaneously using nanotechnology and a diverse class of antisense oligomers can be used as an effective approach for lymphoma therapy.
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Linfoma , MicroARNs , Ácidos Nucleicos de Péptidos , Humanos , Ácidos Nucleicos de Péptidos/farmacología , Antagomirs , MicroARNs/genética , Linfoma/tratamiento farmacológico , Linfoma/genética , Línea Celular , Línea Celular TumoralRESUMEN
Since the discovery of microRNAs (miRNAs) in Caenorhabditis elegans, our understanding of their cellular function has progressed continuously. Today, we have a good understanding of miRNA-mediated gene regulation, miRNA-mediated cross talk between genes including competing endogenous RNAs, and miRNA-mediated signaling transduction both in normal human physiology and in diseases.Besides, these noncoding RNAs have shown their value for clinical applications, especially in an oncological context. They can be used as reliable biomarkers for cancer diagnosis and prognosis and attract increasing attention as potential therapeutic targets. Many achievements made in the miRNA field are based on joint efforts from computational and molecular biologists. Systems biology approaches, which integrate computational and experimental methods, have played a fundamental role in uncovering the cellular functions of miRNAs.In this chapter, we review and discuss the role of miRNAs in oncology from a system biology perspective. We first describe biological facts about miRNA genetics and function. Next, we discuss the role of miRNAs in cancer progression and review the application of miRNAs in cancer diagnostics and therapy. Finally, we elaborate on the role that miRNAs play in cancer gene regulatory networks. Taken together, we emphasize the importance of systems biology approaches in our continued efforts to study miRNA cancer regulation.
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MicroARNs , Neoplasias , Humanos , MicroARNs/genética , Biología de Sistemas/métodos , Redes Reguladoras de Genes , Neoplasias/diagnóstico , Neoplasias/genética , Neoplasias/terapia , Regulación de la Expresión Génica , Biología Computacional/métodosRESUMEN
Previously, we identified miR-125b as a key regulator of the undifferentiated state of hair follicle stem cells. Here, we show that in both mice and humans, miR-125b is abundantly expressed, particularly at early stages of malignant progression to squamous cell carcinoma (SCC), the second most prevalent cancer worldwide. Moreover, when elevated in normal murine epidermis, miR-125b promotes tumor initiation and contributes to malignant progression. We further show that miR-125b can confer "oncomiR addiction" in early stage malignant progenitors by delaying their differentiation and favoring an SCC cancer stem cell (CSC)-like transcriptional program. To understand how, we systematically identified and validated miR125b targets that are specifically associated with tumors that are dependent on miR-125b. Through molecular and genetic analysis of these targets, we uncovered new insights underlying miR-125b's oncogenic function. Specifically, we show that, on the one hand, mir-125b directly represses stress-responsive MAP kinase genes and associated signaling. On the other hand, it indirectly prolongs activated (phosphorylated) EGFR signaling by repressing Vps4b (vacuolar protein-sorting 4 homolog B), encoding a protein implicated in negatively regulating the endosomal sorting complexes that are necessary for the recycling of active EGFR. Together, these findings illuminate miR-125b as an important microRNA regulator that is shared between normal skin progenitors and their early malignant counterparts.
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Carcinoma de Células Escamosas/fisiopatología , Diferenciación Celular/genética , MicroARNs/metabolismo , Neoplasias Cutáneas/fisiopatología , ATPasas Asociadas con Actividades Celulares Diversas , Adenosina Trifosfatasas/metabolismo , Animales , Carcinoma de Células Escamosas/genética , Supervivencia Celular/genética , Transformación Celular Neoplásica/genética , Progresión de la Enfermedad , Complejos de Clasificación Endosomal Requeridos para el Transporte/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Queratinocitos/citología , Queratinocitos/patología , Ratones , MicroARNs/genética , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Transducción de Señal , Neoplasias Cutáneas/genética , TranscriptomaRESUMEN
microRNAs are small non-coding RNAs that regulate several genes post-transcriptionally by complementarity pairing. Since discovery, they have been reported to be involved in a variety of biological functions and pathologies including cancer. In cancer, they can act as a tumor suppressor or oncomiR depending on the cell type. Studies have shown that miRNA-based therapy, either by inhibiting an oncomiR or by inducing a tumor suppressor, is effective in cancer treatment. This review focusses on the role of miRNA in cancer, therapeutic approaches with miRNAs and how they can be effectively delivered into a system. We have also summarized the patents and clinical trials in progress for miRNA therapy.
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MicroARNs , Neoplasias , Regulación Neoplásica de la Expresión Génica , Genes Supresores de Tumor , Humanos , MicroARNs/genética , Neoplasias/genética , Neoplasias/patología , Neoplasias/terapiaRESUMEN
For more than two decades, the view of the roles of non-coding RNAs (ncRNAs) has been radically changing. These RNA molecules that are transcribed from our genome do not have the capacity to encode proteins, but are critical regulators of gene expression at different levels. Our knowledge is constantly enriched by new reports revealing the role of these new molecular players in the development of many pathological conditions, including cancer. One of the ncRNA classes includes short RNA molecules called microRNAs (miRNAs), which are involved in the post-transcriptional control of gene expression affecting various cellular processes. The aberrant expression of miRNAs with oncogenic and tumor-suppressive function is associated with cancer initiation, promotion, malignant transformation, progression and metastasis. Oncogenic miRNAs, also known as oncomirs, mediate the downregulation of tumor-suppressor genes and their expression is upregulated in cancer. Nowadays, miRNAs show promising application in diagnosis, prediction, disease monitoring and therapy response. Our review presents a current view of the oncogenic role of miR-1290 with emphasis on its properties as a cancer biomarker in clinical medicine.
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Biomarcadores de Tumor/genética , Regulación Neoplásica de la Expresión Génica , MicroARNs/genética , Neoplasias/diagnóstico , Humanos , Neoplasias/genéticaRESUMEN
Cervical cancer (CC) is one of the leading causes of death in women due to cancer and a major concern in the developing world. Persistent human papilloma virus (HPV) infection is the major causative agent for CC. Besides HPV infection, genetic and epigenetic factors including microRNA (miRNA) also contribute to the malignant transformation. Earlier studies have revealed that miRNAs participate in cell proliferation, invasion and metastasis, angiogenesis, and chemoresistance processes by binding and inversely regulating the target oncogenes or tumor suppressor genes. Based on functions and mechanistic insights, miRNAs have been identified as cellular modulators that have an enormous role in diagnosis, prognosis, and cancer therapy. Signatures of miRNA could be used as diagnostic markers which are necessary for early diagnosis and management of CC. The therapeutic potential of miRNAs has been shown in CC; however, more comprehensive clinical trials are required for the clinical translation of miRNA-based diagnostics and therapeutics. Understanding the molecular mechanism of miRNAs and their target genes has been useful to develop miRNA-based therapeutic strategies for CC and overcome chemoresistance. In this review, we summarize the role of miRNAs in the development, progression, and metastasis of CC as well as chemoresistance. Further, we discuss the diagnostic and therapeutic potential of miRNAs to overcome chemoresistance and treatment of CC.
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MicroARNs/genética , Papillomaviridae/genética , Infecciones por Papillomavirus/genética , Neoplasias del Cuello Uterino/patología , Resistencia a Antineoplásicos , Femenino , Humanos , Papillomaviridae/aislamiento & purificación , Papillomaviridae/patogenicidad , Infecciones por Papillomavirus/metabolismo , Infecciones por Papillomavirus/patología , Infecciones por Papillomavirus/virología , Pronóstico , Neoplasias del Cuello Uterino/tratamiento farmacológico , Neoplasias del Cuello Uterino/genética , Neoplasias del Cuello Uterino/virologíaRESUMEN
BACKGROUND: Several natural products, extensively studied for their anticancer activities, have been found to play an efficient role in preventing prostate cancer (PCa). Recently many natural agents have been reported to modulate microRNAs (miRNAs), that are involved in cancer cell growth. The microRNAs are endogenous small noncoding ribonucleic acid molecules that regulate various biological processes through an elegant mechanism of post-transcriptional control of gene expression. Besides being involved in cancer initiation, progression, angiogenesis, inflammation, they have been reported to be responsible for chemoresistance, and radioresistance of tumors. The dysregulated miRNA expression has been associated with many cancers including PCa. Over the past several years, it has been found that natural agents are good regulators of miRNAs and have a role in PCa also. Understanding the molecular mechanisms involving miRNAs by natural agents could result in developing useful strategies to combat this deadly disease. METHODS: In order to collect research articles, the PubMed search engine was used with keywords 'prostate cancer' and 'natural agents' and 2007 papers were retrieved, further refinement with keywords 'phytochemical' and 'prostate cancer' showed 503 papers. Data was collected from research articles, published from 2010 to 2021. From these, research articles showing miRNA-mediated mechanisms were selected. RESULTS: In this review, we have summarized the information available on the modulation of miRNAs by natural agents, their derivatives, and various combinatorial strategies with chemo/radiation therapy for the mitigation of PCa. CONCLUSIONS: Based on the current review of literature, it has been found that the use of natural agents is a novel approach for altering miRNA expression strongly associated with PCa development, recurrence and resistance.
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Regulación Neoplásica de la Expresión Génica , MicroARNs/metabolismo , Fitoquímicos/farmacología , Neoplasias de la Próstata/genética , Humanos , Masculino , Fitoquímicos/uso terapéutico , Neoplasias de la Próstata/tratamiento farmacológicoRESUMEN
Immune checkpoint blockade targeting PD-1 (PDCD1)/PD-L1 (CD274) is increasingly used for multiple cancers. However, efficacy and adverse-related events vary significantly. This bioinformatic study interrogated molecular differences pertaining to PDCD1/CD274 and their correlated genes on a pan-cancer basis to identify differences between cancer types. Patient RNA-seq data from fifteen cancer types were accessed on cBioPortal to determine the role of PDCD1/CD274 in patient survival and to identify positively and negatively correlated genes, which were also assessed for clinical relevance. Genes correlating with PDCD1/CD274 across multiple cancers were taken forward for drug repurposing via DRUGSURV and microRNA analysis using miRDB and miRabel. MicroRNAs were also screened for clinical relevance using OncomiR. Forty genes were consistently correlated with PDCD1/CD274 across multiple cancers, with the cancers themselves exhibiting a differential role for the correlated genes in terms of patient survival. Esophageal and renal cancers in particular stood out in this regard as having a unique survival profile. Forty-nine putative microRNAs were identified as being linked to the PDCD1/CD274 network, which were taken forward and further assessed for clinical relevance using OncomiR and previously published literature. One hundred and thirty significant survival associations for 46 microRNAs across fourteen groups of cancers were identified. Finally, a total of 23 putative repurposed drugs targeting multiple components of the PDCD1/CD274 network were identified, which may represent immunotherapeutic adjuvants. Taken together, these results shed light on the varying PDCD1/CD274 networks between individual cancers and signpost a need for more cancer-specific investigations and treatments.
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Antígeno B7-H1/genética , Neoplasias/genética , Receptor de Muerte Celular Programada 1/genética , Biología Computacional/métodos , Regulación Neoplásica de la Expresión Génica/genética , Humanos , MicroARNs/genéticaRESUMEN
Numerous molecular factors disrupt the correctness of the cell cycle process leading to the development of cancer due to increased cell proliferation. Among known causative factors of such process is abnormal gene expression. Nowadays in the light of current knowledge such alterations are frequently considered in the context of mRNA-miRNA correlation. One of the molecular factors with potential value in tumorigenesis is the feedback loop between MYC and E2F genes in which miR-17-5p and miR-20a from the miR-17-92 cluster are involved. The current literature shows that overexpression of the members of the OncomiR-1 are involved in the development of many solid tumors. In the present work, we investigated the expression of components of the MYC/E2F/miR-17-92 network and their closely related elements including members of MYC and E2F families and miRNAs from two paralogs of miR-17-92: miR-106b-25 and miR-106a-363, in the most common brain tumors of childhood, pilocytic astrocytoma (PA), WHO grade 1; ependymoma (EP), WHO grade 2; and medulloblastoma (MB), WHO grade 4. We showed that the highest gene expression was observed in the MYC family for MYCN and in the E2F family for E2F2. Positive correlation was observed between the gene expression and tumor grade and type, with the highest expression being noted for medulloblastomas, followed by ependymomas, and the lowest for pilocytic astrocytomas. Most members of miR-17-92, miR-106a-363 and miR-106b-25 clusters were upregulated and the highest expression was noted for miR-18a and miR-18b. The rest of the miRNAs, including miR-19a, miR-92a, miR-106a, miR-93, or miR-25 also showed high values. miR-17-5p, miR-20a obtained a high level of expression in medulloblastomas and ependymomas, while close to the control in the pilocytic astrocytoma samples. miRNA expression also depended on tumor grade and histology.
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Astrocitoma/genética , Neoplasias Encefálicas/genética , Factores de Transcripción E2F/genética , MicroARNs/genética , Proteínas Proto-Oncogénicas c-myc/genética , Astrocitoma/patología , Neoplasias Encefálicas/patología , Carcinogénesis/genética , Línea Celular Tumoral , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica/genética , Redes Reguladoras de Genes/genética , Humanos , Pediatría , ARN Largo no Codificante , ARN Mensajero/genéticaRESUMEN
The triple-negative phenotype is the most prevalent form of human breast cancer worldwide and is characterized by poor survival, high aggressiveness, and recurrence. Microvesicles (MV) are shredded plasma membrane components and critically mediate cell-cell communication, but can also induce cancer proliferation and metastasis. Previous studies have revealed that protease-activated receptor 2 (PAR2) contributes significantly to human triple-negative breast cancer (TNBC) progression by releasing nano-size MV and promoting cell proliferation, migration, and invasion. MV isolated from highly aggressive human TNBC cells impart metastatic potential to nonmetastatic cells. Over-expression of microRNA221 (miR221) has also been reported to enhance the metastatic potential of human TNBC, but miR221's relationship to PAR2-induced MV is unclear. Here, using isolated MV, immunoblotting, quantitative RT-PCR, FACS analysis, and enzymatic assays, we show that miR221 is translocated via human TNBC-derived MV, which upon fusion with recipient cells, enhance their proliferation, survival, and metastasis both in vitro and in vivo by inducing the epithelial-to-mesenchymal transition (EMT). Administration of anti-miR221 significantly impaired MV-induced expression of the mesenchymal markers Snail, Slug, N-cadherin, and vimentin in the recipient cells, whereas restoring expression of the epithelial marker E-cadherin. We also demonstrate that MV-associated miR221 targets phosphatase and tensin homolog (PTEN) in the recipient cells, followed by AKT Ser/Thr kinase (AKT)/NF-κB activation, which promotes EMT. Moreover, elevated miR221 levels in MV derived from human TNBC patients' blood could induce cell proliferation and metastasis in recipient cells. In summary, miR221 transfer from TNBC cells via PAR2-derived MV induces EMT and enhances the malignant potential of recipient cells.
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Micropartículas Derivadas de Células/genética , MicroARNs/genética , Neoplasias de la Mama Triple Negativas/genética , Adulto , Cadherinas/genética , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Micropartículas Derivadas de Células/metabolismo , Transición Epitelial-Mesenquimal , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , MicroARNs/metabolismo , Persona de Mediana Edad , Fosfohidrolasa PTEN/genética , Fosfohidrolasa PTEN/metabolismo , Receptor PAR-2/genética , Receptor PAR-2/metabolismo , Transducción de Señal , Factores de Transcripción de la Familia Snail/genética , Neoplasias de la Mama Triple Negativas/metabolismo , Neoplasias de la Mama Triple Negativas/patología , Vimentina/genéticaRESUMEN
Although several studies have reported that microRNA (miR)-92b-3p is involved in various cellular processes related to carcinogenesis, its physiological role in clear cell renal cell carcinoma (ccRCC) remains unclear. To clarify the role of miR-92b-3p in ccRCC, we compared miR-92b-3p expression levels in ccRCC tissues and adjacent normal renal tissues. Significant upregulation of miR-92b-3p was observed in ccRCC tissues. Overexpression of miR-92b-3p using a miRNA mimic promoted proliferation, migration, and invasion activities of ACHN cells. Functional inhibition of miR-92b-3p by a hairpin miRNA inhibitor suppressed Caki-2 cell growth and invasion activities in vitro. Mechanistically, it was found that miR-92b-3p directly targeted the TSC1 gene, a known upstream regulator of mTOR. Overexpression of miR-92b-3p decreased the protein expression of TSC1 and enhanced the downstream phosphorylation of p70S6 kinase, suggesting that the mTOR signaling pathway was activated by miR-92b-3p in RCC cells. Importantly, a multivariate Cox proportion hazard model, based on TNM staging and high levels of miR-92b-3p, revealed that miR-92b-3p expression (high vs. low hazard ratio, 2.86; 95% confidence interval, 1.20-6.83; P = .018) was a significant prognostic factor for overall survival of ccRCC patients with surgical management. Taken together, miR-92b-3p was found to act as an oncomiR, promoting cell proliferation by downregulating TSC1 in ccRCC.
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Carcinogénesis/genética , Carcinoma de Células Renales/genética , MicroARNs/genética , Proteína 1 del Complejo de la Esclerosis Tuberosa/genética , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/genética , Carcinoma de Células Renales/patología , Proliferación Celular/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Riñón/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , PronósticoRESUMEN
MicroRNAs (miRNAs) can act not only as tumor suppressor genes but also as oncogenes. Oncogenic miRNAs (oncomiRs) could therefore provide opportunities for the treatment of human malignancies. Here, we aimed to identify oncomiRs present in oral squamous cell carcinoma (OSCC) and addressed whether targeting these miRNAs might be useful in treatment for cancer. Functional screening for oncomiRs in a human OSCC cell line (GFP-SAS) was carried out using the miRCURY LNA microRNA Knockdown Library - Human version 12.0. We identified a locked nucleic acid (LNA)/DNA antisense oligonucleotide against miR-361-3p (LNA-miR-361-3p) which showed the largest degree of growth inhibition of GFP-SAS cells. Transfection with a synthetic mimic of mature miR-361-3p resulted in an approximately 20% increase in the growth of GFP-SAS cells. We identified odd-skipped related 2 (OSR2) as a miR-361-3p target gene. Transfection of GFP-SAS cells with LNA-miR-361-3p caused a significant increase in the expression levels of OSR2. Cotransfection of a OSR2 3'-UTR luciferase reporter plasmid and LNA-miR-361-3p into GFP-SAS cells produced higher levels of luciferase activity than in cells cotransfected with the LNA-nontarget. We assessed the effect of LNA-miR-361-3p on the in vivo growth of GFP-SAS cells. We found that LNA-miR-361-3p significantly reduced the size of s.c. xenografted GFP-SAS tumors, compared to the control group treated with LNA-NT. Finally, we observed that miR-361-3p is overexpressed in OSCC tissues. These results suggest that miR-361-3p supports the growth of human OSCC cells both in vitro and in vivo and that targeting miR-361-3p could be a useful therapeutic approach for patients with OSCC.
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Carcinoma de Células Escamosas/genética , MicroARNs/antagonistas & inhibidores , MicroARNs/genética , Neoplasias de la Boca/genética , Animales , Carcinogénesis/genética , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/patología , Línea Celular Tumoral , Proliferación Celular/genética , Femenino , Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Ratones , Ratones Desnudos , Neoplasias de la Boca/tratamiento farmacológico , Neoplasias de la Boca/patología , Oligonucleótidos/genética , Oligonucleótidos/uso terapéutico , Factores de Transcripción/genéticaRESUMEN
MicroRNAs (miRs) are non-protein-coding small RNAs that control the gene expression posttranscriptionally. miRs can regulate different cellular functions as well as many pathological conditions. Dysregulated miR expression profiles have been identified in different cancer types including lung cancer, breast cancer, and prostate cancer. The expression of miRs varies according to their roles in each specific cancer type. Although many miRs and their target genes have been identified in different cancers, data are still scant to validate those target genes and the mechanistic role of these miRs. The possibility of targeting cancer-associated miRs is suggested to open a new field for cancer therapy. Therapeutic strategies targeting miRs involve neutralization of the oncogenic miRs by antagomirs using locked nucleic acid oligonucleotides, miR sponges, or the restoration/overexpression of tumor-suppressing miRs that are downregulated or depleted in cancers. Although it is suggested that therapeutic applications of miRs in different pathological conditions will make a huge revolution in gene therapy, there is still an enormous challenge in employing these strategies efficiently in cancer inhibition, seemingly, due to the complexity of cancer and the current inefficient development of delivery systems for the therapeutic miRs.
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Neoplasias de la Mama/genética , Regulación Neoplásica de la Expresión Génica/fisiología , MicroARNs/fisiología , Línea Celular Tumoral , Femenino , HumanosRESUMEN
MicroRNAs (miRNAs) act as negative regulators of gene expression in the cytoplasm. Previous studies have identified the presence of miRNAs in the nucleus. Here we study human breast cancer-derived cell-lines (MCF-7 and MDA-MB-231) and a non-tumorigenic cell-line (MCF-10A) and compare their miRNA sequences at the spliceosome fraction (SF). We report that the levels of miRNAs found in the spliceosome, their identity, and pre-miRNA segmental composition are cell-line specific. One such miRNA is miR-7704 whose genomic position overlaps HAGLR, a cancer-related lncRNA. We detected an inverse expression of miR-7704 and HAGLR in the tested cell lines. Specifically, inhibition of miR-7704 caused an increase in HAGLR expression. Furthermore, elevated levels of miR-7704 slightly altered the cell-cycle in MDA-MB-231. Altogether, we show that SF-miR-7704 acts as a tumor-suppressor gene with HAGLR being its nuclear target. The relative levels of miRNAs found in the spliceosome fractions (e.g., miR-100, miR-30a, and let-7 family) in non-tumorigenic relative to cancer-derived cell-lines was monitored. We found that the expression trend of the abundant miRNAs in SF was different from that reported in the literature and from the observation of large cohorts of breast cancer patients, suggesting that many SF-miRNAs act on targets that are different from the cytoplasmic ones. Altogether, we report on the potential of SF-miRNAs as an unexplored route for cancerous cell state.
Asunto(s)
Biomarcadores de Tumor/genética , Neoplasias de la Mama/patología , Regulación Neoplásica de la Expresión Génica , MicroARNs/genética , ARN Largo no Codificante/genética , Empalmosomas/genética , Apoptosis , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Proliferación Celular , Femenino , Perfilación de la Expresión Génica , Humanos , Células Tumorales CultivadasRESUMEN
Multiple myeloma (MM) is a cancerous bone disease characterized by malignant transformation of plasma cells in the bone marrow. MM is considered to be the second most common blood malignancy, with 20,000 new cases reported every year in the USA. Extensive research is currently enduring to validate diagnostic and therapeutic means to manage MM. microRNAs (miRNAs) were shown to be dysregulated in MM cases and to have a potential role in either progression or suppression of MM. Therefore, researchers investigated miRNAs levels in MM plasma cells and created tools to test their impact on tumor growth. In the present review, we discuss the most recently discovered miRNAs and their regulation in MM. Furthermore, we emphasized utilizing miRNAs as potential targets in the diagnosis, prognosis and treatment of MM, which can be useful for future clinical management.