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1.
Mol Ther Nucleic Acids ; 23: 930-943, 2021 Mar 05.
Artículo en Inglés | MEDLINE | ID: mdl-33614241

RESUMEN

Deregulation of noncoding RNAs, including microRNAs (miRs), is implicated in the pathogenesis of many human cancers, including breast cancer. Through extensive analysis of The Cancer Genome Atlas, we found that expression of miR-22-3p is markedly lower in triple-negative breast cancer (TNBC) than in normal breast tissue. The restoration of miR-22-3p expression led to significant inhibition of TNBC cell proliferation, colony formation, migration, and invasion. We demonstrated that miR-22-3p reduces eukaryotic elongation factor 2 kinase (eEF2K) expression by directly binding to the 3' untranslated region of eEF2K mRNA. Inhibition of EF2K expression recapitulated the effects of miR-22-3p on TNBC cell proliferation, motility, invasion, and suppression of phosphatidylinositol 3-kinase/Akt and Src signaling. Systemic administration of miR-22-3p in single-lipid nanoparticles significantly suppressed tumor growth in orthotopic MDA-MB-231 and MDA-MB-436 TNBC models. Evaluation of the tumor response, following miR-22-3p therapy in these models using a novel mathematical model factoring in various in vivo parameters, demonstrated that the therapy is highly effective against TNBC. These findings suggest that miR-22-3p functions as a tumor suppressor by targeting clinically significant oncogenic pathways and that miR-22-3p loss contributes to TNBC growth and progression. The restoration of miR-22-3p expression is a potential novel noncoding RNA-based therapy for TNBC.

2.
Oncogene ; 39(4): 801-813, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31554935

RESUMEN

The role of RNA-dependent protein kinase R (PKR) and its association with misfolded protein expression in cancer cells are unclear. Herein we report that PKR regulates misfolded protein clearance by preventing it release through exosomes and promoting lysosomal degradation of misfolded prion proteins in cancer cells. We demonstrated that PKR contributes to the lysosome function and regulates misfolded prion protein clearance. We hypothesized that PKR-associated lysosome function is critical for cancer but not normal cell survival, representing an effective approach for highly targeted cancer therapy. In screening a compound library, we identified two PKR-associated compounds 1 and 2 (Pac 1 and 2) did not affect normal cells but selectively induced cell death in cancer cells depending on their PKR expression status. Pac 1 significantly inhibited the growth of human lung and breast xenograft tumors in mice with no toxicity. Pac 1 binds to PI4K2A and disrupts the PKR/PI4K2A-associated lysosome complex, contributing to destabilization of cancer cell lysosomes and triggering cell death. We observed that PKR and PI4K2A play significant prognostic roles in breast cancer patients. These results demonstrate that targeting of a PI4K2A/PKR lysosome complex may be an effective approach for cancer therapy.


Asunto(s)
Antineoplásicos/farmacología , Lisosomas/metabolismo , Neoplasias/tratamiento farmacológico , Fosfotransferasas (Aceptor de Grupo Alcohol)/antagonistas & inhibidores , Proteolisis , Respuesta de Proteína Desplegada , eIF-2 Quinasa/antagonistas & inhibidores , Animales , Antineoplásicos/química , Línea Celular Tumoral , Supervivencia Celular , Bases de Datos Genéticas/estadística & datos numéricos , Exosomas/metabolismo , Femenino , Humanos , Ratones , Ratones SCID , Antígenos de Histocompatibilidad Menor/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patología , Fosfotransferasas (Aceptor de Grupo Alcohol)/metabolismo , Pronóstico , Pliegue de Proteína , Tasa de Supervivencia , Ensayos Antitumor por Modelo de Xenoinjerto , eIF-2 Quinasa/metabolismo
3.
Mol Ther Nucleic Acids ; 14: 301-317, 2019 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-30654191

RESUMEN

KRAS is one of the most frequently mutated proto-oncogenes in pancreatic ductal adenocarcinoma (PDAC) and aberrantly activated in triple-negative breast cancer (TNBC). A profound role of microRNAs (miRNAs) in the pathogenesis of human cancer is being uncovered, including in cancer therapy. Using in silico prediction algorithms, we identified miR-873 as a potential regulator of KRAS, and we investigated its role in PDAC and TNBC. We found that reduced miR-873 expression is associated with shorter patient survival in both cancers. miR-873 expression is significantly repressed in PDAC and TNBC cell lines and inversely correlated with KRAS levels. We demonstrate that miR-873 directly bound to the 3' UTR of KRAS mRNA and suppressed its expression. Notably, restoring miR-873 expression induced apoptosis; recapitulated the effects of KRAS inhibition on cell proliferation, colony formation, and invasion; and suppressed the activity of ERK and PI3K/AKT, while overexpression of KRAS rescued the effects mediated by miR-873. Moreover, in vivo delivery of miR-873 nanoparticles inhibited KRAS expression and tumor growth in PDAC and TNBC tumor models. In conclusion, we provide the first evidence that miR-873 acts as a tumor suppressor by targeting KRAS and that miR-873-based gene therapy may be a therapeutic strategy in PDAC and TNBC.

4.
Clin Cancer Res ; 24(17): 4225-4241, 2018 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-29748184

RESUMEN

Purpose: Recent studies indicated that dysregulation of noncoding RNAs (ncRNA) such as miRNAs is involved in pathogenesis of various human cancers. However, the molecular mechanisms underlying miR-34a are not fully understood in triple-negative breast cancer (TNBC).Experimental Design: We performed in vitro functional assays on TNBC cell lines to investigate the role of miR-34a in FOXM1/eEF2K signaling axis. TNBC tumor xenograft models were used for in vivo therapeutic delivery of miR-34a.Results: In this study, we investigated the role of p53-driven ncRNA miR-34a and found that miR-34a is associated with significantly longer patient survival in TNBC and inversely correlated with levels of proto-oncogenic eEF2K, which was associated with significantly shorter overall patient survival. We showed that miR-34a directly binds to the 3'-untranslated region of eEF2K and FOXM1 mRNAs and suppresses their expression, leading to inhibition of TNBC cell proliferation, motility, and invasion. Notably, restoring miR-34a expression recapitulated the effects of inhibition of eEF2K and FOXM1, the transcription factor for eEF2K and the direct target of p53, in TNBC cell lines, whereas overexpression of eEF2K and FOXM1 rescued the effects and signaling pathways mediated by miR-34a. Moreover, in vivo therapeutic delivery of miR-34a nanoparticles by systemic intravenous administration delayed tumor growth of two different orthotopic TNBC tumor xenograft models by inhibiting eEF2K and FOXM1, intratumoral proliferation and angiogenesis, and inducing apoptosis.Conclusions: Overall, our findings provide new insights into the tumor suppressor role of miR-34a by dual-targeting of FOXM1/eEF2K signaling axis and suggest that miR-34a-based gene therapy may be a potential therapeutic strategy in TNBC. Clin Cancer Res; 24(17); 4225-41. ©2018 AACR.


Asunto(s)
Quinasa del Factor 2 de Elongación/genética , Proteína Forkhead Box M1/genética , MicroARNs/genética , Neoplasias de la Mama Triple Negativas/genética , Animales , Apoptosis/genética , Carcinogénesis/genética , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Supervivencia Celular/genética , Regulación Neoplásica de la Expresión Génica/genética , Xenoinjertos , Humanos , Ratones , Interferencia de ARN , Transducción de Señal , Neoplasias de la Mama Triple Negativas/patología
5.
Peptides ; 52: 90-7, 2014 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-24333973

RESUMEN

Recent studies have revealed that ghrelin may be an antioxidant and anti-inflammatory agent in many organs, however its role in chronic liver injury (CLI) remains unclear. The role of nitric oxide (NO) in CLI is controversial as evidence suggests that NO is either a primary mediator of liver cell injury or exhibits a protective effect against injurious stimuli. Recent evidence demonstrated that the therapeutic potential for ghrelin was through eNOS activation and increase in NO production. However, its role on NO production in the liver has not been previously investigated. The aim of this study was to investigate the role of ghrelin in treatment of CLI, and whether this action is mediated through NO. Forty male rats were divided into four groups: Group I: Control; Group II: chronic liver injury (CLI); Group III: CLI+Ghrelin; and Group IV: CLI+Ghrelin+l-NAME. Liver enzymes and tumor necrosis factor alpha (TNF-α), were measured to assess hepatocellular injury. Liver tissue collagen content, malondialdehyde (MDA), gene expression of Bax, Bcl-2, and eNOS were assessed to determine the mechanism of ghrelin action. Results showed that ghrelin decreased serum liver enzymes and TNF-α levels. Ghrelin also reduced liver tissue collagen, MDA, and Bax gene expression, and increased Bcl-2 and eNOS gene expression. The effects on TNF-α, collagen, MDA, Bax, and eNOS were partially reversed in Group IV, suggesting that ghrelin's action could be through modulation of NO levels. Therefore, ghrelin's hepatoprotective effect is partially mediated by NO release.


Asunto(s)
Cirrosis Hepática/metabolismo , Hígado/lesiones , Hígado/metabolismo , Óxido Nítrico/metabolismo , Animales , Enfermedad Crónica , Inhibidores Enzimáticos/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Ghrelina/farmacología , Hígado/patología , Cirrosis Hepática/patología , Masculino , Malondialdehído/metabolismo , NG-Nitroarginina Metil Éster/farmacología , Óxido Nítrico Sintasa de Tipo III/antagonistas & inhibidores , Óxido Nítrico Sintasa de Tipo III/biosíntesis , Ratas , Proteína X Asociada a bcl-2/biosíntesis
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