RESUMEN
Triple-negative breast cancer (TNBC) is the most lethal subtype of breast cancer and significantly associated with poor prognosis and high risk of recurrence. miR-34a has been identified as a potent tumor suppressor whose expression is dramatically downregulated in TNBC. Currently, rectification of miRNA abnormality serves as a novel tumor therapeutic strategy. miR-34a is thus used as powerful antitumor agent for miRNA-based therapy against TNBC. However, miRNA-based antitumor therapy is challenged by effective targeted delivery of miRNA. In the present study, nanodiamond (ND), protamine (PS) and folic acid (FA) were used to construct ND-based layer-by-layer nanohybrids through a self-assembly approach for targeted miR-34a delivery in TNBC cells and xenograft TNBC tumors. We found that the targeted delivery of miR-34a remarkably suppressed cell proliferation, migration and induced the apoptosis of TNBC cells in vitro and inhibited tumor growth in vivo via down-regulating Fra-1 expression. The data suggest a great potential of ND-based nanohybrids for targeted intratumoral delivery of miR-34a for TNBC therapy.
RESUMEN
Initiation of zygotic transcription in mammals is poorly understood. In mice, zygotic transcription is first detected shortly after pronucleus formation in 1-cell embryos, but the identity of the transcribed loci and mechanisms regulating their expression are not known. Using total RNA-Seq, we have found that transcription in 1-cell embryos is highly promiscuous, such that intergenic regions are extensively expressed and thousands of genes are transcribed at comparably low levels. Striking is that transcription can occur in the absence of defined core-promoter elements. Furthermore, accumulation of translatable zygotic mRNAs is minimal in 1-cell embryos because of inefficient splicing and 3' processing of nascent transcripts. These findings provide novel insights into regulation of gene expression in 1-cell mouse embryos that may confer a protective mechanism against precocious gene expression that is the product of a relaxed chromatin structure present in 1-cell embryos. The results also suggest that the first zygotic transcription itself is an active component of chromatin remodeling in 1-cell embryos.
Asunto(s)
Regiones no Traducidas 3'/fisiología , Embrión de Mamíferos/metabolismo , Regulación del Desarrollo de la Expresión Génica/fisiología , Empalme del ARN/fisiología , Transcripción Genética/fisiología , Cigoto/metabolismo , Animales , Cromatina/metabolismo , Ensamble y Desensamble de Cromatina/fisiología , Embrión de Mamíferos/citología , Ratones , Cigoto/citologíaRESUMEN
Metastatic relapse is a leading cause of cancer-associated death and one of the major obstacles for effective therapy against triple-negative breast cancer. To address this problem, a miRNA-delivering nanocapsule technology based on hyaluronic acid (HA)/protamine sulfate (PS) interpolyelectrolyte complexes (HP-IPECs) is developed for efficient encapsulation and intracellular delivery microRNA-34a (miR-34a), which is a potent endogenous tumor suppressor of breast cancer. The nanocapsules are successfully generated through a self-assembly approach mediated by an electrostatic interaction. In vitro and in vivo experiments illustrate that miR-34a can be efficiently encapsulated into HP-IPECs and delivered into breast cancer cells or breast cancer tissues. Nanocomplex-assisted delivery of miR-34a induces cell apoptosis and suppresses migration, proliferation, and tumor growth of breast cancer cells via targeting CD44 and a Notch-1-signaling pathway. The obtained results suggest that HP-IPECs have a great potential as a biodegradable vector for microRNA-based therapy against triple-negative breast cancer.
Asunto(s)
Ácido Hialurónico/química , MicroARNs/metabolismo , Nanocápsulas/química , Protaminas/química , Neoplasias de la Mama Triple Negativas/metabolismo , Animales , Apoptosis , Muerte Celular , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Electrólitos , Femenino , Técnicas de Transferencia de Gen , Humanos , Inmunohistoquímica , Etiquetado Corte-Fin in Situ , Ratones Endogámicos BALB C , Ratones Desnudos , Neoplasias de la Mama Triple Negativas/patología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Metastatic relapse, development of drug resistance in cancer cells and adverse side effects of chemotherapeutic agents are the major obstacles for effective chemotherapy against triple-negative breast cancer. To address these problems, miR-34a, a potent endogenous tumor suppressive molecule in breast cancer, was co-encapsulated with doxorubicin (DOX) into hyaluronic acid (HA)-chitosan (CS) nanoparticles (NPs) and simultaneously delivered into breast cancer cells for improved therapeutic effects of drug. DOX-miR-34a co-loaded HA-CS NPs were successfully prepared through ionotropic gelation method in water. In vitro and in vivo experiments showed that miR-34a and DOX can be efficiently encapsulated into HA-CS NPs and delivered into tumor cells or tumor tissues and enhance anti-tumor effects of DOX by suppressing the expression of non-pump resistance and anti-apoptosis proto-oncogene Bcl-2. In addition, intracellular restoration of miR-34a inhibited breast cancer cell migration via targeting Notch-1 signaling. The obtained data suggest that co-delivery of DOX and miR-34a could achieve synergistic effects on tumor suppression and nanosystem-based co-delivery of tumor suppressive miRNAs and chemotherapeutic agents may be a promising combined therapeutic strategy for enhanced anti-tumor therapy.
Asunto(s)
Quitosano/química , Doxorrubicina/uso terapéutico , Sistemas de Liberación de Medicamentos , Ácido Hialurónico/química , MicroARNs/metabolismo , Nanopartículas/química , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Animales , Apoptosis/efectos de los fármacos , Apoptosis/genética , Secuencia de Bases , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Movimiento Celular/genética , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Doxorrubicina/farmacología , Endocitosis/efectos de los fármacos , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Luz , Ratones , MicroARNs/genética , Datos de Secuencia Molecular , Nanopartículas/ultraestructura , Proto-Oncogenes Mas , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Estabilidad del ARN/efectos de los fármacos , Dispersión de Radiación , Solventes , Resultado del Tratamiento , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/patologíaRESUMEN
The expression of miR-203 has been reported to be significantly down-regulated in esophageal cancer. We showed here that overexpression of miR-203 in esophageal cancer cells dramatically increased cell apoptosis and inhibited cell proliferation, migration and invasion as well as tumor growth and down-regulated miR-21 expression. We subsequently identified that small GTPase Ran was a target gene of miR-203. Furthermore, Ran restoration partially counteracted the tumor suppressive effects of miR-203 and increased miR-21 expression. Taken together, our findings suggest that miR-203 may act as novel tumor suppressor in esophageal cancer through down-regulating the expression of Ran and miR-21.
Asunto(s)
Carcinoma de Células Escamosas/metabolismo , Neoplasias Esofágicas/metabolismo , MicroARNs/genética , Proteína de Unión al GTP ran/genética , Regiones no Traducidas 3' , Animales , Apoptosis , Secuencia de Bases , Sitios de Unión , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patología , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Regulación hacia Abajo , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patología , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Ratones , Ratones Endogámicos BALB C , MicroARNs/metabolismo , Invasividad Neoplásica , Trasplante de Neoplasias , Interferencia de ARN , Carga Tumoral , Proteína de Unión al GTP ran/metabolismoRESUMEN
We report an innovative approach for miRNA-203 delivery in esophageal cancer cells using protamine sulphate (PS)-nanodiamond (ND) nanoparticles. The efficient delivery of miR-203 significantly suppressed the proliferation and migration of cancer cells through targeting Ran and ΔNp63, exhibiting a great potential for PS@ND nanoparticles in miRNA-based cancer therapy.