RESUMEN
Aggressiveness and drug resistance are major challenges in the clinical treatment of glioblastoma (GBM). Our previously research reported a novel candidate oncogene ribosomal protein L22 like 1 (RPL22L1). The aim of this study was to elucidate the potential role and mechanism of RPL22L1 in progression and temozolomide (TMZ) resistance of GBM. Online database, tissue microarrays and clinical tissue specimens were used to evaluate the expression and clinical implication of RPL22L1 in GBM. We performed cell function assays, orthotopic and subcutaneous xenograft tumor models to evaluate the effects and molecular mechanisms of RPL22L1 on GBM. RPL22L1 expression was significantly upregulated in GBM and associated with poorer prognosis. RPL22L1 overexpression enhanced GBM cell proliferation, migration, invasion, TMZ resistance and tumorigenicity, which could be reduced by RPL22L1 knockdown. Further, we found RPL22L1 promoted mesenchymal phenotype of GBM and the impact of these effects was closely related to EGFR/STAT3 pathway. Importantly, we observed that STAT3 specific inhibitor (Stattic) significantly inhibited the malignant functions of RPL22L1, especially on TMZ resistance. RPL22L1 overexpressed increased combination drug sensitive of Stattic and TMZ both in vitro and in vivo. Moreover, Stattic effectively restored the sensitive of RPL22L1 induced TMZ resistance in vitro and in vivo. Our study identified a novel candidate oncogene RPL22L1 which promoted the GBM malignancy through STAT3 pathway. And we highlighted that Stattic combined with TMZ therapy might be an effective treatment strategy in RPL22L1 high-expressed GBM patients.
Asunto(s)
Neoplasias Encefálicas , Glioblastoma , Humanos , Temozolomida/uso terapéutico , Glioblastoma/tratamiento farmacológico , Glioblastoma/genética , Glioblastoma/patología , Línea Celular Tumoral , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Oncogenes , Resistencia a Antineoplásicos/genética , Antineoplásicos Alquilantes/farmacología , Antineoplásicos Alquilantes/uso terapéutico , Ensayos Antitumor por Modelo de Xenoinjerto , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismo , Proteínas Ribosómicas/genética , Proteínas Ribosómicas/metabolismoRESUMEN
Glioblastoma (GBM), the most common malignant primary brain cancer in adults, nearly always becomes resistant to current treatments, including the chemotherapeutic temozolomide (TMZ). The long noncoding RNA (lncRNA) TMZ-associated lncRNA in GBM recurrence (lnc-TALC) promotes GBM resistance to TMZ. Exosomes can release biochemical cargo into the tumor microenvironment (TME) or transfer their contents, including lncRNAs, to other cells as a form of intercellular communication. In this study, we found that lnc-TALC could be incorporated into exosomes and transmitted to tumor-associated macrophages (TAM) and could promote M2 polarization of the microglia. This M2 polarization correlated with secretion of the complement components C5/C5a, which occurred downstream of lnc-TALC binding to ENO1 to promote the phosphorylation of p38 MAPK. In addition, C5 promoted the repair of TMZ-induced DNA damage, leading to chemotherapy resistance, and C5a-targeted immunotherapy showed improved efficacy that limited lnc-TALC-mediated TMZ resistance. Our results reveal that exosome-transmitted lnc-TALC could remodel the GBM microenvironment and reduce tumor sensitivity to TMZ chemotherapy, indicating that the lnc-TALC-mediated cross-talk between GBM cells and microglia could attenuate chemotherapy efficacy and pointing to potential combination therapy strategies to overcome TMZ resistance in GBM.See related Spotlight by Zhao and Xie, p. 1372.
Asunto(s)
Complemento C5/genética , Resistencia a Antineoplásicos/efectos de los fármacos , Exosomas/genética , Glioblastoma/tratamiento farmacológico , Glioblastoma/genética , Microglía/metabolismo , ARN Largo no Codificante/genética , Animales , Línea Celular Tumoral , Modelos Animales de Enfermedad , Humanos , Ratones , Transfección , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Rationale: Glioma is the most common primary malignant brain tumor in adults. Chemoresistance of temozolomide (TMZ), the first-line chemotherapeutic agent, is a major issue in the management of patients with glioma. Alterations of alpha thalassemia/mental retardation syndrome X-linked (ATRX) gene constitute one of the most prevalent genetic abnormalities in gliomas. Therefore, elucidation of the role of ATRX contributing to TMZ resistance in glioma is urgently needed. Methods: We performed the bioinformatics analysis of gene expression, and DNA methylation profiling, as well as RNA and ChIP-seq data sets. CRISPR-Cas9 gene editing system was used to achieve the ATRX knockout in TMZ resistant cells. In vitro and in vivo experiments were carried out to investigate the role of ATRX contributing to TMZ resistance in glioma. Results: We found that ATRX expression was upregulated via DNA demethylation mediated by STAT5b/TET2 complex and strengthened DNA damage repair by stabilizing PARP1 protein in TMZ resistant cells. ATRX elicited PARP1 stabilization by the down-regulating of FADD expression via the H3K27me3 enrichment, which was dependent on ATRX/EZH2 complex in TMZ resistant cells. Magnetic resonance imaging (MRI) revealed that the PARP inhibitor together with TMZ inhibited glioma growth in ATRX wild type TMZ resistant intracranial xenograft models. Conclusions: The present study further illustrated the novel mechanism of the ATRX/PARP1 axis contributing to TMZ resistance. Our results provided substantial new evidence that PARP inhibitor might be a potential adjuvant agent in overcoming ATRX mediated TMZ resistance in glioma.
Asunto(s)
Antineoplásicos Alquilantes/farmacología , Neoplasias Encefálicas/tratamiento farmacológico , Metilación de ADN , Resistencia a Antineoplásicos/genética , Proteína Potenciadora del Homólogo Zeste 2/fisiología , Proteína de Dominio de Muerte Asociada a Fas/fisiología , Regulación Neoplásica de la Expresión Génica/genética , Glioma/tratamiento farmacológico , Proteínas de Neoplasias/fisiología , Poli(ADP-Ribosa) Polimerasa-1/fisiología , Temozolomida/farmacología , Proteína Nuclear Ligada al Cromosoma X/fisiología , Animales , Antineoplásicos Alquilantes/uso terapéutico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Sistemas CRISPR-Cas , Daño del ADN , Reparación del ADN , ADN de Neoplasias/genética , Proteínas de Unión al ADN/fisiología , Dioxigenasas , Proteína Potenciadora del Homólogo Zeste 2/genética , Edición Génica , Técnicas de Inactivación de Genes , Glioma/genética , Glioma/metabolismo , Código de Histonas , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Regiones Promotoras Genéticas , Proteínas Proto-Oncogénicas/fisiología , Factor de Transcripción STAT5/fisiología , Temozolomida/uso terapéutico , Ensayo de Tumor de Célula Madre , Regulación hacia Arriba , Proteína Nuclear Ligada al Cromosoma X/antagonistas & inhibidores , Proteína Nuclear Ligada al Cromosoma X/genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
NoncoRNA (http://www.ncdtcdb.cn:8080/NoncoRNA/) is a manually curated database of experimentally supported non-coding RNAs (ncRNAs) and drug target associations that aim to potentially provide a high-quality data resource for exploring drug sensitivity/resistance-related ncRNAs in various human cancers. ncRNA are RNA molecular that do not encode proteins, but are involved in gene regulation and cellular functions in variety of human diseases, including neurodegenerative diseases and cancers. Here, we developed NoncoRNA which contained 8233 entries between 5568 ncRNAs and 154 drugs in 134 cancers. Each entry in the NoncoRNA contains detailed information on the ncRNAs, drugs, and cancers, the ncRNA expression pattern and experimental detection techniques, drug response and other targets, literature references, and other information. NoncoRNA offers a user-friendly, open access web interface to easily browse, search, and download data. NoncoRNA also provides a submission page for researchers to submit newly validated ncRNA-drug-cancer associations. NoncoRNA might serve as an immeasurable resource for understanding the roles of ncRNAs in cancer therapy.
Asunto(s)
Antineoplásicos/farmacología , Bases de Datos de Ácidos Nucleicos , Neoplasias/tratamiento farmacológico , ARN no Traducido/genética , Descubrimiento de Drogas , Resistencia a Antineoplásicos , Humanos , Terapia Molecular Dirigida , Neoplasias/genéticaRESUMEN
Activation of receptor tyrosine kinase (RTK) protein is frequently observed in malignant progression of gliomas. In this study, the crosstalk activation of epidermal growth factor receptor (EGFR) and mesenchymal-epithelial transition factor (MET) signaling pathways is demonstrated to contribute to temozolomide (TMZ) resistance, resulting in an unfavorable prognosis for patients with glioblastoma. To simultaneously mitigate EGFR and MET activation, a dual functionalized brain-targeting nanoinhibitor, BIP-MPC-NP, is developed by conjugating Inherbin3 and cMBP on the surface of NHS-PEG8-Mal modified MPC-nanoparticles. In the presence of BIP-MPC-NP, DNA damage repair is attenuated and TMZ sensitivity is enhanced via the down-regulation of E2F1 mediated by TTP in TMZ resistant glioma. In vivo magnetic resonance imaging (MRI) shows a significant repression in tumor growth and a prolonged survival of mice after injection of the BIP-MPC-NP and TMZ. These results demonstrate the promise of this nanoinhibitor as a feasible strategy overcoming TMZ resistance in glioma.
