RESUMO
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.
Assuntos
Neoplasias Encefálicas , Glioblastoma , Humanos , Temozolomida/uso terapêutico , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Glioblastoma/patologia , Linhagem Celular Tumoral , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Oncogenes , Resistencia a Medicamentos Antineoplásicos/genética , Antineoplásicos Alquilantes/farmacologia , Antineoplásicos Alquilantes/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Proteínas Ribossômicas/genética , Proteínas Ribossômicas/metabolismoRESUMO
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.
Assuntos
Complemento C5/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Exossomos/genética , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Microglia/metabolismo , RNA Longo não Codificante/genética , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Humanos , Camundongos , Transfecção , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
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.
Assuntos
Antineoplásicos/farmacologia , Bases de Dados de Ácidos Nucleicos , Neoplasias/tratamento farmacológico , RNA não Traduzido/genética , Descoberta de Drogas , Resistencia a Medicamentos Antineoplásicos , Humanos , Terapia de Alvo Molecular , Neoplasias/genéticaRESUMO
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.
Assuntos
Antineoplásicos Alquilantes/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Metilação de DNA , Resistencia a Medicamentos Antineoplásicos/genética , Proteína Potenciadora do Homólogo 2 de Zeste/fisiologia , Proteína de Domínio de Morte Associada a Fas/fisiologia , Regulação Neoplásica da Expressão Gênica/genética , Glioma/tratamento farmacológico , Proteínas de Neoplasias/fisiologia , Poli(ADP-Ribose) Polimerase-1/fisiologia , Temozolomida/farmacologia , Proteína Nuclear Ligada ao X/fisiologia , Animais , Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Sistemas CRISPR-Cas , Dano ao DNA , Reparo do DNA , DNA de Neoplasias/genética , Proteínas de Ligação a DNA/fisiologia , Dioxigenases , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Edição de Genes , Técnicas de Inativação de Genes , Glioma/genética , Glioma/metabolismo , Código das Histonas , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas/fisiologia , Fator de Transcrição STAT5/fisiologia , Temozolomida/uso terapêutico , Ensaio Tumoral de Célula-Tronco , Regulação para Cima , Proteína Nuclear Ligada ao X/antagonistas & inibidores , Proteína Nuclear Ligada ao X/genética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
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.