RESUMO
The sensitivity of breast cancer cells to epirubicin (EPI) is closely related to the efficacy of the drug and the prognosis of patients. A growing body of research has suggested that autophagy is involved in the treatment of a variety of cancers, including breast cancer, and modifies the sensitivity of anticancer drugs. However, the mechanism by which autophagy participates in cancer therapy and modulates drug sensitivity has not been fully elucidated. In this study, we showed that the expression of Autophagy/Beclin 1 regulator 1 (Ambra1), a key protein of autophagy, was negatively correlated with EPI sensitivity in breast cancer cells. In addition, it altered the sensitivity of breast cancer cells to EPI by regulating EPI-induced autophagy. As a potential mechanism, we demonstrated that autophagy-related protein 12 (ATG12) was a downstream protein that Ambra1-regulated EPI-induced autophagy. Therefore, Ambra1 plays an important role in regulating the sensitivity of breast cancer cells to EPI. And the regulatory effect of Ambra1 on EPI sensitivity is achieved through the regulation of autophagy by targeting ATG12. Overall, we propose a novel mechanism by which autophagy modulates the sensitivity of breast cancer cells to EPI. ATG12 is a novel targeting protein of Ambra1 in regulating EPI-induced autophagy. In addition, the important role of Ambra1 in modulating the sensitivity of breast cancer cells to EPI is confirmed in vivo. This finding indicates that Ambra1 might be a target for developing breast cancer treatments.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Antibióticos Antineoplásicos/farmacologia , Proteína 12 Relacionada à Autofagia/metabolismo , Autofagia/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Epirubicina/farmacologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Antibióticos Antineoplásicos/uso terapêutico , Apoptose , Proteína 12 Relacionada à Autofagia/genética , Proteína Beclina-1/genética , Proteína Beclina-1/metabolismo , Neoplasias da Mama/patologia , Sobrevivência Celular/efeitos dos fármacos , Epirubicina/uso terapêutico , Humanos , Células MCF-7 , Camundongos Endogâmicos BALB C , Camundongos Nus , RNA Interferente Pequeno/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND MiR-101-3p can promote apoptosis and inhibit proliferation, invasion, and metastasis in breast cancer (BC) cells. However, its mechanisms in BC are not fully understood. Therefore, a comprehensive analysis of the target genes, pathways, and networks of miR-101-3p in BC is necessary. MATERIAL AND METHODS The miR-101 profiles for 781 patients with BC from The Cancer Genome Atlas (TCGA) were analyzed. Gene expression profiling of GSE31397 with miR-101-3p transfected MCF-7 cells and scramble control cells was downloaded from Gene Expression Omnibus (GEO), and the differentially expressed genes (DEGs) were identified. The potential genes targeted by miR-101-3p were also predicted. Gene Ontology (GO) and pathway and network analyses were constructed for the DEGs and predicted genes. RESULTS In the TCGA data, a low level of miR-101-2 expression might represent a diagnostic (AUC: 0.63) marker, and the miR-101-1 was a prognostic (HR=1.79) marker. MiR-101-1 was linked to the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), and miR-101-2 was associated with the tumor (T), lymph node (N), and metastasis (M) stages of BC. Moreover, 427 genes were selected from the 921 DEGs in GEO and the 7924 potential target genes from the prediction databases. These genes were related to transcription, metabolism, biosynthesis, and proliferation. The results were also significantly enriched in the VEGF, mTOR, focal adhesion, Wnt, and chemokine signaling pathways. CONCLUSIONS MiR-101-1 and miR-101-2 may be prospective biomarkers for the prognosis and diagnosis of BC, respectively, and are associated with diverse clinical parameters. The target genes of miR-101-3p regulate the development and progression of BC. These results provide insight into the pathogenic mechanism and potential therapies for BC.
Assuntos
Neoplasias da Mama/genética , MicroRNAs/genética , Biomarcadores Tumorais/genética , Neoplasias da Mama/metabolismo , Biologia Computacional , Feminino , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Ontologia Genética , Humanos , Células MCF-7 , MicroRNAs/metabolismo , Prognóstico , Estudos Prospectivos , RNA Mensageiro/genética , Receptores de Estrogênio/genéticaRESUMO
Phyllanthus emblica (P. emblica) is a traditionally edible fruit that is good for treatment of biliary diseases, bronchitis, etc. It has obvious anti-inflammatory activity, but few studies focus on its anti-inflammatory active substance basis. The purpose of this study was to explore the material basis of anti-inflammatory activity of P. emblica, purify, and identify anti-inflammatory active monomers. Fisetin and gallic acid, which were identified after separation from ethanol extract components of P. emblica, exhibited the best anti-inflammatory effects, markedly inhibiting nitric oxide and proinflammatory cytokine levels in LPS-stimulated macrophages. In particular, fisetin with significant anti-inflammatory activity was firstly identified from P. emblica. For the first time, our research systematically revealed the material basis of the anti-inflammatory effects of P. emblica from the perspective of the composition of the bioactive substances and provided scientific research methods and ideas for researching bioactive monomers in other plant extracts.
RESUMO
The cancer susceptibility candidate 9 (CASC9) gene has been reported to exert an oncogenic effect in several types of cancer. However, its role in lung squamous cell carcinoma (LUSC) is unknown. Therefore, the present study examined the expression of CASC9 in LUSC and noncancer tissues by reverse transcriptionquantitative polymerase chain reaction assays and by data mining of highthroughput public databases, including The Cancer Genome Atlas, the Gene Expression Omnibus, ArrayExpress and the Cancer Cell Line Encyclopedia. In vitro experiments were conducted to investigate the effects of CASC9 on the viability and the proliferation of LUSC cells. Furthermore, consulting the alteration status of CASC9 in LUSC from cBioPortal, functional enrichment analysis of coexpressed genes, prediction of potential transcription factors, and inspection of adjacent proteincoding genes were conducted to explore the potential molecular mechanism of CASC9 in LUSC. The results revealed that CASC9 was overexpressed in LUSC tissue, and significantly associated with the malignant progression of LUSC. In vitro experiments demonstrated that CASC9 knockdown by RNA interference attenuated the viability and proliferation of LUSC cells. Multiple copies of CASC9 gene were detected in 4 of 179 available sequenced LUSC cases. A functional enrichment analysis of 200 coexpressed genes indicated that these genes were significantly associated with terms, including 'cellcell junction organization', 'desmosome organization', 'epidermis development', 'Hippo signaling pathway', 'pathogenic Escherichia coli infection' and 'PID HIF1 TF pathway'. Three genes, Fosrelated antigen 2 (FOSL2), SWI/SNF complex subunit SMARCC2, and transcription factor COE1 (EBF1), were predicted by lncRNAMap to be associated with CASC9. Among these, the expression of FOSL2 and EBF1 was positively and negatively correlated with the expression of CASC9, respectively. Two adjacent proteincoding genes, cysteinerich secretory protein LCCL domaincontaining 1 and hepatocyte nuclear factor 4γ, were also positively correlated with CASC9 expression. In conclusion, the present data suggest that CASC9 serves as an oncogene in LUSC and may be a promising target for alternative therapeutic options for patients with this condition.
Assuntos
Carcinoma de Células Escamosas/genética , Redes Reguladoras de Genes , Neoplasias Pulmonares/genética , RNA Longo não Codificante/genética , Regulação para Cima , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular , Biologia Computacional , Proteínas de Ligação a DNA , Mineração de Dados , Progressão da Doença , Feminino , Antígeno 2 Relacionado a Fos/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/patologia , Masculino , Transativadores/genética , Fatores de Transcrição/genéticaRESUMO
A series of 4-(6-(3-nitroguanidino)hexanamido)pyrrolidine derivatives were synthesized and evaluated for their abilities to inhibit inducible nitric oxide synthase (iNOS) isoform. All target compounds were prepared in 11 steps from commercially trans-4-hydroxy-L-proline. The preliminary pharmacological test showed that three compounds, 17, 21, and 30, have the good potency (IC(50)=2.36, 2.68, 2.5 microM, respectively) which are compared to the NOS inhibitor N(G)-nitroarginine(L-NNA) (IC(50)=14.74 microM), and could be used as lead compounds for exploring new iNOS inhibitors in the future.