RESUMO
Metastases constitute the greatest causes of deaths from cancer. However, no effective therapeutic options currently exist for cancer patients with metastasis. Estrogen receptor ß (ERß), as a member of the nuclear receptor superfamily, shows potent tumor-suppressive activities in many cancers. To investigate whether modulation of ERß could serve as a therapeutic strategy for cancer metastasis, we examined whether the selective ERß agonist LY500307 could suppress lung metastasis of triple-negative breast cancer (TNBC) and melanoma. Mechanistically, while we observed that LY500307 potently induced cell death of cancer cells metastasized to lung in vivo, it does not mediate apoptosis of cancer cells in vitro, indicating that the cell death-inducing effects of LY500307 might be mediated by the tumor microenvironment. Pathological examination combined with flow cytometry assays indicated that LY500307 treatment induced significant infiltration of neutrophils in the metastatic niche. Functional experiments demonstrated that LY500307-treated cancer cells show chemotactic effects for neutrophils and that in vivo neutrophil depletion by Ly6G antibody administration could reverse the effects of LY500307-mediated metastasis suppression. RNA sequencing analysis showed that LY500307 could induce up-regulation of IL-1ß in TNBC and melanoma cells, which further triggered antitumor neutrophil chemotaxis. However, the therapeutic effects of LY500307 treatment for suppression of lung metastasis was attenuated in IL1B-/- murine models, due to failure to induce antitumor neutrophil infiltration in the metastatic niche. Collectively, our study demonstrated that pharmacological activation of ERß could augment innate immunity to suppress cancer metastatic colonization to lung, thus providing alternative therapeutic options for cancer patients with metastasis.
Assuntos
Antineoplásicos/farmacologia , Benzopiranos/farmacologia , Moduladores de Receptor Estrogênico/farmacologia , Receptor beta de Estrogênio/agonistas , Imunidade Inata/efeitos dos fármacos , Neoplasias Pulmonares/secundário , Neoplasias Mamárias Experimentais/patologia , Melanoma Experimental/secundário , Infiltração de Neutrófilos/efeitos dos fármacos , Neoplasias de Mama Triplo Negativas/terapia , Animais , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Benzopiranos/uso terapêutico , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Moduladores de Receptor Estrogênico/uso terapêutico , Estrogênios , Feminino , Interleucina-1beta/deficiência , Interleucina-1beta/genética , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/terapia , Neoplasias Mamárias Experimentais/imunologia , Neoplasias Mamárias Experimentais/terapia , Melanoma Experimental/imunologia , Melanoma Experimental/terapia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neoplasias Hormônio-Dependentes/imunologia , Neoplasias Hormônio-Dependentes/secundário , Neoplasias Hormônio-Dependentes/terapia , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Organismos Livres de Patógenos Específicos , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologiaRESUMO
Background Esophageal cancer (ESCA) is one of the most common cancers in the digestive tract. Approximately 300000 people on an average die of ESCA per year worldwide. The determination of key microRNAs for the prognosis of ESCA is of indispensable significance in the clinical treatment. Methods The differentially expressed microRNAs were screened by analyzing The Cancer Genome Atlas (TCGA) database. By using the survival data of the database, we analyzed correlation between patients' survival time and miR-550a expression levels. Differential expression analysis and gene set enrichment analysis were performed using the targeted data. Results It was found that patients with high miR-550a expression levels had shorter survival time. Data mining and signal pathway enrichment analysis of TCGA database showed that abnormal miR-550a expressions affected the recurrence of tumors by the muscle system regulation. Conclusions Through the proposed investigation, miR-550a is found to be a potential biomarker as well as non-coding therapeutic target for esophagus cancer. These results suggest that miR-550a may serve as a therapeutic target and predictor for ESCA survival.
Assuntos
Biomarcadores Tumorais/metabolismo , Bases de Dados de Ácidos Nucleicos , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/mortalidade , MicroRNAs/metabolismo , RNA Neoplásico/metabolismo , Biomarcadores Tumorais/genética , Mineração de Dados , Intervalo Livre de Doença , Neoplasias Esofágicas/genética , Feminino , Humanos , MicroRNAs/genética , Músculos/metabolismo , RNA Neoplásico/genética , Taxa de SobrevidaRESUMO
BACKGROUND: The current TNM staging system plays a central role in lung adenocarcinoma (LUAD) prognosis. However, it may not adequately stratify the risk of tumor recurrence. With the aid of gene expression profiling, we identified 31 lncRNAs whose expressions in tumor tissues could be used as a risk indicator for the guidance of lung cancer therapy. This exploratory analysis may shed new light on identification of potential prognostic factors. MATERIALS AND METHODS: A survival prediction scoring model was developed from the data that are publicly available in The Cancer Genome Atlas (TCGA) LUAD RNA Sequencing dataset. Multivariate Cox regression analysis and Kaplan-Meier analysis were performed on a cohort of 254 stage I lung carcinoma patients with survival records. RESULTS: Our model indicates that the panels comprising 31 lncRNAs are highly associated with overall survival (OS): 18.9% (95% CI: 10.4%-34.5%) and 89.5% (95% CI: 80.7%-99.2%) for the high- and low-risk group, respectively. The specificity and sensitivity of the model are verified, which show that the area under receiver operating characteristic curve yields 0.881, meaning our model has good accuracy and it is feasible for further applications. CONCLUSION: The 31-lncRNA model might be able to predict OS in patients with LUAD with high accuracy. Its further applications in biomolecular experiments using clinical samples with independent cohorts of patients are needed to verify the results.
RESUMO
BACKGROUND: Ovarian cancer constitutes one of the most lethal gynecologic malignancies for females. Currently, early detection strategies and therapeutic options for ovarian cancer are far from satisfactory, leading to high diagnosis rates at late stages and disease relapses. New avenues of therapy are needed that target key processes in ovarian cancer progression. While a variety of non-coding RNAs have been proven to regulate ovarian cancer metastatic progression, the functional roles of RNA-binding proteins (RBPs) in this process are less well defined. RESULTS: In this study, we identify that the RBP sorbin and SH3 domain containing 2 (SORBS2) is a potent suppressor of ovarian cancer metastatic colonization. Mechanistic studies show that SORBS2 binds the 3' untranslated regions (UTRs) of WFDC1 (WAP four-disulfide core domain 1) and IL-17D (Interleukin-17D), two secreted molecules that are shown to act as metastasis suppressors. Enhanced expression of either WFDC1 or IL-17D potently represses SORBS2 depletion-mediated cancer metastasis promotion. By enhancing the stability of these gene transcripts, SORBS2 suppresses ovarian cancer invasiveness and affects monocyte to myeloid-derived suppressor cell and M2-like macrophage polarization, eliciting a tumor-suppressive immune microenvironment. CONCLUSIONS: Our data illustrate a novel post-transcriptional network that links cancer progression and immunomodulation within the tumor microenvironment through SORBS2-mediated transcript stabilization.
Assuntos
Proteínas de Homeodomínio/metabolismo , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/secundário , Estabilidade de RNA , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/metabolismo , Proteínas Adaptadoras de Transdução de Sinal , Animais , Linhagem Celular Tumoral , Feminino , Proteínas de Homeodomínio/química , Humanos , Interleucina-17/genética , Interleucina-17/metabolismo , Macrófagos/imunologia , Camundongos Nus , Proteínas dos Microfilamentos/genética , Células Supressoras Mieloides/imunologia , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/metabolismo , Domínios Proteicos , Proteínas/genética , Proteínas/metabolismo , Proteínas de Ligação a RNA/química , Microambiente TumoralRESUMO
BACKGROUND: Studies have shown that the ligand of programmed cell death protein 1 (B7-H1, CD274 or PD-L1) is related to lung cancer driver genes. Although studies have examined the association between lung cancer driver gene mutations or expression and PD-L1 expression, the present studies have not been mined the correlation systematically and genome-widely. METHODS: All relevant published PD-L1 articles with driver genes data and the RNA-seq dataset from The Cancer Genome Atlas (TCGA) were analyzed. We performed meta-analysis for data included in the selected literature, and then independently explored the correlation between genes by co-expression analysis of RNA-seq data in the TCGA database. RESULTS: A sum of 9,934 lung cancer cases were collected from 34 published studies. Higher PD-L1 expression was associated with wild-type epidermal growth factor receptor (EGFR) [odds ratio (OR): 0.68, 95% confidence interval (CI): 0.48-0.96, P=0.03], Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation (OR: 1.27, 95% CI: 1.02-1.58, P=0.03) or non-adenocarcinoma histology (OR: 0.68, 95% CI: 0.47-0.98, P=0.04). In addition, our analysis from TCGA data indicated that, compared with lung adenocarcinoma, the expression of PD-L1 was significantly higher than that of squamous cell carcinoma patients (P=0.023). The expression of targetable driver genes showed no correlations with PD-L1 expression in non-small cell lung cancer (NSCLC). CONCLUSIONS: Our results suggest the presence of EGFR wild-type, KRAS gene mutations or squamous cell carcinoma were associated with high PD-L1expression, which provides potential benefited population for the administration of PD-1/PD-L1 blockade in human lung cancer.
RESUMO
Long noncoding RNAs (lncRNAs) are transcribed by genomic regions (exceeding 200 nucleotides in length) that do not encode proteins. While the exquisite regulation of lncRNA transcription can provide signals of malignant transformation, lncRNAs control pleiotropic cancer phenotypes through interactions with other cellular molecules including DNA, protein, and RNA. Recent studies have demonstrated that dysregulation of lncRNAs is influential in proliferation, angiogenesis, metastasis, invasion, apoptosis, stemness, and genome instability in colorectal cancer (CRC), with consequent clinical implications. In this review, we explicate the roles of different lncRNAs in CRC, and the potential implications for their clinical application.
Assuntos
Neoplasias Colorretais/genética , Regulação Neoplásica da Expressão Gênica , RNA Longo não Codificante/genética , Transdução de Sinais/genética , Apoptose/genética , Proliferação de Células/genética , Neoplasias Colorretais/irrigação sanguínea , Neoplasias Colorretais/patologia , Instabilidade Genômica/genética , Humanos , Modelos Genéticos , Neovascularização Patológica/genéticaRESUMO
The majority of patients with epithelial ovarian cancer are diagnosed at a late stage when the peritoneal metastases exist; however, there is little knowledge of the metastatic process in this disease setting. In this study, we report the identification of the long noncoding RNA LINC00092 as a nodal driver of metastatic progression mediated by cancer-associated fibroblasts (CAF). Prometastatic properties of CAFs in vitro and in vivo were found to associate with elevated expression of the chemokine CXCL14. In clinical specimens, elevated levels of CXCL14 in CAFs also correlated with poor prognosis. Notably, CXCL14-high CAFs mediated upregulation of LINC00092 in ovarian cancer cells, the levels of which also correlated with poor prognosis in patients. Mechanistic studies showed that LINC00092 bound a glycolytic enzyme, the fructose-2,6-biphosphatase PFKFB2, thereby promoting metastasis by altering glycolysis and sustaining the local supportive function of CAFs. Overall, our study uncovered a positive feedback loop in the metabolism of CXCL14-positive CAFs and ovarian cancer cells that is critical for metastatic progression. Cancer Res; 77(6); 1369-82. ©2017 AACR.