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1.
Sci Rep ; 10(1): 1713, 2020 Feb 03.
Artículo en Inglés | MEDLINE | ID: mdl-32015424

RESUMEN

Prognostic biomarkers for recurrence of Oral Squamous Cell Carcinoma (OSCC) are urgently needed. We aimed to independently validate a 4-gene expression signature (MMP1, COL4A1, P4HA2, THBS2) predictive of OSCC recurrence risk. Gene expression was measured using Nanostring nCounter® in 245 histologically normal surgical resection margins from 62 patients. Association between risk scores for individual patients and recurrence was assessed by Kaplan-Meier analysis. Signature performance was quantified by concordance index (CI), hazard ratio (HR) and the area under receiver operating characteristics (AUC). Risk scores for recurrence were significantly higher than recurrence-free patients (p = 9.58e-7, Welch's t-test). A solid performance of the 4-gene signature was determined: CI = 0.64, HR = 3.38 (p = 1.4E-4; log-rank test), AUC = 0.71. We showed that three margins per patient are sufficient to preserve predictive performance (CI = 0.65; HR = 2.92; p = 2.94e-3; AUC = 0.71). Association between the predicted risk scores and recurrence was assessed and showed HR = 2.44 (p = 9.6E-3; log-rank test, N = 62). Signature performance analysis was repeated using an optimized threshold (70th percentile of risks), resulting in HR = 3.38 (p = 1.4E-4; log-rank test, N = 62). The 4-gene signature was validated as predictive of recurrence risk in an independent cohort of patients with resected OSCC and histologically negative margins, and is potentially applicable for clinical decision making on adjuvant treatment and disease monitoring.

2.
Bioinformatics ; 2020 Jan 24.
Artículo en Inglés | MEDLINE | ID: mdl-31977031

RESUMEN

MOTIVATION: Gene sets over-representation analysis (GSOA) is a common technique of enrichment analysis that measures the overlap between a gene set and selected instances (e.g., pathways). Despite its popularity, there is currently no established standard for visualisation of GSOA results. RESULTS: Here, we propose a visual exploration of the GSOA results by showing the relationships among the enriched instances; while highlighting important instance attributes, such as significance, closeness (centrality) and clustering. AVAILABILITY: GSOAP is implemented as an R package and is available at https://github.com/tomastokar/gsoap.

3.
PLoS One ; 14(5): e0217421, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31150430

RESUMEN

Despite progress in treatment strategies, only ~24% of pancreatic ductal adenocarcinoma (PDAC) patients survive >1 year. Our goal was to elucidate deregulated pathways modulated by microRNAs (miRNAs) in PDAC and Vater ampulla (AMP) cancers. Global miRNA expression was identified in 19 PDAC, 6 AMP and 25 paired, histologically normal pancreatic tissues using the GeneChip 4.0 miRNA arrays. Computational approaches were used for miRNA target prediction/identification of miRNA-regulated pathways. Target gene expression was validated in 178 pancreatic cancer and 4 pancreatic normal tissues from The Cancer Genome Atlas (TCGA). 20 miRNAs were significantly deregulated (FC≥2 and p<0.05) (15 down- and 5 up-regulated) in PDAC. miR-216 family (miR-216a-3p, miR-216a-5p, miR-216b-3p and miR-216b-5p) was consistently down-regulated in PDAC. miRNA-modulated pathways are associated with innate and adaptive immune system responses in PDAC. AMP cancers showed 8 down- and 1 up-regulated miRNAs (FDR p<0.05). Most enriched pathways (p<0.01) were RAS and Nerve Growth Factor signaling. PDAC and AMP display different global miRNA expression profiles and miRNA regulated networks/tumorigenesis pathways. The immune response was enriched in PDAC, suggesting the existence of immune checkpoint pathways more relevant to PDAC than AMP.

4.
J Clin Invest ; 129(6): 2463-2479, 2019 03 26.
Artículo en Inglés | MEDLINE | ID: mdl-30912767

RESUMEN

Rationale Tumor infiltrating lymphocytes are widely associated with positive outcomes, yet carry key indicators of a systemic failed immune response against unresolved cancer. Cancer immunotherapies can reverse their tolerance phenotypes, while preserving tumor-reactivity and neoantigen-specificity shared with circulating immune cells. Objectives We performed comprehensive transcriptomic analyses to identify gene signatures common to circulating and tumor infiltrating lymphocytes in the context of clear cell renal cell carcinoma. Modulated genes also associated with disease outcome were validated in other cancer types. Findings Using bioinformatics, we identified practical diagnostic markers and actionable targets of the failed immune response. On circulating lymphocytes, three genes, LEF1, FASLG, and MMP9, could efficiently stratify patients from healthy control donors. From their associations with resistance to cancer immunotherapies and microbial infections, we uncovered not only pan-cancer, but pan-pathology failed immune response profiles. A prominent lymphocytic matrix metallopeptidase cell migration pathway, is central to a panoply of diseases and tumor immunogenicity, correlates with multi-cancer recurrence, and identifies a feasible, non-invasive approach to pan-pathology diagnoses. Conclusions The non-invasive differently expressed genes we have identified warrant future investigation towards the development of their potential in precision diagnostics and precision pan-disease immunotherapeutics.

5.
Transplantation ; 103(6): e146-e158, 2019 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-30801542

RESUMEN

BACKGROUND: Interstitial fibrosis/tubular atrophy (IFTA) is an important cause of kidney allograft loss; however, noninvasive markers to identify IFTA or guide antifibrotic therapy are lacking. Using angiotensin II (AngII) as the prototypical inducer of IFTA, we previously identified 83 AngII-regulated proteins in vitro. We developed mass spectrometry-based assays for quantification of 6 AngII signature proteins (bone marrow stromal cell antigen 1, glutamine synthetase [GLNA], laminin subunit beta-2, lysophospholipase I, ras homolog family member B, and thrombospondin-I [TSP1]) and hypothesized that their urine excretion will correlate with IFTA in kidney transplant patients. METHODS: Urine excretion of 6 AngII-regulated proteins was quantified using selected reaction monitoring and normalized by urine creatinine. Immunohistochemistry was used to assess protein expression of TSP1 and GLNA in kidney biopsies. RESULTS: The urine excretion rates of AngII-regulated proteins were found to be increased in 15 kidney transplant recipients with IFTA compared with 20 matched controls with no IFTA (mean log2[fmol/µmol of creatinine], bone marrow stromal cell antigen 1: 3.8 versus 3.0, P = 0.03; GLNA: 1.2 versus -0.4, P = 0.03; laminin subunit beta-2: 6.1 versus 5.4, P = 0.06; lysophospholipase I: 2.1 versus 0.6, P = 0.002; ras homolog family member B: 1.2 versus -0.1, P = 0.006; TSP1_GGV: 2.5 versus 1.9; P = 0.15; and TSP1_TIV: 2.0 versus 0.6, P = 0.0006). Receiver operating characteristic curve analysis demonstrated an area under the curve = 0.86 for the ability of urine AngII signature proteins to discriminate IFTA from controls. Urine excretion of AngII signature proteins correlated strongly with chronic IFTA and total inflammation. In a separate cohort of 19 kidney transplant recipients, the urine excretion of these 6 proteins was significantly lower following therapy with AngII inhibitors (P < 0.05). CONCLUSIONS: AngII-regulated proteins may represent markers of IFTA and guide antifibrotic therapies.

6.
Genes Immun ; 20(3): 207-213, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-29728609

RESUMEN

Citrobacter rodentium is a murine pathogen causing transmissible colonic hyperplasia and colitis with a pathogenic mechanism similar to foodborne enterohaemorrhagic Escherichia coli in humans. Mechanisms underlying intestinal responses to C. rodentium infection are incompletely understood. We identified 24 colonic microRNAs (miRNAs) as significantly deregulated in response to C. rodentium, including miR-7a, -17, -19a, -20a, -20b, -92a, -106a, -132, -200a, and -2137; most of these miRNAs belong to the oncogenic miR-17-92 clusters. Pathways involved in cell cycle, cancers, and immune responses were enriched among the predicted targets of these miRNAs. We further demonstrated that an apoptosis facilitator, Bim, is a candidate gene target of miRNA-mediated host response to the infection. These findings suggest that host miRNAs participate in C. rodentium pathogenesis and may represent novel treatment targets.


Asunto(s)
Infecciones por Enterobacteriaceae/genética , MicroARNs/genética , Animales , Citrobacter rodentium/patogenicidad , Infecciones por Enterobacteriaceae/inmunología , Infecciones por Enterobacteriaceae/microbiología , Ratones , MicroARNs/metabolismo , Transcriptoma
7.
Cancer Res ; 78(17): 5124-5134, 2018 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-29986997

RESUMEN

Brain metastases (BM) result from the spread of primary tumors to the brain and are a leading cause of cancer mortality in adults. Secondary tissue colonization remains the main bottleneck in metastatic development, yet this "premetastatic" stage of the metastatic cascade, when primary tumor cells cross the blood-brain barrier and seed the brain before initiating a secondary tumor, remains poorly characterized. Current studies rely on specimens from fully developed macrometastases to identify therapeutic options in cancer treatment, overlooking the potentially more treatable "premetastatic" phase when colonizing cancer cells could be targeted before they initiate the secondary brain tumor. Here we use our established brain metastasis initiating cell (BMIC) models and gene expression analyses to characterize premetastasis in human lung-to-BM. Premetastatic BMIC engaged invasive and epithelial developmental mechanisms while simultaneously impeding proliferation and apoptosis. We identified the dopamine agonist apomorphine to be a potential premetastasis-targeting drug. In vivo treatment with apomorphine prevented BM formation, potentially by targeting premetastasis-associated genes KIF16B, SEPW1, and TESK2 Low expression of these genes was associated with poor survival of patients with lung adenocarcinoma. These results illuminate the cellular and molecular dynamics of premetastasis, which is subclinical and currently impossible to identify or interrogate in human patients with BM. These data present several novel therapeutic targets and associated pathways to prevent BM initiation.Significance: These findings unveil molecular features of the premetastatic stage of lung-to-brain metastases and offer a potential therapeutic strategy to prevent brain metastases. Cancer Res; 78(17); 5124-34. ©2018 AACR.


Asunto(s)
Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Terapia Molecular Dirigida , Metástasis de la Neoplasia/tratamiento farmacológico , Apomorfina/farmacología , Apoptosis/efectos de los fármacos , Barrera Hematoencefálica/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/patología , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/secundario , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Dopamina/metabolismo , Agonistas de Dopamina/farmacología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Cinesina/genética , Pulmón/patología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Metástasis de la Neoplasia/genética , Metástasis de la Neoplasia/patología , Proteínas Serina-Treonina Quinasas/genética , Selenoproteína W/genética
8.
Oncotarget ; 9(10): 9137-9155, 2018 Feb 06.
Artículo en Inglés | MEDLINE | ID: mdl-29507679

RESUMEN

In many cancers, significantly down- or upregulated genes are found within chromosomal regions with DNA copy number alteration opposite to the expression changes. Generally, this paradox has been overlooked as noise, but can potentially be a consequence of interference of epigenetic regulatory mechanisms, including microRNA-mediated control of mRNA levels. To explore potential associations between microRNAs and paradoxes in non-small-cell lung cancer (NSCLC) we curated and analyzed lung adenocarcinoma (LUAD) data, comprising gene expressions, copy number aberrations (CNAs) and microRNA expressions. We integrated data from 1,062 tumor samples and 241 normal lung samples, including newly-generated array comparative genomic hybridization (aCGH) data from 63 LUAD samples. We identified 85 "paradoxical" genes whose differential expression consistently contrasted with aberrations of their copy numbers. Paradoxical status of 70 out of 85 genes was validated on sample-wise basis using The Cancer Genome Atlas (TCGA) LUAD data. Of these, 41 genes are prognostic and form a clinically relevant signature, which we validated on three independent datasets. By meta-analysis of results from 9 LUAD microRNA expression studies we identified 24 consistently-deregulated microRNAs. Using TCGA-LUAD data we showed that deregulation of 19 of these microRNAs explains differential expression of the paradoxical genes. Our results show that deregulation of paradoxical genes is crucial in LUAD and their expression pattern is maintained epigenetically, defying gene copy number status.

9.
Hum Genomics ; 12(1): 16, 2018 03 27.
Artículo en Inglés | MEDLINE | ID: mdl-29587854

RESUMEN

MicroRNAs (miRNAs) are crucial regulators of gene expression in normal development and cellular homeostasis. While miRNA repositories contain thousands of unique sequences, they primarily contain molecules that are conserved across several tissues, largely excluding lineage and tissue-specific miRNAs. By analyzing small non-coding RNA sequencing data for abundance and secondary RNA structure, we discovered 103 miRNA candidates previously undescribed in liver tissue. While expression of some of these unannotated sequences is restricted to non-malignant tissue, downregulation of most of the sequences was detected in liver tumors, indicating their importance in the maintenance of liver homeostasis. Furthermore, target prediction revealed the involvement of the unannotated miRNA candidates in fatty-acid metabolism and tissue regeneration, which are key pathways in liver biology. Here, we provide a comprehensive analysis of the undiscovered liver miRNA transcriptome, providing new resources for a deeper exploration of organ-specific biology and disease.


Asunto(s)
Hígado/metabolismo , MicroARNs/genética , Transcriptoma/genética , Secuencia Conservada/genética , Perfilación de la Expresión Génica , Regulación de la Expresión Génica/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , MicroARNs/metabolismo , Especificidad de Órganos , Análisis de Secuencia de ARN
10.
Nucleic Acids Res ; 46(D1): D360-D370, 2018 01 04.
Artículo en Inglés | MEDLINE | ID: mdl-29194489

RESUMEN

MicroRNAs are important regulators of gene expression, achieved by binding to the gene to be regulated. Even with modern high-throughput technologies, it is laborious and expensive to detect all possible microRNA targets. For this reason, several computational microRNA-target prediction tools have been developed, each with its own strengths and limitations. Integration of different tools has been a successful approach to minimize the shortcomings of individual databases. Here, we present mirDIP v4.1, providing nearly 152 million human microRNA-target predictions, which were collected across 30 different resources. We also introduce an integrative score, which was statistically inferred from the obtained predictions, and was assigned to each unique microRNA-target interaction to provide a unified measure of confidence. We demonstrate that integrating predictions across multiple resources does not cumulate prediction bias toward biological processes or pathways. mirDIP v4.1 is freely available at http://ophid.utoronto.ca/mirDIP/.


Asunto(s)
Bases de Datos Genéticas , MicroARNs/metabolismo , ARN Mensajero/metabolismo , Humanos , ARN Mensajero/química
11.
Acta Neuropathol ; 134(6): 923-940, 2017 12.
Artículo en Inglés | MEDLINE | ID: mdl-28766011

RESUMEN

Brain metastases (BM) are the most common brain tumor in adults and are a leading cause of cancer mortality. Metastatic lesions contain subclones derived from their primary lesion, yet their functional characterization is limited by a paucity of preclinical models accurately recapitulating the metastatic cascade, emphasizing the need for a novel approach to BM and their treatment. We identified a unique subset of stem-like cells from primary human patient brain metastases, termed brain metastasis-initiating cells (BMICs). We now establish a BMIC patient-derived xenotransplantation (PDXT) model as an investigative tool to comprehensively interrogate human BM. Using both in vitro and in vivo RNA interference screens of these BMIC models, we identified SPOCK1 and TWIST2 as essential BMIC regulators. SPOCK1 in particular is a novel regulator of BMIC self-renewal, modulating tumor initiation and metastasis from the lung to the brain. A prospective cohort of primary lung cancer specimens showed that SPOCK1 was overexpressed only in patients who ultimately developed BM. Protein-protein interaction network mapping between SPOCK1 and TWIST2 identified novel pathway interactors with significant prognostic value in lung cancer patients. Of these genes, INHBA, a TGF-ß ligand found mutated in lung adenocarcinoma, showed reduced expression in BMICs with knockdown of SPOCK1. In conclusion, we have developed a useful preclinical model of BM, which has served to identify novel putative BMIC regulators, presenting potential therapeutic targets that block the metastatic process, and transform a uniformly fatal systemic disease into a locally controlled and eminently more treatable one.


Asunto(s)
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/secundario , Regulación Neoplásica de la Expresión Génica , Metástasis de la Neoplasia/genética , Metástasis de la Neoplasia/fisiopatología , Adenocarcinoma/genética , Adenocarcinoma/patología , Adenocarcinoma/fisiopatología , Adulto , Anciano , Anciano de 80 o más Años , Animales , Neoplasias Encefálicas/fisiopatología , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/fisiopatología , Línea Celular Tumoral , Femenino , Humanos , Masculino , Ratones Endogámicos NOD , Ratones SCID , Persona de Mediana Edad , Trasplante de Neoplasias , Estudios Prospectivos , Proteoglicanos/genética , Proteoglicanos/metabolismo , Interferencia de ARN , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Proteína 1 Relacionada con Twist/genética , Proteína 1 Relacionada con Twist/metabolismo
13.
Clin Cancer Res ; 23(14): 3769-3780, 2017 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-28174235

RESUMEN

Purpose: Head and neck squamous cell carcinomas (HNSCCs) cause more than 300,000 deaths worldwide each year. Locoregional and distant recurrences represent worse prognostic events and accepted surrogate markers of patients' overall survival. No valid biomarker and salvage therapy exist to identify and treat patients at high-risk of recurrence. We aimed to verify if selected miRNAs could be used as biomarkers of recurrence in HNSCC.Experimental Design: A NanoString array was used to identify miRNAs associated with locoregional recurrence in 44 patients with HNSCC. Bioinformatic approaches validated the signature and identified potential miRNA targets. Validation experiments were performed using an independent cohort of primary HNSCC samples and a panel of HNSCC cell lines. In vivo experiments validated the in vitro results.Results: Our data identified a four-miRNA signature that classified HNSCC patients at high- or low-risk of recurrence. These miRNAs collectively impinge on the epithelial-mesenchymal transition process. In silico and wet lab approaches showed that miR-9, expressed at high levels in recurrent HNSCC, targets SASH1 and KRT13, whereas miR-1, miR-133, and miR-150, expressed at low levels in recurrent HNSCC, collectively target SP1 and TGFß pathways. A six-gene signature comprising these targets identified patients at high risk of recurrences, as well. Combined pharmacological inhibition of SP1 and TGFß pathways induced HNSCC cell death and, when timely administered, prevented recurrence formation in a preclinical model of HNSCC recurrence.Conclusions: By integrating different experimental approaches and competences, we identified critical mediators of recurrence formation in HNSCC that may merit to be considered for future clinical development. Clin Cancer Res; 23(14); 3769-80. ©2017 AACR.


Asunto(s)
Carcinoma de Células Escamosas/genética , Neoplasias de Cabeza y Cuello/genética , MicroARNs/genética , Recurrencia Local de Neoplasia/genética , Adulto , Anciano , Animales , Biomarcadores de Tumor/genética , Carcinoma de Células Escamosas/patología , Línea Celular Tumoral , Transición Epitelial-Mesenquimal/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Neoplasias de Cabeza y Cuello/patología , Humanos , Queratina-13/genética , Masculino , Ratones , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Transducción de Señal , Factor de Transcripción Sp1/genética , Carcinoma de Células Escamosas de Cabeza y Cuello , Factor de Crecimiento Transformador beta/genética , Proteínas Supresoras de Tumor/genética , Ensayos Antitumor por Modelo de Xenoinjerto
14.
Sci Rep ; 6: 32773, 2016 09 08.
Artículo en Inglés | MEDLINE | ID: mdl-27604570

RESUMEN

While Brassica oleracea vegetables have been linked to cancer prevention, the exact mechanism remains unknown. Regulation of gene expression by cross-species microRNAs has been previously reported; however, its link to cancer suppression remains unexplored. In this study we address both issues. We confirm plant microRNAs in human blood in a large nutrigenomics study cohort and in a randomized dose-controlled trial, finding a significant positive correlation between the daily amount of broccoli consumed and the amount of microRNA in the blood. We also demonstrate that Brassica microRNAs regulate expression of human genes and proteins in vitro, and that microRNAs cooperate with other Brassica-specific compounds in a possible cancer-preventive mechanism. Combined, we provide strong evidence and a possible multimodal mechanism for broccoli in cancer prevention.

15.
Clin Proteomics ; 13: 16, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27499720

RESUMEN

BACKGROUND: Angiotensin-II (Ang II) mediates progression of autosomal-dominant polycystic kidney disease (ADPKD) and other chronic kidney diseases (CKD). However, markers of kidney Ang II activity are lacking. We previously defined 83 Ang II-regulated proteins in vitro, which reflected kidney Ang II activity in vivo. METHODS: In this study, we developed selected reaction monitoring (SRM) assays for quantification of Ang II-regulated proteins in urine of ADPKD and CKD patients. We demonstrated that 47 of 83 Ang II-regulated transcripts were differentially expressed in cystic compared to normal kidney tissue. We then developed SRM assays for 18 Ang II-regulated proteins overexpressed in cysts and/or secreted in urine. Methods that yielded CV ≤ 6 % for control proteins, and recovery ~100 % were selected. Heavy-labeled peptides corresponding to 13 identified Ang II-regulated peptides were spiked into urine samples of 17 ADPKD patients, 9 patients with CKD predicted to have high kidney Ang II activity and 11 healthy subjects. Samples were then digested and analyzed on triple-quadrupole mass spectrometer in duplicates. RESLUTS: Calibration curves demonstrated linearity (R(2) > 0.99) and within-run CVs < 9 % in the concentration range of 7/13 peptides. Peptide concentrations were normalized by urine creatinine. Deamidated peptide forms were monitored, and accounted for <15 % of the final concentrations. Urine excretion rates of proteins BST1, LAMB2, LYPA1, RHOB and TSP1 were significantly different (p < 0.05, one-way ANOVA) between patients with CKD, those with ADPKD and healthy controls. Urine protein excretion rates were highest in CKD patients and lowest in ADPKD patients. Univariate analysis demonstrated significant association between urine protein excretion rates of most proteins and disease group (p < 0.05, ANOVA) as well as sex (p < 0.05, unpaired t test). Multivariate analysis across protein concentration, age and sex demonstrated good separation between ADPKD and CKD patients. CONCLUSIONS: We have optimized methods for quantification of Ang II-regulated proteins, and we demonstrated that they reflected differences in underlying kidney disease in this pilot study. High urine excretion of Ang II-regulated proteins in CKD patients likely reflects high kidney Ang II activity. Low excretion in ADPKD appears related to lack of communication between cysts and tubules. Future studies will determine whether urine excretion rate of Ang II-regulated proteins correlates with kidney Ang II activity in larger cohorts of chronic kidney disease patients.

16.
Oncotarget ; 7(20): 28920-34, 2016 May 17.
Artículo en Inglés | MEDLINE | ID: mdl-27081085

RESUMEN

Herein, we aimed at identifying global transcriptome microRNA (miRNA) changes and miRNA target genes in lung adenocarcinoma. Samples were selected as training (N = 24) and independent validation (N = 34) sets. Tissues were microdissected to obtain >90% tumor or normal lung cells, subjected to miRNA transcriptome sequencing and TaqMan quantitative PCR validation. We further integrated our data with published miRNA and mRNA expression datasets across 1,491 lung adenocarcinoma and 455 normal lung samples. We identified known and novel, significantly over- and under-expressed (p ≤ 0.01 and FDR≤0.1) miRNAs in lung adenocarcinoma compared to normal lung tissue: let-7a, miR-10a, miR-15b, miR-23b, miR-26a, miR-26b, miR-29a, miR-30e, miR-99a, miR-146b, miR-181b, miR-181c, miR-421, miR-181a, miR-574 and miR-1247. Validated miRNAs included let-7a-2, let-7a-3, miR-15b, miR-21, miR-155 and miR-200b; higher levels of miR-21 expression were associated with lower patient survival (p = 0.042). We identified a regulatory network including miR-15b and miR-155, and transcription factors with prognostic value in lung cancer. Our findings may contribute to the development of treatment strategies in lung adenocarcinoma.


Asunto(s)
Adenocarcinoma/genética , Redes Reguladoras de Genes/genética , Neoplasias Pulmonares/genética , MicroARNs/genética , Transcriptoma , Adenocarcinoma/mortalidad , Adenocarcinoma del Pulmón , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Perfilación de la Expresión Génica , Humanos , Estimación de Kaplan-Meier , Neoplasias Pulmonares/mortalidad , Masculino , Persona de Mediana Edad , Factores de Transcripción/genética
17.
Oncotarget ; 6(29): 27461-77, 2015 Sep 29.
Artículo en Inglés | MEDLINE | ID: mdl-26314961

RESUMEN

Brain metastases (BM) represent the most common tumor to affect the adult central nervous system. Despite the increasing incidence of BM, likely due to consistently improving treatment of primary cancers, BM remain severely understudied. In this study, we utilized patient-derived stem cell lines from lung-to-brain metastases to examine the regulatory role of STAT3 in brain metastasis initiating cells (BMICs). Annotation of our previously described BMIC regulatory genes with protein-protein interaction network mapping identified STAT3 as a novel protein interactor. STAT3 knockdown showed a reduction in BMIC self-renewal and migration, and decreased tumor size in vivo. Screening of BMIC lines with a library of STAT3 inhibitors identified one inhibitor to significantly reduce tumor formation. Meta-analysis identified the oncomir microRNA-21 (miR-21) as a target of STAT3 activity. Inhibition of miR-21 displayed similar reductions in BMIC self-renewal and migration as STAT3 knockdown. Knockdown of STAT3 also reduced expression of known downstream targets of miR-21. Our studies have thus identified STAT3 and miR-21 as cooperative regulators of stemness, migration and tumor initiation in lung-derived BM. Therefore, STAT3 represents a potential therapeutic target in the treatment of lung-to-brain metastases.


Asunto(s)
Neoplasias Encefálicas/secundario , Regulación Neoplásica de la Expresión Génica , Neoplasias Pulmonares/patología , MicroARNs/metabolismo , Factor de Transcripción STAT3/metabolismo , Animales , Línea Celular Tumoral , Movimiento Celular , Genes Reguladores , Humanos , Concentración 50 Inhibidora , Ratones , Ratones Endogámicos NOD , Ratones SCID , Metástasis de la Neoplasia , Trasplante de Neoplasias , Mapeo de Interacción de Proteínas , Proteómica , ARN Interferente Pequeño/metabolismo , Células Madre/citología
18.
Theor Biol Med Model ; 10: 40, 2013 Jun 14.
Artículo en Inglés | MEDLINE | ID: mdl-23767791

RESUMEN

BACKGROUND: Mitochondrial outer membrane permeabilization (MOMP) is one of the most important points in the majority of apoptotic signaling cascades and it is controlled by a network of interactions between the members of the Bcl-2 family. METHODS: To understand the role of individual members of this family within the MOMP regulation, we have constructed a Boolean network-based model of interactions between the Bcl-2 proteins. RESULTS: Computational simulations have revealed the existence of trapping states which, independently from the incoming stimuli, block the occurrence of MOMP. Our results emphasize the role of the antiapoptotic protein Mcl-1 in the majority of these configurations. We demonstrate here the importance of the Bid and Bim for activation of effectors Bax and Bak, and the irreversibility of this activation. The model further points to the antiapoptotic protein Bcl-w as a key factor preventing Bax activation. CONCLUSIONS: In spite of relative simplicity, the Boolean network-based model provides useful insight into main functioning logic of the Bcl-2 switch, consistent with experimental findings.


Asunto(s)
Almacenamiento y Recuperación de la Información , Membranas Mitocondriales/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo
19.
PLoS One ; 8(12): e81861, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-24386084

RESUMEN

Interactions between individual members of the B-cell lymphoma 2 (Bcl-2) family of proteins form a regulatory network governing mitochondrial outer membrane permeabilization (MOMP). Bcl-2 family initiated MOMP causes release of the inter-membrane pro-apoptotic proteins to cytosol and creates a cytosolic environment suitable for the executionary phase of apoptosis. We designed the mathematical model of this regulatory network where the synthesis rates of the Bcl-2 family members served as the independent inputs. Using computational simulations, we have then analyzed the response of the model to up-/downregulation of the Bcl-2 proteins. Under several assumptions, and using estimated reaction parameters, a non-linear stimulus-response emerged, whose characteristics are associated with bistability and switch-like behavior. Interestingly, using the principal component analysis (PCA) we have shown that the given model of the Bcl-2 family interactions classifies the random combinations of inputs into two distinct classes, and responds to these by one of the two qualitatively distinct outputs. As we showed, the emergence of this behavior requires specific organization of the interactions between particular Bcl-2 proteins.


Asunto(s)
Membranas Mitocondriales/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/fisiología , Citosol/metabolismo , Regulación de la Expresión Génica , Modelos Biológicos , Modelos Teóricos , Permeabilidad , Análisis de Componente Principal , Transducción de Señal
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