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1.
Nat Commun ; 10(1): 5438, 2019 Nov 28.
Artículo en Inglés | MEDLINE | ID: mdl-31780666

RESUMEN

Gene function in cancer is often cell type-specific. The epithelial cell-specific transcription factor ELF3 is a documented tumor suppressor in many epithelial tumors yet displays oncogenic properties in others. Here, we show that ELF3 is an oncogene in the adenocarcinoma subtype of lung cancer (LUAD), providing genetic, functional, and clinical evidence of subtype specificity. We discover a region of focal amplification at chromosome 1q32.1 encompassing the ELF3 locus in LUAD which is absent in the squamous subtype. Gene dosage and promoter hypomethylation affect the locus in up to 80% of LUAD analyzed. ELF3 expression was required for tumor growth and a pan-cancer expression network analysis supports its subtype and tissue specificity. We further show that ELF3 displays strong prognostic value in LUAD but not LUSC. We conclude that, contrary to many other tumors of epithelial origin, ELF3 is an oncogene and putative therapeutic target in LUAD.

3.
Front Genet ; 10: 138, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30894871

RESUMEN

Transcriptome sequencing has led to the widespread identification of long non-coding RNAs (lncRNAs). Subsequently, these genes have been shown to hold functional importance in human cellular biology, which can be exploited by tumors to drive the hallmarks of cancer. Due to the complex tertiary structure and unknown binding motifs of lncRNAs, there is a growing disparity between the number of lncRNAs identified and those that have been functionally characterized. As such, lncRNAs deregulated in cancer may represent critical components of cancer pathways that could serve as novel therapeutic intervention points. Pseudogenes are non-coding DNA sequences that are defunct relatives of their protein-coding parent genes but retain high sequence similarity. Interestingly, certain lncRNAs expressed from pseudogene loci have been shown to regulate the protein-coding parent genes of these pseudogenes in trans particularly because of this sequence complementarity. We hypothesize that this phenomenon occurs more broadly than previously realized, and that aberrant expression of lncRNAs overlapping pseudogene loci provides an alternative mechanism of cancer gene deregulation. Using RNA-sequencing data from two cohorts of lung adenocarcinoma, each paired with patient-matched non-malignant lung samples, we discovered 104 deregulated pseudogene-derived lncRNAs. Remarkably, many of these deregulated lncRNAs (i) were expressed from the loci of pseudogenes related to known cancer genes, (ii) had expression that significantly correlated with protein-coding parent gene expression, and (iii) had lncRNA protein-coding parent gene expression that was significantly associated with survival. Here, we uncover evidence to suggest the lncRNA-pseudogene-protein-coding gene axis as a prominent mechanism of cancer gene regulation in lung adenocarcinoma, and highlights the clinical utility of exploring the non-coding regions of the cancer transcriptome.

4.
J Immunother Cancer ; 7(1): 13, 2019 01 16.
Artículo en Inglés | MEDLINE | ID: mdl-30651131

RESUMEN

BACKGROUND: The tumor microenvironment (TME) is a complex mixture of tumor epithelium, stroma and immune cells, and the immune component of the TME is highly prognostic for tumor progression and patient outcome. In lung cancer, anti-PD-1 therapy significantly improves patient survival through activation of T cell cytotoxicity against tumor cells. Direct contact between CD8+ T cells and target cells is necessary for CD8+ T cell activity, indicating that spatial organization of immune cells within the TME reflects a critical process in anti-tumor immunity. Current immunohistochemistry (IHC) imaging techniques identify immune cell numbers and densities, but lack assessment of cell-cell spatial relationships (or "cell sociology"). Immune functionality, however, is often dictated by cell-to-cell contact and cannot be resolved by simple metrics of cell density (for example, number of cells per mm2). To address this issue, we developed a Hyperspectral Cell Sociology technology platform for the analysis of cell-cell interactions in multi-channel IHC-stained tissue. METHODS: Tissue sections of primary tumors from lung adenocarcinoma patients with known clinical outcome were stained using multiplex IHC for CD3, CD8, and CD79a, and hyperspectral image analysis determined the phenotype of all cells. A Voronoi diagram for each cell was used to approximate cell boundaries, and the cell type of all neighboring cells was identified and quantified. Monte Carlo analysis was used to assess whether cell sociology patterns were likely due to random distributions of the cells. RESULTS: High density of intra-tumoral CD8+ T cells was significantly associated with non-recurrence of tumors. A cell sociology pattern of CD8+ T cells surrounded by tumor cells was more significantly associated with non-recurrence compared to CD8+ T cell density alone. CD3+ CD8- T cells surrounded by tumor cells was also associated with non-recurrence, but at a similar significance as cell density alone. Cell sociology metrics improved recurrence classifications of 12 patients. Monte Carlo re-sampling analysis determined that these cell sociology patterns were non-random. CONCLUSION: Hyperspectral Cell Sociology expands our understanding of the complex interplay between tumor cells and immune infiltrate. This technology could improve predictions of responses to immunotherapy and lead to a deeper understanding of anti-tumor immunity.

5.
Int J Genomics ; 2018: 6972397, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30057905

RESUMEN

Despite advancements in therapeutic strategies, diagnostic and prognostic molecular markers of kidney cancer remain scarce, particularly in patients who do not harbour well-defined driver mutations. Recent evidence suggests that a large proportion of the human noncoding transcriptome has escaped detection in early genomic explorations. Here, we undertake a large-scale analysis of small RNA-sequencing data from both clear cell renal cell carcinoma (ccRCC) and nonmalignant samples to generate a robust set of miRNAs that remain unannotated in kidney tissues. We find that these novel kidney miRNAs are also expressed in renal cancer cell lines. Moreover, these sequences are differentially expressed between ccRCC and matched nonmalignant tissues, implicating their involvement in ccRCC biology and potential utility as tumour-specific markers of disease. Indeed, we find some of these miRNAs to be significantly associated with patient survival. Finally, target prediction and subsequent pathway analysis reveals that miRNAs previously unannotated in kidney tissues may target genes involved in ccRCC tumourigenesis and disease biology. Taken together, our results represent a new resource for the study of kidney cancer and underscore the need to characterize the unexplored areas of the transcriptome.

6.
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
7.
Clin Cancer Res ; 23(21): 6555-6566, 2017 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-28790117

RESUMEN

Purpose: Our previous screening efforts found that inhibition of PAPSS1 increases the potency of DNA-damaging agents in non-small cell lung cancer (NSCLC) cell lines. Here, we explored the clinical relevance of PAPSS1 and further investigated it as a therapeutic target in preclinical model systems.Experimental Design: PAPSS1 expression and cisplatin IC50 values were assessed in 52 lung adenocarcinoma cell lines. Effects of PAPSS1 inhibition on A549 cisplatin sensitivity under hypoxic and starvation conditions, in 3D spheroids, as well as in zebrafish and mouse xenografts, were evaluated. Finally, the association between PAPSS1 expression levels and survival in patients treated with standard chemotherapy was assessed.Results: Our results show a positive correlation between low PAPSS1 expression and increased cisplatin sensitivity in lung adenocarcinoma. In vitro, the potentiation effect was greatest when A549 cells were serum-starved under hypoxic conditions. When treated with low-dose cisplatin, PAPSS1-deficient A549 spheroids showed a 58% reduction in size compared with control cells. In vivo, PAPSS1 suppression and low-dose cisplatin treatment inhibited proliferation of lung tumor cells in zebrafish xenografts and significantly delayed development of subcutaneous tumors in mice. Clinical data suggest that NSCLC and ovarian cancer patients with low PAPSS1 expression survive longer following platinum-based chemotherapy.Conclusions: These results suggest that PAPSS1 inhibition enhances cisplatin activity in multiple preclinical model systems and that low PAPSS1 expression may serve as a biomarker for platin sensitivity in cancer patients. Developing strategies to target PAPSS1 activity in conjunction with platinum-based chemotherapy may offer an approach to improving treatment outcomes. Clin Cancer Res; 23(21); 6555-66. ©2017 AACR.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Cisplatino/administración & dosificación , Resistencia a Antineoplásicos/efectos de los fármacos , Complejos Multienzimáticos/genética , Sulfato Adenililtransferasa/genética , Células A549 , Animales , Apoptosis/efectos de los fármacos , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Proliferación Celular/efectos de los fármacos , Cisplatino/efectos adversos , Resistencia a Antineoplásicos/genética , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Ratones , Ensayos Antitumor por Modelo de Xenoinjerto
8.
Expert Rev Respir Med ; 11(9): 749-761, 2017 09.
Artículo en Inglés | MEDLINE | ID: mdl-28715922

RESUMEN

INTRODUCTION: The imprinted DLK1-DIO3 locus at 14q32.1-32.31 holds biological significance in fetal development, whereby imprinting errors are causal to developmental disorders. Emerging evidence has implicated this locus in other diseases including cancer, highlighting the biological parallels between fetal organ and tumour development. Areas covered: Controlled regulation of gene expression from the imprinted DLK1-DIO3 locus at 14q32.1-32.31 is crucial for proper fetal development. Deregulation of locus gene expression due to imprinting errors has been mechanistically linked to the developmental disorders Kagami-Ogata Syndrome and Temple Syndrome. In adult tissues, deregulation of locus genes has been associated with multiple malignancies although the causal genetic mechanisms remain largely uncharacterised. Here, we summarize the genetic mechanisms underlying the developmental disorders that arise as a result of improper locus imprinting and the resulting developmental phenotypes, emphasizing both the coding and noncoding components of the locus. We further highlight biological parallels common to both fetal development and disease, with a specific focus on lung development, respiratory disease, and lung cancer. Expert commentary: Many commonalities between respiratory and developmental defects have emerged with respect to the 14q32 locus, emphasizing the importance of studying the effects of imprinting on gene regulation patterns at this locus in both biological settings.


Asunto(s)
Desarrollo Fetal/genética , Impresión Genómica , Péptidos y Proteínas de Señalización Intercelular/genética , Yoduro Peroxidasa/genética , Proteínas de la Membrana/genética , Neoplasias/genética , Trastornos Respiratorios/genética , Disomía Uniparental/genética , Animales , Proteínas de Unión al Calcio , Cromosomas Humanos Par 14/genética , Humanos , Fenotipo
9.
Oncotarget ; 7(49): 80957-80966, 2016 Dec 06.
Artículo en Inglés | MEDLINE | ID: mdl-27829231

RESUMEN

Deregulation of the imprinted DLK1-DIO3 locus at chromosome 14q32.1-14q32.31 has been associated with developmental and respiratory disorders, including cancer. In lung cancer, deregulation of imprinting at DLK1-DIO3 was recently described in smokers. Deregulated expression of a microRNA (miRNA) cluster mapping to this locus was also associated with patient outcome, suggesting the importance of this locus to lung cancer disease phenotypes. The DLK1-DIO3 locus is complex, and encodes several protein-coding genes, in addition to long and short non-coding RNAs. While the role of miRNAs is established, the biological importance of another relevant class of small RNAs, PIWI-interacting RNAs (piRNAs), has not been investigated. When somatically expressed, piRNAs regulate gene transcription through DNA methylation. Interestingly, their expression patterns have been observed to be altered in cancer and correlated with patient outcome. Here, we characterize the somatic expression of piRNAs encoded at DLK1-DIO3 in two independent cohorts of lung adenocarcinoma and lung squamous cell carcinoma and investigate their associations with patient outcome. We find that the expression of piRNAs encoded at DLK1-DIO3 enhances the prognostic potential of small non-coding RNAs specific to this locus in predicting patient outcome, further emphasizing the importance of regulation at this locus in lung cancer.


Asunto(s)
Adenocarcinoma/genética , Biomarcadores de Tumor/genética , Carcinoma de Células Escamosas/genética , Sitios Genéticos , Impresión Genómica , Péptidos y Proteínas de Señalización Intercelular/genética , Yoduro Peroxidasa/genética , Neoplasias Pulmonares/genética , Proteínas de la Membrana/genética , ARN Interferente Pequeño/genética , Adenocarcinoma/mortalidad , Adenocarcinoma/patología , Adenocarcinoma/terapia , Adenocarcinoma del Pulmón , Adulto , Anciano , Anciano de 80 o más Años , Proteínas de Unión al Calcio , Carcinoma de Células Escamosas/mortalidad , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/terapia , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Predisposición Genética a la Enfermedad , Humanos , Estimación de Kaplan-Meier , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/terapia , Masculino , Persona de Mediana Edad , Fenotipo , Modelos de Riesgos Proporcionales , Factores de Riesgo , Factores de Tiempo , Transcriptoma , Resultado del Tratamiento
10.
Mol Cancer ; 15(1): 67, 2016 10 27.
Artículo en Inglés | MEDLINE | ID: mdl-27784305

RESUMEN

Lung cancer is a leading cause of cancer-related deaths worldwide. Lung cancer risk factors, including smoking and exposure to environmental carcinogens, have been linked to chronic inflammation. An integral feature of inflammation is the activation, expansion and infiltration of diverse immune cell types, including CD4+ T cells. Within this T cell subset are immunosuppressive regulatory T (Treg) cells and pro-inflammatory T helper 17 (Th17) cells that act in a fine balance to regulate appropriate adaptive immune responses.In the context of lung cancer, evidence suggests that Tregs promote metastasis and metastatic tumor foci development. Additionally, Th17 cells have been shown to be an integral component of the inflammatory milieu in the tumor microenvironment, and potentially involved in promoting distinct lung tumor phenotypes. Studies have shown that the composition of Tregs and Th17 cells are altered in the tumor microenvironment, and that these two CD4+ T cell subsets play active roles in promoting lung cancer progression and metastasis.We review current knowledge on the influence of Treg and Th17 cells on lung cancer tumorigenesis, progression, metastasis and prognosis. Furthermore, we discuss the potential biological and clinical implications of the balance among Treg/Th17 cells in the context of the lung tumor microenvironment and highlight the potential prognostic function and relationship to metastasis in lung cancer.


Asunto(s)
Neoplasias Pulmonares/inmunología , Linfocitos T Reguladores/metabolismo , Células Th17/metabolismo , Animales , Progresión de la Enfermedad , Humanos , Ratones , Metástasis de la Neoplasia , Microambiente Tumoral
11.
Oral Oncol ; 55: 43-48, 2016 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-26852287

RESUMEN

OBJECTIVES: As HPV-induced cases of oral malignancy increase, it is important to understand the molecular differences between HPV positive and negative head and neck squamous cell carcinoma (HNSCC). PIWI-interacting RNAs (piRNAs) are a class of small non-coding RNAs aberrantly expressed in cancer. We analyzed global piRNA expression patterns to define the HNSCC piRNA transcriptome and assess whether HPV infection status associates with changes in piRNA levels. MATERIALS AND METHODS: A total of 498 HNSCC small RNA sequencing libraries were acquired from the Cancer Genomics Hub (cgHUB) Data Repository and a custom sequence analysis pipeline was developed to deduce piRNA expression from raw sequencing data. Expression matrices were aligned to clinicopathological features in order to analyze piRNA expression patterns across different HNSCC groups. The association of a piRNA signature with HPV-positive patient survival was evaluated using a Cox proportional hazard model. RESULTS: Analysis of piRNA levels between HNSCC and non-malignant tissues revealed distinct expression patterns, with 87 piRNAs exclusively expressed in tumor samples. HPV infection status affected the expression of 41 of these piRNAs. Eleven (26.8%) piRNAs were significantly downregulated in HPV16/18 tumors compared to other HPV types. Remarkably, expression of a combination of five-piRNAs in HPV-positive HNSCC tumors was associated with worse overall survival. CONCLUSION: The expression of specific piRNAs is deregulated in HNSCC, and changes with both HPV status and type. Importantly, a five-piRNA signature is able to delineate a subset of HPV-positive HNSCC patients with poor outcome, highlighting the potential utility of piRNAs in patient management.


Asunto(s)
Carcinoma de Células Escamosas/genética , Neoplasias de Cabeza y Cuello/genética , Infecciones por Papillomavirus/genética , ARN Interferente Pequeño/genética , Carcinoma de Células Escamosas/virología , Estudios de Casos y Controles , Neoplasias de Cabeza y Cuello/virología , Humanos , Infecciones por Papillomavirus/virología , Modelos de Riesgos Proporcionales , Análisis de Secuencia de ARN
12.
Mol Cancer ; 15: 5, 2016 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-26768585

RESUMEN

PIWI-interacting RNAs (piRNAs) are emerging players in cancer genomics. Originally described in the germline, there are over 20,000 piRNA genes in the human genome. In contrast to microRNAs, piRNAs interact with PIWI proteins, another member of the Argonaute family, and function primarily in the nucleus. There, they are involved in the epigenetic silencing of transposable elements in addition to the transcriptional regulation of genes. It has recently been demonstrated that piRNAs are also expressed across a variety of human somatic tissue types in a tissue-specific manner. An increasing number of studies have shown that aberrant piRNA expression is a signature feature across multiple tumour types; however, their specific tumorigenic functions remain unclear. In this article, we discuss the emerging functional roles of piRNAs in a variety of cancers, and highlight their potential clinical utilities.


Asunto(s)
Neoplasias/genética , ARN Interferente Pequeño/metabolismo , Regulación Neoplásica de la Expresión Génica , Células Germinativas/metabolismo , Humanos , Modelos Biológicos , Neoplasias/diagnóstico , Pronóstico
13.
Gastric Cancer ; 19(2): 660-665, 2016 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-25779424

RESUMEN

The poor survival and recurrence rate in gastric adenocarcinoma highlights the need for cancer gene discovery. Towards this end, we globally assessed the expression of an emerging class of small non-coding RNAs, called PIWI-interacting RNAs (piRNAs). We analysed the transcriptomes of 358 non-malignant stomach tissue and gastric adenocarcinoma samples, and found that nearly half of the expressed piRNAs were overexpressed in tumours. Our gastric piRNA atlas showed that most piRNAs were embedded in protein-coding sequences rather than known piRNA clusters. Furthermore, we identified a three-piRNA signature associated with recurrence-free survival. In this proof-of-principle study, we demonstrate the potential clinical utility of piRNAs in gastric cancer.


Asunto(s)
Adenocarcinoma/genética , ARN Interferente Pequeño , Neoplasias Gástricas/genética , Adenocarcinoma/mortalidad , Adenocarcinoma/patología , Regulación Neoplásica de la Expresión Génica , Humanos , Recurrencia Local de Neoplasia/genética , Neoplasias Gástricas/mortalidad , Neoplasias Gástricas/patología , Análisis de Supervivencia , Transcriptoma
14.
Sci Rep ; 5: 10423, 2015 May 27.
Artículo en Inglés | MEDLINE | ID: mdl-26013764

RESUMEN

Human PIWI-interacting RNAs (piRNAs) are known to be expressed in germline cells, functionally silencing LINEs and SINEs. Their expression patterns in somatic tissues are largely uncharted. We analyzed 6,260 human piRNA transcriptomes derived from non-malignant and tumour tissues from 11 organs. We discovered that only 273 of the 20,831 known piRNAs are expressed in somatic non-malignant tissues. However, expression patterns of these piRNAs were able to distinguish tissue-of-origin. A total of 522 piRNAs are expressed in corresponding tumour tissues, largely distinguishing tumour from non-malignant tissues in a cancer-type specific manner. Most expressed piRNAs mapped to known transcripts, contrary to "piRNA clusters" reported in germline cells. We showed that piRNA expression can delineate clinical features, such as histological subgroups, disease stages, and survival. PiRNAs common to many cancer types might represent a core gene-set that facilitates cancer growth, while piRNAs unique to individual cancer types likely contribute to cancer-specific biology.


Asunto(s)
Neoplasias/genética , ARN Interferente Pequeño/metabolismo , Análisis por Conglomerados , Genoma Humano , Células Germinativas/metabolismo , Humanos , Estadificación de Neoplasias , Neoplasias/mortalidad , Neoplasias/patología , Pronóstico , ARN Neoplásico/genética , ARN Neoplásico/metabolismo , Análisis de Supervivencia , Transcriptoma
15.
BMC Cancer ; 14: 778, 2014 Oct 24.
Artículo en Inglés | MEDLINE | ID: mdl-25342220

RESUMEN

BACKGROUND: Cigarette smoke is associated with the majority of lung cancers: however, 25% of lung cancer patients are non-smokers, and half of all newly diagnosed lung cancer patients are former smokers. Lung tumors exhibit distinct epidemiological, clinical, pathological, and molecular features depending on smoking status, suggesting divergent mechanisms underlie tumorigenesis in smokers and non-smokers. MicroRNAs (miRNAs) are integral contributors to tumorigenesis and mediate biological responses to smoking. Based on the hypothesis that smoking-specific miRNA differences in lung adenocarcinomas reflect distinct tumorigenic processes selected by different smoking and non-smoking environments, we investigated the contribution of miRNA disruption to lung tumor biology and patient outcome in the context of smoking status. METHODS: We applied a whole transcriptome sequencing based approach to interrogate miRNA levels in 94 patient-matched lung adenocarcinoma and non-malignant lung parenchymal tissue pairs from current, former and never smokers. RESULTS: We discovered novel and distinct smoking status-specific patterns of miRNA and miRNA-mediated gene networks, and identified miRNAs that were prognostically significant in a smoking dependent manner. CONCLUSIONS: We conclude that miRNAs disrupted in a smoking status-dependent manner affect distinct cellular pathways and differentially influence lung cancer patient prognosis in current, former and never smokers. Our findings may represent promising biologically relevant markers for lung cancer prognosis or therapeutic intervention.


Asunto(s)
Adenocarcinoma/etiología , Adenocarcinoma/mortalidad , Neoplasias Pulmonares/etiología , Neoplasias Pulmonares/mortalidad , MicroARNs/genética , Fumar , Adenocarcinoma/patología , Adenocarcinoma del Pulmón , Adulto , Anciano , Análisis por Conglomerados , Estudios de Cohortes , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Redes Reguladoras de Genes , Humanos , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Evaluación del Resultado de la Atención al Paciente , Pronóstico , Interferencia de ARN
16.
Int J Endocrinol ; 2014: 546347, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25298778

RESUMEN

Pheochromocytomas (PCC) are rare tumors that arise in chromaffin tissue of the adrenal gland. PCC are frequently inherited through predisposing mutations in genes such as the von Hippel-Lindau (VHL) tumor suppressor. VHL is part of the VHL elongin BC protein complex that also includes CUL2/5, TCEB1, TCEB2, and RBX1; in normoxic conditions this complex targets hypoxia-inducible factor 1 alpha (HIF1A) for degradation, thus preventing a hypoxic response. VHL inactivation by genetic mechanisms, such as mutation and loss of heterozygosity, inhibits HIF1A degradation, even in the presence of oxygen, and induces a pseudohypoxic response. However, the described <10% VHL mutation rate cannot account for the high frequency of hypoxic response observed. Indeed, little is known about genetic mechanisms disrupting other complex component genes. Here, we show that, in a panel of 171 PCC tumors, 59.6% harbored gene copy number loss (CNL) of at least one complex component. CNL significantly reduced gene expression and was associated with enrichment of gene targets controlled by HIF1. Interestingly, we show that VHL-related renal clear cell carcinoma harbored disruption of VHL alone. Our results indicate that VHL elongin BC protein complex components other than VHL could be important for PCC tumorigenesis and merit further investigation.

17.
Environ Health ; 11: 89, 2012 Nov 22.
Artículo en Inglés | MEDLINE | ID: mdl-23173984

RESUMEN

The cause of lung cancer is generally attributed to tobacco smoking. However lung cancer in never smokers accounts for 10 to 25% of all lung cancer cases. Arsenic, asbestos and radon are three prominent non-tobacco carcinogens strongly associated with lung cancer. Exposure to these agents can lead to genetic and epigenetic alterations in tumor genomes, impacting genes and pathways involved in lung cancer development. Moreover, these agents not only exhibit unique mechanisms in causing genomic alterations, but also exert deleterious effects through common mechanisms, such as oxidative stress, commonly associated with carcinogenesis. This article provides a comprehensive review of arsenic, asbestos, and radon induced molecular mechanisms responsible for the generation of genetic and epigenetic alterations in lung cancer. A better understanding of the mode of action of these carcinogens will facilitate the prevention and management of lung cancer related to such environmental hazards.


Asunto(s)
Arsénico/toxicidad , Asbestos/toxicidad , Carcinógenos Ambientales/toxicidad , Neoplasias Pulmonares/inducido químicamente , Exposición a Riesgos Ambientales/efectos adversos , Exposición a Riesgos Ambientales/prevención & control , Humanos , Radón
18.
Int J Gynecol Cancer ; 22(9): 1557-63, 2012 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-23095774

RESUMEN

OBJECTIVE: Long noncoding RNAs (lncRNAs) are a unique class of messenger RNA-like transcripts of at least 200 nucleotides in length with no significant protein-coding capacity. Aberrant lncRNA expression is emerging as a major component of the cancer transcriptome. Here, we sought to determine if differential lncRNA expression is a feature of the human cervical intraepithelial neoplasia (CIN) transcriptome. METHODS: Sequence data were derived from 16 long serial analyses of gene expression (L-SAGE) libraries constructed from cervical specimens representing mild (CIN1), moderate (CIN2), and severe (CIN3) histopathologic grades of CIN. A novel lncRNA discovery pipeline was developed to query the expression of lncRNAs within the SAGE data sets. RESULTS: A total of 2,230,370 sequence tags were delineated from the 16 SAGE libraries, representing the expression of 367,482 unique tags at varying abundance. Using a novel stepwise filtering strategy, we analyzed the cervical SAGE libraries and identified the expression profiles of 1056 lncRNAs in the human cervix. We present the first lncRNA expression profile derived from nonneoplastic cervical tissue and establish that changes in lncRNA expression do occur in cervical intraepithelial lesions. Our analysis also shows statistically significant aberrant expression of lncRNAs in the 3 CIN grades, suggesting that these unique noncoding RNA transcripts may contribute to the development and progression of precursor lesions. CONCLUSIONS: Through the analysis of L-SAGE libraries constructed from cervical specimens, we provide the first lncRNA expression profile of the cervix and demonstrate aberrant expression in early-stage neoplasia.


Asunto(s)
Neoplasia Intraepitelial Cervical/genética , ARN Largo no Codificante/genética , Neoplasias del Cuello Uterino/genética , Adulto , Algoritmos , Análisis por Conglomerados , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Estudios de Asociación Genética , Humanos , Análisis por Micromatrices , Persona de Mediana Edad , Adulto Joven
19.
Genet Res Int ; 2012: 737416, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22852089

RESUMEN

Lung cancer biology has traditionally focused on genomic and epigenomic deregulation of protein-coding genes to identify oncogenes and tumor suppressors diagnostic and therapeutic targets. Another important layer of cancer biology has emerged in the form of noncoding RNAs (ncRNAs), which are major regulators of key cellular processes such as proliferation, RNA splicing, gene regulation, and apoptosis. In the past decade, microRNAs (miRNAs) have moved to the forefront of ncRNA cancer research, while the role of long noncoding RNAs (lncRNAs) is emerging. Here we review the mechanisms by which miRNAs and lncRNAs are deregulated in lung cancer, the technologies that can be applied to detect such alterations, and the clinical potential of these RNA species. An improved comprehension of lung cancer biology will come through the understanding of the interplay between deregulation of non-coding RNAs, the protein-coding genes they regulate, and how these interactions influence cellular networks and signalling pathways.

20.
Metabolomics (Los Angel) ; 2(3): 1000108, 2012 Mar 21.
Artículo en Inglés | MEDLINE | ID: mdl-25221729

RESUMEN

Each year about 1.4 million people die from lung cancer worldwide. Despite efforts in prevention, diagnosis and treatment, survival rate remains poor for this disease. This unfortunate situation is largely due to the fact that a high proportion of cases are diagnosed at advanced stages, highlighting the great need for identifying new biomarkers in order to improve early diagnosis and treatment. Recent studies on microRNAs have not only shed light on their involvement in tumor development and progression, but also suggested their potential utility as biomarkers for subtype diagnostics, staging and prediction of treatment response. This review article summarizes the impact of microRNAs on lung cancer biology, and highlights their role in the detection and classification of lung cancer as well as direct targets for drug development.

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