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1.
J Pathol ; 255(1): 16-29, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34021911

RESUMO

The transcription factor SOX9 is a key regulator of multiple developmental processes and is frequently re-expressed in non-small cell lung cancer (NSCLC). Its precise role in the progression of NSCLC histotypes has, however, remained elusive. We show that SOX9 expression relates to poor overall survival and invasive histopathology in human non-mucinous adenocarcinoma and is absent in murine early minimally invasive and low in human in situ adenocarcinoma. Interestingly, despite wide SOX9 expression across advanced NSCLC histotypes, its genetic deletion in the murine KrasG12D ;Lkb1fl/fl model selectively disrupted only the growth of papillary NSCLC, without affecting the initiation of precursor lesions or growth of mucinous or squamous tissue. Spatial tissue phenotyping indicated a requirement of SOX9 expression for the progression of surfactant protein C-expressing progenitor cells, which gave rise to papillary tumours. Intriguingly, while SOX9 expression was dispensable for squamous tissue formation, its loss in fact led to enhanced squamous tumour metastasis, which was associated with altered collagen IV deposition in the basement membrane. Our work therefore demonstrates histopathology-selective roles for SOX9 in NSCLC progression, namely as a promoter for papillary adenocarcinoma progression, but an opposing metastasis-suppressing role in squamous histotype tissue. This attests to a pleiotropic SOX9 function, linked to the cell of origin and microenvironmental tissue contexts. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Fatores de Transcrição SOX9/metabolismo , Animais , Progressão da Doença , Humanos , Camundongos
2.
BMC Cancer ; 19(1): 507, 2019 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-31138176

RESUMO

BACKGROUND: Deletion of the CDKN2A locus is centrally involved in the development of several malignancies. In malignant pleural mesothelioma (MPM), it is one of the most frequently reported genomic alteration. MPM is strongly associated with a patients' asbestos exposure. However, the status of CDKN2A and the expression of the corresponding protein, p16, in relation to MPM patient's asbestos exposure is poorly known. Copy number alterations in 2p16, 9q33.1 and 19p13 have earlier been shown to accumulate in lung cancer in relation to asbestos exposure but their status in MPM is unclear. METHODS: We studied DNA copy numbers for CDKN2A using fluorescence in situ hybridization (FISH) and p16 expression by immunohistochemistry (IHC) in 92 MPM patients, 75 of which with known asbestos exposure status. We also studied, in MPM, copy number alterations in 2p16, 9q33.1 and 19p13 by FISH. RESULTS: We were unable to detect an association between p16 expression and pulmonary asbestos fiber count in MPM tumor cells. However, significantly more MPM patients with high pulmonary asbestos fiber count (> 1 million fibers per gram [f/g]) had stromal p16 immunoreactivity than MPM of patients with low exposure (≤ 0.5 million f/g) (51.4% vs 16.7%; p = 0.035, Chi-Square). We found that an abnormal copy number of CDKN2A in MPM tumor cells associated with a high pulmonary asbestos fiber count (p = 0.044, Fisher's Exact test, two-tailed). In contrast to our earlier findings in asbestos associated lung cancer, DNA copy number changes in 2p16, 9q33 and 19p13 were not frequent in MPM although single cases with variable copy numbers on those regions were seen. CONCLUSIONS: We found two instances where the gene locus CDKN2A or its corresponding protein expression, is associated with high asbestos exposure levels. This suggests that there may be biological differences between the mesotheliomas with high pulmonary asbestos fiber count and those with low fiber count.


Assuntos
Amianto/efeitos adversos , Inibidor p16 de Quinase Dependente de Ciclina/genética , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Variações do Número de Cópias de DNA , Neoplasias Pulmonares/metabolismo , Mesotelioma/metabolismo , Idoso , Cromossomos Humanos/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Hibridização in Situ Fluorescente , Neoplasias Pulmonares/induzido quimicamente , Neoplasias Pulmonares/genética , Masculino , Mesotelioma/induzido quimicamente , Mesotelioma/genética , Mesotelioma Maligno , Pessoa de Meia-Idade , Células Estromais/metabolismo , Análise Serial de Tecidos
3.
J Pathol ; 245(1): 101-113, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29443392

RESUMO

A key question in precision medicine is how functional heterogeneity in solid tumours informs therapeutic sensitivity. We demonstrate that spatial characteristics of oncogenic signalling and therapy response can be modelled in precision-cut slices from Kras-driven non-small-cell lung cancer with varying histopathologies. Unexpectedly, profiling of in situ tumours demonstrated that signalling stratifies mostly according to histopathology, showing enhanced AKT and SRC activity in adenosquamous carcinoma, and mitogen-activated protein kinase (MAPK) activity in adenocarcinoma. In addition, high intertumour and intratumour variability was detected, particularly of MAPK and mammalian target of rapamycin (mTOR) complex 1 activity. Using short-term treatment of slice explants, we showed that cytotoxic responses to combination MAPK and phosphoinositide 3-kinase-mTOR inhibition correlate with the spatially defined activities of both pathways. Thus, whereas genetic drivers determine histopathology spectra, histopathology-associated and spatially variable signalling activities determine drug sensitivity. Our study is in support of spatial aspects of signalling heterogeneity being considered in clinical diagnostic settings, particularly to guide the selection of drug combinations. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.


Assuntos
Carcinogênese/genética , Neoplasias Pulmonares/patologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Transdução de Sinais/genética , Animais , Linhagem Celular Tumoral , Proliferação de Células/genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Proteínas Quinases Ativadas por Mitógeno/genética , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia
4.
Acta Oncol ; 57(8): 1109-1116, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29463166

RESUMO

BACKGROUND: Pulmonary carcinoids (PC) are rare malignant neoplasms that cover approximately 1% of all lung cancers. PCs are classified by histological criteria as either typical (TC) or atypical (AC). Histological subtype is the most studied prognostic factor. The aim of this study was to evaluate if other tissue or clinical features are associated with patient outcomes. MATERIAL AND METHODS: We retrospectively reviewed clinical records of 133 PC patients who underwent operation in the Helsinki University Hospital between 1990 and 2013. Tissue specimens were re-evaluated, processed into tissue microarray format and stained immunohistochemically with serotonin, calcitonin, adrenocorticotropic hormone (ACTH), thyroid transcription factor-1 (TTF-1) and Ki-67. Survival and risk analyses were performed. RESULTS: Based on histology, 75% (n = 100) of the tumors were TCs and 25% (n = 33) ACs. TCs had higher 10-year disease-specific survival (DSS) rate than ACs (99% (95% CI, 93-100%) for TCs vs. 82% (95% CI, 61-92%) for ACs). Hormonally active tumors expressing serotonin, calcitonin or ACTH were noted in 53% of the specimens but hormonal expression was not associated with DSS. TTF-1 was positive in 78% of the specimens but was not associated with DSS. Ki-67 index varied between <1% and 15%. Ki-67 ≥ 2.5% was associated with shorter DSS (p = .004). The presence of metastatic disease (p = .001), tumor size ≥30 mm (p = .021) and atypical histology (p = .011) were also associated with disease-specific mortality. CONCLUSIONS: We conclude that PCs are uncommon tumors. When resected, the long-term survival is in general favorable. In this consecutive, single-institution cohort of patients, presence of metastatic disease, tumor size, histological subtype and Ki-67 index were associated with shorter disease-specific survival. As TC and AC have different clinical behaviors, the correct tumor classification at the time of diagnosis is a necessity.


Assuntos
Tumor Carcinoide/mortalidade , Tumor Carcinoide/patologia , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Hormônio Adrenocorticotrópico/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/metabolismo , Calcitonina/metabolismo , Tumor Carcinoide/cirurgia , Intervalo Livre de Doença , Feminino , Humanos , Antígeno Ki-67/metabolismo , Neoplasias Pulmonares/cirurgia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Serotonina/metabolismo
5.
Int J Cancer ; 141(10): 2014-2029, 2017 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-28722770

RESUMO

Previous studies have revealed a robust association between exposure to asbestos and human lung cancer. Accumulating evidence has highlighted the role of epigenome deregulation in the mechanism of carcinogen-induced malignancies. We examined the impact of asbestos on DNA methylation. Our genome-wide studies (using Illumina HumanMethylation450K BeadChip) of lung cancer tissue and paired normal lung from 28 asbestos-exposed or non-exposed patients, mostly smokers, revealed distinctive DNA methylation changes. We identified a number of differentially methylated regions (DMR) and differentially variable, differentially methylated CpGs (DVMC), with individual CpGs further validated by pyrosequencing in an independent series of 91 non-small cell lung cancer and paired normal lung. We discovered and validated BEND4, ZSCAN31 and GPR135 as significantly hypermethylated in lung cancer. DMRs in genes such as RARB (FDR 1.1 × 10-19 , mean change in beta [Δ] -0.09), GPR135 (FDR 1.87 × 10-8 , mean Δ -0.09) and TPO (FDR 8.58 × 10-5 , mean Δ -0.11), and DVMCs in NPTN, NRG2, GLT25D2 and TRPC3 (all with p <0.05, t-test) were significantly associated with asbestos exposure status in exposed versus non-exposed lung tumors. Hypomethylation was characteristic to DVMCs in lung cancer tissue from asbestos-exposed subjects. When DVMCs related to asbestos or smoking were analyzed, 96% of the elements were unique to either of the exposures, consistent with the concept that the methylation changes in tumors may be specific for risk factors. In conclusion, we identified novel DNA methylation changes associated with lung tumors and asbestos exposure, suggesting that changes may be present in causal pathway from asbestos exposure to lung cancer.


Assuntos
Amianto/efeitos adversos , Biomarcadores Tumorais/genética , Metilação de DNA , Estudo de Associação Genômica Ampla , Neoplasias Pulmonares/etiologia , Estudos de Casos e Controles , Ilhas de CpG , Epigênese Genética , Seguimentos , Humanos , Neoplasias Pulmonares/patologia , Masculino , Prognóstico
6.
Duodecim ; 132(6): 593-9, 2016.
Artigo em Fi | MEDLINE | ID: mdl-27132299

RESUMO

Besides histological classification of lung cancers, molecular biological examination of tumors is part of modern diagnostics of lung cancers, and cancer therapies are based on molecular biological diagnosis. Current laboratory technique enables the examination of many mutations as part of standard routine diagnosis, necessitating functional multidisciplinary collaboration, with the pathologist playing a central role in the handling of the specimens. In the future, especially pathologists, pulmonary specialists and oncologists are expected to need a good command of molecular biological data on lung cancer, but basic knowledge will be required also from other physicians working with lung cancer patients.


Assuntos
Neoplasias Pulmonares/patologia , Patologia Molecular , Humanos , Neoplasias Pulmonares/genética , Mutação
7.
Genes Chromosomes Cancer ; 52(5): 503-11, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23362162

RESUMO

The development of tyrosine kinase inhibitor treatments has made it important to test cancer patients for clinically significant gene mutations that influence the benefit of treatment. Targeted next-generation sequencing (NGS) provides a promising method for diagnostic purposes by enabling the simultaneous detection of multiple mutations in various genes in a single test. The aim of our study was to screen EGFR, KRAS, and BRAF mutations by targeted NGS and commonly used real-time polymerase chain reaction (PCR) methods to evaluate the feasibility of targeted NGS for the detection of the mutations. Furthermore, we aimed to identify potential novel mutations by targeted NGS. We analyzed formalin-fixed, paraffin-embedded (FFPE) tumor tissue specimens from 81 non-small cell lung carcinoma patients. We observed a significant concordance (from 96.3 to 100%) of the EGFR, KRAS, and BRAF mutation detection results between targeted NGS and real-time PCR. Moreover, targeted NGS revealed seven nonsynonymous single-nucleotide variations and one insertion-deletion variation in EGFR not detectable by the real-time PCR methods. The potential clinical significance of these variants requires elucidation in future studies. Our results support the use of targeted NGS in the screening of EGFR, KRAS, and BRAF mutations in FFPE tissue material.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Receptores ErbB/genética , Neoplasias Pulmonares/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas/genética , Proteínas ras/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise Mutacional de DNA/métodos , Feminino , Fixadores/química , Formaldeído/química , Estudos de Associação Genética , Testes Genéticos/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mutação INDEL , Masculino , Pessoa de Meia-Idade , Técnicas de Diagnóstico Molecular , Inclusão em Parafina , Proteínas Proto-Oncogênicas p21(ras) , Reação em Cadeia da Polimerase em Tempo Real
8.
Duodecim ; 130(7): 701-4, 2014.
Artigo em Fi | MEDLINE | ID: mdl-24772787

RESUMO

ALK inhibitor therapy is individual cancer treatment, in which the targeted drug therapy is directed to a patient group that is likely to benefit from the therapy. The detection in the tumor of ALK gene (anaplastic lymphoma kinase) rearrangement is a prerequisite for the ALK inhibitor therapy for non-small cell lung carcinoma. The ALK assay should be performed for non-squamous cellular non-small cell lung carcinomas, especially adenocarcinomas. It is not recommended to be based on the patients' clinical features. The immunohistochemical method is well suited for screening of ALK positivity. The present recommendation is to ascertain the ALK gene rearrangement from immunopositive specimens by using the FISH procedure.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Neoplasias Pulmonares/diagnóstico , Receptores Proteína Tirosina Quinases/análise , Quinase do Linfoma Anaplásico , Biomarcadores Tumorais/análise , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente
9.
Bioorg Med Chem ; 21(6): 1483-8, 2013 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-23036334

RESUMO

Malignant mesothelioma is a neoplasm deriving from mesothelial cells, which line the body cavities. The most common type is malignant pleural mesothelioma (MPM), which is a locally aggressive malignancy with poor prognosis. To improve both the clinical diagnostics and treatment it is necessary to identify novel molecular targets which are characteristic for MPM. Although carbonic anhydrase (CA) enzymes have been linked to pH regulation and spread of cancer cells, they have not been thoroughly studied in MPM specimens. We investigated by immunohistochemistry the expression of CA isozymes II, VII, IX, and XII in a series of 27 histological MPM tumor samples. CA IX was absent in the normal lung alveolar cells, whereas it was abundantly expressed in the normal pleural mesothelium and malignant mesothelioma cells. CA VII also showed weak or moderate reactions in several cases of mesotheliomas. Neither high expression of CA VII nor CA IX did correlate significantly with the survival of the patients. The very high expression of CA IX in MPM suggests that it could represent a novel molecular target for cancer research applications.


Assuntos
Antígenos de Neoplasias/metabolismo , Anidrases Carbônicas/metabolismo , Mesotelioma/enzimologia , Neoplasias Pleurais/enzimologia , Antígenos de Neoplasias/química , Antineoplásicos/uso terapêutico , Anidrase Carbônica IX , Anidrases Carbônicas/química , Humanos , Concentração de Íons de Hidrogênio , Imuno-Histoquímica , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Mesotelioma/tratamento farmacológico , Mesotelioma/patologia , Neoplasias Pleurais/tratamento farmacológico , Neoplasias Pleurais/patologia , Taxa de Sobrevida
10.
J Cell Physiol ; 227(6): 2605-12, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21882188

RESUMO

Transforming growth factor-ß (TGF-ß) is a diverse cytokine regulating growth, apoptosis, differentiation, adhesion, invasion, and extracellular matrix production. Dysregulation of TGF-ß is associated with fibrotic disorders and epithelial-mesenchymal transition, and has been linked with idiopathic pulmonary fibrosis (IPF). Cysteine-rich protein 1 (CRP1) is a small LIM-domain containing protein involved in smooth muscle differentiation. Here, we show that TGF-ß1 increases the expression of CRP1 protein and that CRP1 levels increase in a biphasic fashion. A rapid transient (15-45 min) increase in CRP1 is followed by a subsequent, sustained increase in CRP1 a few hours afterwards that lasts several days. We find that TGF-ß1 regulates the expression of CRP1 through Smad and non-conventional p38 MAPK signaling pathways in a transcription-independent manner and that the induction occurs concomitant with an increase in myofibroblast differentiation. Using CRP1 silencing by shRNA, we identify CRP1 as a novel factor mediating cell contractility. Furthermore, we localize CRP1 to fibroblastic foci in IPF lungs and find that CRP1 is significantly more expressed in IPF as compared to control lung tissue. The results show that CRP1 is a novel TGF-ß1 regulated protein that is expressed in fibrotic lesions and may be relevant in the IPF disease.


Assuntos
Proteínas de Transporte/metabolismo , Fibrose Pulmonar Idiopática/metabolismo , Proteínas com Domínio LIM/metabolismo , Pulmão/metabolismo , Miofibroblastos/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Animais , Proteínas de Transporte/genética , Estudos de Casos e Controles , Diferenciação Celular , Linhagem Celular Tumoral , Forma Celular , Humanos , Fibrose Pulmonar Idiopática/genética , Fibrose Pulmonar Idiopática/patologia , Proteínas com Domínio LIM/genética , Pulmão/patologia , Camundongos , Miofibroblastos/patologia , Células NIH 3T3 , Interferência de RNA , Transdução de Sinais , Proteína Smad2/genética , Proteína Smad2/metabolismo , Fatores de Tempo , Transfecção , Regulação para Cima , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
11.
Cell Tissue Res ; 348(3): 491-503, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22434388

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a progressive disease of unknown cause. The pathogenesis of the disease is characterized by fibroblast accumulation and excessive transforming growth factor-ß (TGF-ß) activation. Although TGF-ß activation is a complex process involving various protein interactions, little is known of the specific routes of TGF-ß storage and activation in human lung. Here, we have systematically analyzed the expression of specific proteins involved in extracellular matrix targeting and activation of TGF-ß. Latent TGF-ß-binding protein (LTBP)-1 was found to be significantly upregulated in IPF patient lungs. LTBP-1 expression was especially high in the fibroblastic foci, in which P-Smad2 immunoreactivity, indicative of TGF-ß signaling activity, was less prominent. In cultured primary lung fibroblasts and epithelial cells, short-interfering-RNA-mediated downregulation of LTBP-1 resulted in either increased or decreased TGF-ß signaling activity, respectively, suggesting that LTBP-1-mediated TGF-ß activation is dependent on the cellular context in the lung. Furthermore, LTBP-1 was shown to colocalize with fibronectin, fibrillin-1 and fibrillin-2 proteins in the IPF lung. Fibrillin-2, a developmental gene expressed only in blood vessels in normal adult lung, was found specifically upregulated in IPF fibroblastic foci. The TGF-ß-activating integrin ß8 subunit was expressed at low levels in both control and IPF lungs. Alterations in extracellular matrix composition, such as high levels of the TGF-ß storage protein LTBP-1 and the re-appearance of fibrillin-2, probably modulate TGF-ß availability and activation in different pulmonary compartments in the fibrotic lung.


Assuntos
Fibrose Pulmonar Idiopática/metabolismo , Pulmão/metabolismo , Pulmão/patologia , Fator de Crescimento Transformador beta1/metabolismo , Adulto , Idoso , Estudos de Casos e Controles , Células Cultivadas , Regulação para Baixo/genética , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Fibrilina-1 , Fibrilina-2 , Fibrilinas , Fibroblastos/metabolismo , Fibroblastos/patologia , Fibronectinas/metabolismo , Humanos , Integrinas/metabolismo , Proteínas de Ligação a TGF-beta Latente/genética , Proteínas de Ligação a TGF-beta Latente/metabolismo , Proteínas dos Microfilamentos/metabolismo , Pessoa de Meia-Idade , Fosforilação , Transporte Proteico , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteína Smad2/metabolismo , Regulação para Cima/genética
12.
J Pathol ; 224(4): 529-39, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21480233

RESUMO

HuR is a ubiquitously expressed RNA-binding protein that modulates gene expression at the post-transcriptional level. It is predominantly nuclear, but can shuttle between the nucleus and the cytoplasm. While in the cytoplasm HuR can stabilize its target transcripts, many of which encode proteins involved in carcinogenesis. While cytoplasmic HuR expression is a marker of reduced survival in breast cancer, its role in precursor lesions of malignant diseases is unclear. To address this we explored HuR expression in atypical ductal hyperplasia (ADH) and in ductal in situ carcinomas (DCIS). We show that cytoplasmic HuR expression is elevated in both ADH and DCIS when compared to normal controls, and that this expression associated with high grade, progesterone receptor negativity and microinvasion and/or tumour-positive sentinel nodes of the DCIS. To study the mechanisms of HuR in breast carcinogenesis, HuR expression was silenced in an immortalized breast epithelial cell line (184B5Me), which led to reduction in anchorage-independent growth, increased programmed cell death and inhibition of invasion. In addition, we identified two novel target transcripts (CTGF and RAB31) that are regulated by HuR and that bind HuR protein in this cell line. Our results show that HuR is aberrantly expressed at early stages of breast carcinogenesis and that its inhibition can lead to suppression of this process. ArrayExpress Accession No. E-MEXP-3035.


Assuntos
Antígenos de Superfície/fisiologia , Neoplasias da Mama/metabolismo , Carcinoma Intraductal não Infiltrante/metabolismo , Proteínas de Ligação a RNA/fisiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos de Superfície/genética , Antígenos de Superfície/metabolismo , Mama/metabolismo , Mama/patologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Carcinoma Intraductal não Infiltrante/genética , Carcinoma Intraductal não Infiltrante/patologia , Transformação Celular Neoplásica/metabolismo , Progressão da Doença , Proteínas ELAV , Proteína Semelhante a ELAV 1 , Células Epiteliais/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Inativação Gênica , Humanos , Hiperplasia , Pessoa de Meia-Idade , Proteínas de Neoplasias/metabolismo , Proteínas de Neoplasias/fisiologia , Lesões Pré-Cancerosas/genética , Lesões Pré-Cancerosas/metabolismo , Lesões Pré-Cancerosas/patologia , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Células Tumorais Cultivadas , Adulto Jovem
13.
Genes Chromosomes Cancer ; 50(8): 585-97, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21563230

RESUMO

Lung cancer has the highest mortality rate of all of the cancers in the world and asbestos-related lung cancer is one of the leading occupational cancers. The identification of asbestos-related molecular changes has long been a topic of increasing research interest. The aim of this study was to identify novel asbestos-related molecular correlates by integrating miRNA expression profiling with previously obtained profiling data (aCGH and mRNA expression) from the same patient material. miRNA profiling was performed on 26 tumor and corresponding normal lung tissue samples from highly asbestos-exposed and non-exposed patients, and on eight control lung tissue samples. Data analyses on miRNA expression, and integration of miRNA and previously obtained mRNA data were performed using Chipster. A separate analysis was used to integrate miRNA and previously obtained aCGH data. Both known and new lung cancer-associated miRNAs and target genes with inverse correlation were discovered. Furthermore, DNA copy number alterations (e.g., gain at 12p13.31) were correlated with the deregulated miRNAs. Specifically, thirteen novel asbestos-related miRNAs (over-expressed: miR-148b, miR-374a, miR-24-1*, Let-7d, Let-7e, miR-199b-5p, miR-331-3p, and miR-96 and under-expressed: miR-939, miR-671-5p, miR-605, miR-1224-5p and miR-202) and inversely correlated target genes (e.g., GADD45A, LTBP1, FOSB, NCALD, CACNA2D2, MTSS1, EPB41L3) were identified. In addition, over-expression of the well known squamous cell carcinoma-associated miR-205 was linked to down-regulation of the DOK4 gene. The miRNAs/genes presented here may represent interesting targets for further investigation and could eventually have potential diagnostic implications.


Assuntos
Amianto/intoxicação , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , MicroRNAs/genética , RNA Mensageiro/genética , Adulto , Idoso , Hibridização Genômica Comparativa/métodos , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/etiologia , Neoplasias Pulmonares/metabolismo , Masculino , Pessoa de Meia-Idade
14.
Am J Respir Cell Mol Biol ; 42(5): 626-32, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-19597127

RESUMO

Idiopathic pulmonary fibrosis (IPF) (histopathology of usual interstitial pneumonia [UIP]) is a progressive disease with poor prognosis. Characteristic features of IPF/UIP include fibroblastic foci, which are patchy lesions of focal, disarranged myofibroblasts. GATA-6 is a transcription factor linked with cell differentiation. Its role in the development of IPF has not previously been investigated. We hypothesized that GATA-6 participates in the differentiation of fibroblasts into myofibroblasts in IPF/UIP lungs. The expression patterns of GATA-6, the mesenchymal marker alpha-smooth muscle actin (alpha-SMA), and markers for proliferation (Ki67) and apoptosis (caspase-3) were analyzed in human IPF/UIP tissue samples. The effects of GATA-6 overexpression and silencing were studied in cell cultures. The results show that the alpha-SMA-positive fibroblastic foci in IPF/UIP lungs are positive for GATA-6, but negative for Ki67 and caspase-3. Cultured human IPF/UIP fibroblasts expressed GATA-6 mRNA, whereas cells from the normal adult lung did not. In cultured A549 lung epithelial cells, the induction of GATA-6 by transforming growth factor-beta1 resulted in simultaneous expression of alpha-SMA and decrease of E-cadherin. The inhibition of GATA-6 expression in fibroblasts showed that GATA-6 mediates the alpha-SMA-inducing signal of transforming growth factor-beta1. In conclusion, the hallmark of IPF/UIP histopathology, the fibroblast focus, consists of differentiated, quiescent cells that prominently express GATA-6.


Assuntos
Fibroblastos/metabolismo , Fibroblastos/patologia , Fator de Transcrição GATA6/metabolismo , Fibrose Pulmonar Idiopática/metabolismo , Fibrose Pulmonar Idiopática/patologia , Actinas/metabolismo , Adulto , Apoptose/efeitos dos fármacos , Biomarcadores/metabolismo , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proteínas de Ligação a DNA/metabolismo , Epitélio/efeitos dos fármacos , Epitélio/metabolismo , Epitélio/patologia , Fibroblastos/efeitos dos fármacos , Fator de Transcrição GATA6/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Mesoderma/efeitos dos fármacos , Mesoderma/metabolismo , Mesoderma/patologia , Transporte Proteico/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fatores de Transcrição/metabolismo , Fator de Crescimento Transformador beta1/farmacologia
15.
Respir Res ; 11: 165, 2010 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-21118554

RESUMO

BACKGROUND: Levels of precursor proteins of collagen I and III are increased in fibrotic pulmonary diseases. This study determined whether the expression of precursors of type I and III collagen proteins would be increased in small and large airways of COPD patients in various stages of the disease reflecting fibrogenesis. METHODS: The levels of precursor proteins of collagen I and III were studied by immunohistochemistry and quantified by image analysis in lung tissue of 16 non-smokers, 20 smokers with normal lung function, 20 smokers with stage I-II COPD and 8 ex-smokers with stage IV COPD. RESULTS: In large airways, the subepithelial layer which was positive for precursor proteins of collagen I and III was thicker in smokers and in stage I-II COPD compared to non-smokers. Large airways in stage IV COPD showed reduced expression of precursor protein of collagen I whereas precursor of collagen III was increased. The amount of precursor protein of collagen III was increased in small airways of smokers and stage I-II COPD but reduced in stage IV COPD. CONCLUSIONS: Precursor proteins of collagen I and III revealed different expression profiles in large and small airways in various stages of COPD. Smoking enhanced expression of both precursors in large airways with a positive correlation with pack-years.


Assuntos
Colágeno Tipo III/metabolismo , Colágeno Tipo I/metabolismo , Pulmão/metabolismo , Doença Pulmonar Obstrutiva Crônica/metabolismo , Fumar/metabolismo , Idoso , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/complicações , Sensibilidade e Especificidade , Distribuição Tecidual
16.
Respir Res ; 11: 123, 2010 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-20836851

RESUMO

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD) are disorders of the lung parenchyma. They share the common denominators of a progressive nature and poor prognosis. The goal was to use non-biased proteomics to discover new markers for these diseases. METHODS: Proteomics of fibrotic vs. control lung tissue suggested decreased levels of several spots in the lung specimens of IPF patients, which were identified as Hemoglobin (Hb) α and ß monomers and Hbα complexes. The Hbα and ß monomers and complexes were investigated in more detail in normal lung and lung specimens of patients with IPF and COPD by immunohistochemistry, morphometry and mass spectrometry (MS). RESULTS: Both Hb monomers, in normal lung, were expressed especially in the alveolar epithelium. Levels of Hbα and ß monomers and complexes were reduced/lost in IPF but not in the COPD lungs when compared to control lung. MS-analyses revealed Hbα modification at cysteine105 (Cysα105), preventing formation of the Hbα complexes in the IPF lungs. Hbα and Hbß were expressed as complexes and monomers in the lung tissues, but were secreted into the bronchoalveolar lavage fluid and/or induced sputum supernatants as complexes corresponding to the molecular weight of the Hb tetramer. CONCLUSIONS: The abundant expression of the oxygen carrier molecule Hb in the normal lung epithelium and its decline in IPF lung are new findings. The loss of Hb complex formation in IPF warrants further studies and may be considered as a disease-specific modification.


Assuntos
Hemoglobinas/biossíntese , Fibrose Pulmonar Idiopática/metabolismo , Pulmão/metabolismo , Fragmentos de Peptídeos/biossíntese , Doença Pulmonar Obstrutiva Crônica/metabolismo , Globinas beta/biossíntese , Adulto , Idoso , Biomarcadores/sangue , Biomarcadores/metabolismo , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Diagnóstico Diferencial , Feminino , Humanos , Fibrose Pulmonar Idiopática/diagnóstico , Fibrose Pulmonar Idiopática/patologia , Pulmão/citologia , Pulmão/patologia , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/sangue , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/patologia , Mucosa Respiratória/citologia , Mucosa Respiratória/metabolismo , Mucosa Respiratória/patologia
17.
Clin Cancer Res ; 15(2): 468-75, 2009 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-19147751

RESUMO

PURPOSE: Asbestos causes DNA damage and the fibers, together with tobacco smoke, have a synergistic effect on lung cancer risk. We recently identified 18 chromosomal regions that showed differences in DNA copy number between the lung tumors of asbestos-exposed and nonexposed patients. One of the previously identified asbestos-associated chromosomal regions at 9q was further analyzed for allelic imbalance and DNA copy number alterations (CNA) in the lung tumors of asbestos-exposed and nonexposed patients. In addition, the ploidy level of the tumors was studied. EXPERIMENTAL DESIGN: Allelic imbalance was analyzed at 9q31.3-34.3 with 15 microsatellite markers in 52 lung tumor samples from asbestos-exposed and nonexposed patients. CNA at 9q32-34.3 were characterized by fluorescent in situ hybridization (FISH) with six bacterial artificial chromosome probes in 95 lung tumors. The ploidy level was analyzed in 100 lung tumors with FISH using three to five centromere probes. RESULTS: Allelic imbalance at 9q31.3-q34.3 was found in all asbestos-exposed patient tumors (100%, 17 of 17) compared with 64% (14 of 22) in the nonexposed cases (P = 0.005). The most significant difference was detected at 9q33.1 (P = 0.002). FISH results showed that also CNA were more frequent at 9q33.1 in the three major histologic types of non-small-cell lung tumors of exposed patients, and the association showed a dose-dependent trend (P = 0.03). Furthermore, we detected more frequent polyploidy among the exposed (48%, 28 of 58) than among the nonexposed (29%, 12 of 42) patient tumors (P < 0.05). CONCLUSIONS: These results provide a basis for the development of a method to identify asbestos-related lung cancer on a molecular level.


Assuntos
Amianto/efeitos adversos , Cromossomos Humanos Par 9 , Neoplasias Pulmonares/induzido quimicamente , Neoplasias Pulmonares/genética , Poliploidia , Idoso , Alelos , Aberrações Cromossômicas , Cromossomos Artificiais Bacterianos , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Hibridização in Situ Fluorescente , Masculino , Repetições de Microssatélites , Pessoa de Meia-Idade
18.
Genes Chromosomes Cancer ; 48(7): 615-23, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19396864

RESUMO

Malignant mesothelioma (MM) is an aggressive cancer arising from mesothelial cells, mainly due to former asbestos exposure. Little is known about the microRNA (miRNA) expression of MM. miRNAs are small noncoding RNAs, which play an essential role in the regulation of gene expression. This study was carried out to analyze the miRNA expression profile of 17 MM samples using miRNA microarray. The analysis distinguished the overall miRNA expression profiles of tumor tissue and normal mesothelium. Differentially expressed miRNAs were found in tumor samples compared with normal sample. Twelve of them, let-7b*, miR-1228*, miR-195*, miR-30b*, miR-32*, miR-345, miR-483-3p, miR-584, miR-595, miR-615-3p, and miR-885-3p, were highly expressed whereas the remaining nine, let-7e*, miR-144*, miR-203, miR-340*, miR-34a*, miR-423, miR-582, miR-7-1*, and miR-9, were unexpressed or had severely reduced expression levels. Target genes for these miRNAs include the most frequently affected genes in MM such as CDKN2A, NF2, JUN, HGF, and PDGFA. Many of the miRNAs were located in chromosomal areas known to be deleted or gained in MM such as 8q24, 1p36, and 14q32. Furthermore, we could identify specific miRNAs for each histopathological subtype of MM. Regarding risk factors such as smoking status and asbestos exposure, significantly differentially expressed miRNAs were identified in smokers versus nonsmokers (miR-379, miR-301a, miR-299-3p, miR-455-3p, and miR-127-3p), but not in asbestos-exposed patients versus nonexposed ones. This could be related to the method of assessment of asbestos exposure as asbestos remains to be the main contributor to the development of MM.


Assuntos
Inibidor p16 de Quinase Dependente de Ciclina/genética , Regulação Neoplásica da Expressão Gênica , Mesotelioma/genética , MicroRNAs/genética , Neurofibromina 2/genética , Proteínas Proto-Oncogênicas c-jun/genética , Idoso , Amianto/intoxicação , Cromossomos Humanos , Análise por Conglomerados , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Feminino , Perfilação da Expressão Gênica/métodos , Humanos , Masculino , Mesotelioma/metabolismo , Mesotelioma/patologia , MicroRNAs/biossíntese , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Neurofibromina 2/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Proteínas Proto-Oncogênicas c-jun/metabolismo , Fatores de Risco , Fumar/genética , Fumar/metabolismo , Análise de Sobrevida
19.
Virchows Arch ; 476(2): 273-283, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31385069

RESUMO

Finnish hospital-integrated biobanks administer millions of formalin-fixed paraffin-embedded tissue samples collected within the clinical diagnostics. According to the Finnish Biobank Act, these samples can be coupled with patients' clinical follow-up data and the data retrieved from national health registries. We collected a nationwide pulmonary carcinoid tumour series from Finnish biobanks to study prognostic factors as well as to explore how the number of tumours found in the Finnish biobanks corresponds to the number of tumours registered by the Finnish Cancer Registry (FCR). Finnish biobanks identified 88% of the tumours registered by the FCR and were able to deliver 63%. The main reasons for lacking samples were paucity of resected primary tumour tissue, incompatible primary diagnosis, and the absence of tissue blocks in the archives. The main bottleneck in the sample application process was retrieving patient data. Altogether, we received 224 tumour samples with appropriate patient data and identified six prognostic factors for shorter disease-specific survival: age over 56 years at the time of diagnosis, tumour size over 2.5 cm, atypical histology, Ki-67 proliferation index higher than 2.5%, hilar/mediastinal lymph node involvement at the time of diagnosis, and the presence of metastatic disease. In conclusion, the Finnish biobank infrastructure offers excellent opportunities for tissue-based research. However, to be able to develop the biobank operations further, involving more medical knowledge in the sample and data acquisition process is a necessity. Also, when working with tissue samples collected over decades, histological expertise is essential for re-evaluation and re-classification of the samples.


Assuntos
Bancos de Espécimes Biológicos , Tumor Carcinoide/patologia , Carcinoma Neuroendócrino/patologia , Neoplasias Pulmonares/patologia , Adulto , Feminino , Finlândia , Humanos , Masculino , Pessoa de Meia-Idade , Sistema de Registros
20.
Acta Oncol ; 48(8): 1137-43, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19863221

RESUMO

PURPOSE. It is unknown to what extent lymph node metastases differ from primary tumours of breast cancer. Our aim was to investigate the similarity between primary breast tumours and the matching lymph node metastases in 59 breast cancer patients. EXPERIMENTAL DESIGN. Immunohistochemical stainings of p53, bax, bc-l2, fas and fasL were performed in primary tumours and the parallel lymph node metastases. RESULTS. When using a cut point of 10%, the concordance between primary tumours and parallel lymph node metastases in the expression of p53 was 85%, bcl-2 79%, bax 69%, fas 59% and fasL 43%. In most tumours the staining status of p53, bcl-2 and bax in the primary tumour and the corresponding lymph node did not change more than 20%. However, these variables could fluctuate in both directions. In 15-25% of the cases, nodal expression was more than 20% lower than in the primary tumours, while in 10-17% of the cases, nodal expression was more than 20% higher than in the primary tumours. In half of the tumours, fas status did not change. Most fasL positive tumours lost positivity in the lymph node metastases or showed positively staining cancer cells only in the peripheral region of the node. A phenotype analysis of combined information of tumour fas/tumour fasL/nodal fas/nodal fasL expression (+/ - ) was assessed. The most frequently observed phenotype was tumour fas - /tumour fasL + /nodal fas - /nodal fasL- (22% of the tumours), although almost all combinations were seen. CONCLUSIONS. The expression of p53, bax, bcl - 2, fas and fasL is not maintained in the matching lymph node metastases of breast cancer. Large studies comparing the expression of relevant tumour biology factors in primary tumours and parallel lymph node metastases and their impact on therapy outcome, especially in the adjuvant setting, are warranted.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/metabolismo , Metástase Linfática , Proteínas de Neoplasias/metabolismo , Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Proteína Ligante Fas/genética , Proteína Ligante Fas/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Metástase Linfática/genética , Metástase Linfática/patologia , Proteínas de Neoplasias/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo , Receptor fas/genética , Receptor fas/metabolismo
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