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1.
Medicine (Baltimore) ; 98(42): e17601, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31626137

RESUMO

BACKGROUND: Lung adenocarcinoma (LA) is a most common form of non-small cell lung cancer (NSCLC). To date, there are still no effective early diagnosis methods for patients to be cured in time. Noncoding RNA plays an important role in oncogenesis and tumor development. The expression profile of circular RNA (circRNA) in peripheral whole blood (PWB) of LA has not been systematically investigated. In this study, we identified the differentially expressed (DE) circRNAs in PWB of LA by high-throughput sequencing. METHODS: Five paired LA and normal participants PWB samples were chosen to investigate the expression profile of circRNAs by high-throughput sequencing. Twenty LA and 10 normal controls PWB samples were subjected to reverse-transcription polymerase chain reaction (RT-PCR) for validation of circRNAs expression profile. Gene Ontology (GO) functional analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, and circRNA-miRNA network analysis was also performed to predict the function of circRNAs in PWB. RESULTS: A total of 10566 circRNAs were identified and annotated, most of the circRNAs were exonic (78.14%). Statistical analysis revealed 4390 DE circRNAs, in which were 3009 upregulated circRNAs and1381downregulated circRNAs in LA. RT-PCR results showed that circRNA expression in LA was higher than that in controls. GO functional analysis, KEGG pathway analysis, and circRNA-miRNA network analysis all showed that circRNAs correlated with tumor development and progression to a certain degree. The current study is the first to systematically characterize and annotate circRNA expression in PWB of LA. Some host genes of the DE circRNAs were involved in tumor signaling pathway and had complicated correlations with tumor related miRNAs, indicating that circRNAs might involve in development and progression of LA. CONCLUSIONS: Our study revealed that circRNAs were abnormally expressed in PWB of LA, which might offer potential targets for the early diagnosis of the disease and new genetic insights into LA.


Assuntos
Adenocarcinoma de Pulmão/genética , Regulação Neoplásica da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala/métodos , RNA/genética , Adenocarcinoma de Pulmão/sangue , Perfilação da Expressão Gênica/métodos , Humanos , RNA/biossíntese , RNA Neoplásico/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais , Regulação para Cima
2.
Zhonghua Bing Li Xue Za Zhi ; 48(10): 772-778, 2019 Oct 08.
Artigo em Chinês | MEDLINE | ID: mdl-31594041

RESUMO

Objective: To study the characteristics of lung adenocarcinoma driver gene variants detected by next generation sequencing (NGS) and quantitative fluorescence PCR. Methods: NGS was performed on 372 surgical resections from primary lung adenocarcinoma patients to detect 10 driver gene mutations, single-nucleotide variants(SNV), insertion/deletion and gene fusions; and quantitative fluorescence PCR were performed on 169 surgical resections from primary lung adenocarcinoma patients to detect nine driver gene hotspot mutations. Variants of VAF (variant allele frequency)≥1.0% were classified into 1 of 4 levels according to the guidelines and the precision oncology knowledge base of OncoKB, and the characteristics were investigated. Results: Sixty seven variants(leve1-4) were found by NGS, the positive rate of total mutations was 86.6% (322/372), in which variants at four levels were detected: levelⅠvariant, which was recognized as biomarker predictive of response to an FDA/NMPA approved drug in non-small cell lung cancer (NSCLC), was 71.2% (265/372);level Ⅱ variant, which was recognized as being standard care by the NCCN or other expert panels, was 3.0% (11/372); levelⅢA, a variant with compelling clinical evidence supports the biomarker as being predictive of response to a drug in this indication 3.0% (11/372); levelⅢB, a variant with compelling clinical evidence supports the biomarker as being predictive of response to a drug in another indication, was 4.3% (16/372); and level Ⅳ, a variant with compelling biological evidence supports the biomarker as being predictive of response to a drug, was 8.1% (30/372). The positive rate of unknown clinical significance and/or benign/likely benign variants was 18.8% (70/372). The positive rate of mutations detected by quantitative fluorescence PCR was 81.7% (138/169). Eighteen of the 20 samples showed concordance between NGS and quantitative fluorescence PCR. The two discordant cases could be due to the lack of coverage of two mutation sites in fluorescence PCR: EGFR c. 2571_2573delinsTCG(p. L858R), and HIP1-ALK_H19:A20 fusion. Conclusions: Lung adenocarcinoma driver gene variants occur mainly in hotspot region, and NGS can comprehensively detect the driver gene variants of significant and potential clinical significance. NGS should be recommended when multiple genes need to be tested.


Assuntos
Adenocarcinoma de Pulmão/genética , Neoplasias Pulmonares/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mutação , Reação em Cadeia da Polimerase
3.
Med Oncol ; 36(11): 91, 2019 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-31560089

RESUMO

The vasoactive intestinal peptide receptor-1(VIPR1) has prominent growth effects on a number of common neoplasms. However, there were contradictions in the effect cross different cancers. We aimed to explore the effect of VIPR1 overexpression on a human lung adenocarcinoma cell line H1299. GEO dataset was used to screen differentially expressed genes in lung adenocarcinoma tissues. The expression of VIPR1 mRNA was determined in the cancer Genome Atlas (TCGA). Immunohistochemical analysis was performed to determine VIPR1 protein expression in lung adenocarcinoma and corresponding adjacent tissues (n = 22). Fluorescence real-time quantitative PCR detected the expression of VIPR1 in human normal lung epithelial cell line BEAS-2B and lung adenocarcinoma cell line H1299. Overexpression strategies were employed to assess functions of VIPR1 expression on several malignant phenotypes in H1299. The expression of VIPR1 was lower in lung adenocarcinoma tissues than that in adjacent tissues. Compared with the normal lung epithelial cells BEAS-2B, VIPR1 was down-regulated in lung cancer cells H1299 (P < 0.05). After the overexpression of VIPR1, we found that VIPR1 significantly inhibited growth, migration, and invasion of H1299 cells (P < 0.05). Our findings point out the tumor suppressor roles of VIPR1 in human LUAD pathogenesis.


Assuntos
Adenocarcinoma de Pulmão/genética , Regulação Neoplásica da Expressão Gênica , Receptores Tipo I de Polipeptídeo Intestinal Vasoativo/genética , Adenocarcinoma de Pulmão/metabolismo , Adenocarcinoma de Pulmão/patologia , Adulto , Idoso , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Feminino , Genes Supressores de Tumor , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , RNA Mensageiro/genética , Receptores Tipo I de Polipeptídeo Intestinal Vasoativo/biossíntese , Regulação para Cima
4.
Cancer Sci ; 110(10): 3215-3224, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31432603

RESUMO

Patient-derived xenograft (PDX) models are a useful tool in cancer biology research. However, the number of lung cancer PDX is limited. In the present study, we successfully established 10 PDX, including three adenocarcinoma (AD), six squamous cell carcinoma (SQ) and one large cell carcinoma (LA), from 30 patients with non-small cell lung cancer (NSCLC) (18 AD, 10 SQ, and 2 LA), mainly in SCID hairless outbred (SHO) mice (Crlj:SHO-Prkdcscid Hrhr ). Histology of SQ, advanced clinical stage (III-IV), status of lymph node metastasis (N2-3), and maximum standardized uptake value ≥10 when evaluated using a delayed 18 F-fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET) scan was associated with successful PDX establishment. Histological analyses showed that PDX had histology similar to that of patients' surgically resected tumors (SRT), whereas components of the microenvironment were replaced with murine cells after several passages. Next-generation sequencing analyses showed that after two to six passages, PDX preserved the majority of the somatic mutations and mRNA expressions of the corresponding SRT. Two out of three PDX with AD histology had epidermal growth factor receptor (EGFR) mutations (L858R or exon 19 deletion) and were sensitive to EGFR tyrosine kinase inhibitors (EGFR-TKI), such as gefitinib and osimertinib. Furthermore, in one of the two PDX with an EGFR mutation, osimertinib resistance was induced that was associated with epithelial-to-mesenchymal transition. This study presented 10 serially transplantable PDX of NSCLC in SHO mice and showed the use of PDX with an EGFR mutation for analyses of EGFR-TKI resistance.


Assuntos
Adenocarcinoma de Pulmão/patologia , Carcinoma de Células Grandes/patologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/patologia , Neoplasias Pulmonares/patologia , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/genética , Idoso , Idoso de 80 Anos ou mais , Animais , Carcinoma de Células Grandes/tratamento farmacológico , Carcinoma de Células Grandes/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Masculino , Camundongos , Camundongos Pelados , Camundongos SCID , Pessoa de Meia-Idade , Mutação , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Microambiente Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Cancer Invest ; 37(8): 367-375, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31462083

RESUMO

The aryl hydrocarbon receptor (AhR) is activated by the ligand, benzo[a]pyrene (B[a]P), a component of smoke that is implicated in lung carcinogenesis in humans. However, the role of B[a]P and AhR in lung cancer malignancy is not well known. In this study, we analyzed the effects of B[a]P and AhR in the 3 D spheroids of human lung cancer cells in vitro. In these spheroids, B[a]P and AhR enhanced cancer cell proliferation. These results suggest that the AhR-dependent effects of B[a]P on cell proliferation may contribute to the adverse effects of continuous smoking with respect to lung cancer malignancy.


Assuntos
Adenocarcinoma de Pulmão/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/agonistas , Benzo(a)pireno/toxicidade , Proliferação de Células/efeitos dos fármacos , Neoplasias Pulmonares/metabolismo , Receptores de Hidrocarboneto Arílico/agonistas , Células A549 , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Receptores de Hidrocarboneto Arílico/genética , Receptores de Hidrocarboneto Arílico/metabolismo , Transdução de Sinais , Esferoides Celulares
6.
Anticancer Res ; 39(8): 4117-4128, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366496

RESUMO

BACKGROUND/AIM: Carbonic anhydrase 12 (CA12) is a membrane-associated enzyme that is highly expressed on many human cancers. It is a poor prognostic marker and hence an attractive target for cancer therapy. This study aimed to develop a humanized CA12-antibody with anti-cancer activity. MATERIALS AND METHODS: Antibody libraries were constructed and screened by the Retrocyte display®. Antibody binding and blocking properties were determined by ELISA, flow cytometry and enzymatic activity assays. Spheroid viability was determined by Cell-Titer-Fluor assay. RESULTS: We developed a novel humanized CA12-specific antibody, 4AG4, which recognized CA12 as an antigen and blocked CA12 enzymatic activity. Our humanized CA12-antibody significantly inhibited spheroid growth of lung adenocarcinoma A549-cells in vitro by blocking CA12 enzymatic activity. Similar anti-tumor effects were recapitulated with CA12-gene knockout of A549-cells. CONCLUSION: Our newly identified humanized CA12-antibody with anti-cancer activity, represents a new tool for the treatment of CA12-positive tumors.


Assuntos
Adenocarcinoma de Pulmão/tratamento farmacológico , Anticorpos Monoclonais Humanizados/farmacologia , Anidrases Carbônicas/genética , Células A549 , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/imunologia , Adenocarcinoma de Pulmão/patologia , Anticorpos Monoclonais Humanizados/imunologia , Anidrases Carbônicas/imunologia , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Esferoides Celulares/efeitos dos fármacos
7.
J Cancer Res Clin Oncol ; 145(9): 2273-2283, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31428934

RESUMO

OBJECTIVES: Recent research has classified lung adenocarcinoma patients with KRAS mutation into three subtypes by co-occurring genetic events in TP53 (KP subgroup), STK11/LKB1 (KL subgroup) and CDKN2A/B inactivation plus TTF-1 low expression (KC subgroup). The aim of this study was to identify valuable biomarkers by searching the candidate molecules that contribute to lung adenocarcinoma pathogenesis, especially KC subtype. MATERIALS AND METHODS: We analyzed the publicly available database and identified the candidate REG4 using the E-GEOD-31210 dataset, and then confirmed by TCGA dataset. In addition, an independent cohort of 55 clinical samples was analyzed by quantitative real-time PCR analysis. Functional studies and RNA sequencing were performed after silencing the REG4 expression. RESULTS: REG4, an important regulator of gastro-intestinal carcinogenesis, was highly expressed in KRAS mutant lung adenocarcinoma with low expression of TTF-1 (KC subtype). The results were validated both by gene expression analysis and immunohistochemistry study in an independent 55 clinical samples from Fudan University Shanghai Cancer Center. Further in vitro and in vivo functional assays revealed silencing REG4 expression significantly reduces cancer cell proliferation and tumorigenesis. Moreover, RNA sequencing and GSEA analysis displayed that REG4 knockdown might induce cell cycle arrest by regulating G2/M checkpoint and E2F targets. CONCLUSION: Our results indicate that REG4 plays an important role in KRAS-driven lung cancer pathogenesis and is a novel biomarker of lung adenocarcinoma subtype. Future studies are required to clarify the underlying mechanisms of REG4 in the division and proliferation of KC tumors and its potential therapeutic value.


Assuntos
Adenocarcinoma de Pulmão/diagnóstico , Biomarcadores Tumorais/genética , Transformação Celular Neoplásica/genética , Proteínas de Ligação a DNA/genética , Neoplasias Pulmonares/diagnóstico , Proteínas Associadas a Pancreatite/genética , Proteínas Proto-Oncogênicas p21(ras)/fisiologia , Fatores de Transcrição/genética , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Animais , Linhagem Celular Tumoral , Transformação Celular Neoplásica/patologia , Estudos de Coortes , Proteínas de Ligação a DNA/metabolismo , Regulação para Baixo/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas Mutantes/genética , Proteínas Mutantes/fisiologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Fatores de Transcrição/metabolismo
9.
Nat Commun ; 10(1): 2978, 2019 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-31278276

RESUMO

There has been a dramatic increase in the detection of lung nodules, many of which are preneoplasia atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA) or invasive adenocarcinoma (ADC). The molecular landscape and the evolutionary trajectory of lung preneoplasia have not been well defined. Here, we perform multi-region exome sequencing of 116 resected lung nodules including AAH (n = 22), AIS (n = 27), MIA (n = 54) and synchronous ADC (n = 13). Comparing AAH to AIS, MIA and ADC, we observe progressive genomic evolution at the single nucleotide level and demarcated evolution at the chromosomal level supporting the early lung carcinogenesis model from AAH to AIS, MIA and ADC. Subclonal analyses reveal a higher proportion of clonal mutations in AIS/MIA/ADC than AAH suggesting neoplastic transformation of lung preneoplasia is predominantly associated with a selective sweep of unfit subclones. Analysis of multifocal pulmonary nodules from the same patients reveal evidence of convergent evolution.


Assuntos
Adenocarcinoma de Pulmão/genética , Evolução Molecular , Neoplasias Pulmonares/genética , Pulmão/patologia , Lesões Pré-Cancerosas/genética , Adenocarcinoma de Pulmão/patologia , Idoso , Idoso de 80 Anos ou mais , Carcinogênese/genética , Feminino , Humanos , Hiperplasia/genética , Hiperplasia/patologia , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Lesões Pré-Cancerosas/patologia , Sequenciamento Completo do Exoma
10.
J Cancer Res Clin Oncol ; 145(9): 2325-2333, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31317326

RESUMO

PURPOSE: Nodal positive lung adenocarcinoma includes wide range of survival. Several methods for the classification of nodal-positive lung cancer have been proposed. However, classification considering the impact of targetable genetic variants are lacking. The possibility of genetic variants for the better stratification of nodal positive lung adenocarcinoma was estimated. METHODS: Mutations of 36 genes between primary sites and metastatic lymph nodes (LNs) were compared using next-generation sequencing. Subsequently, mutations in EGFR and BRAF, rearrangements in ALK and ROS1 were evaluated in 69 resected pN1-2M0 adenocarcinoma cases. Recurrence-free survival (RFS), post-recurrence survival (PRS), and overall survival (OS) were evaluated with respect to targetable variants and tyrosine kinase inhibitor (TKI) therapy after recurrence. RESULTS: About 90% of variants were shared and allele frequencies were similar between primary and metastatic sites. In 69 pN1-2M0 cases, EGFR/ALK were positive in primary sites of 39 cases and same EGFR/ALK variants were confirmed in metastatic LNs of 96.7% tissue-available cases. Multivariate analyses indicated positive EGFR/ALK status was associated with worse RFS (HR 2.366; 95% CI 1.244-4.500; P = 0.009), and PRS was prolonged in cases receiving TKI therapy (no post-recurrence TKI therapies, HR 3.740; 95% CI 1.449-9.650; P = 0.006). OS did not differ with respect to targetable variants or TKI therapy. CONCLUSIONS: Cases harbouring targetable genetic variants had a higher risk of recurrence, but PRS was prolonged by TKI therapy. Classification according to the targetable genetic status provides a basis for predicting recurrence and determining treatment strategies after recurrence.


Assuntos
Adenocarcinoma de Pulmão/diagnóstico , Neoplasias Pulmonares/diagnóstico , Pulmão/metabolismo , Linfonodos/metabolismo , Mutação , Transcriptoma/genética , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Idoso , Idoso de 80 Anos ou mais , Análise Mutacional de DNA/métodos , Feminino , Regulação Neoplásica da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Pulmão/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Linfonodos/patologia , Metástase Linfática , Masculino , Análise em Microsséries/métodos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Prognóstico , Estudos Retrospectivos
11.
DNA Cell Biol ; 38(8): 814-823, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31314552

RESUMO

Lung cancer is known to cause high mortality and morbidity. The study aimed to explore the association between rs3733845 and rs3733846 polymorphisms in the promoter region of miR-143/145 and the risk of lung cancer among 575 nonsmoking cases and 575 cancer-free controls in a Chinese female population. We genotyped two single nucleotide polymorphisms (SNPs) in the promoter region of miR-143/145 in 575 cases and 575 controls using TaqMan allelic discrimination method. Logistic regression analysis was conducted to assess the association between polymorphisms in the promoter of miR-143/miR-145 and risk of lung cancer females. Crossover analysis was used to explore the interaction between the two SNPs and environmental risk factors (cooking oil fume exposure and passive smoking exposure). The results showed that both rs3733845 and rs3733846 polymorphisms were associated with an increased lung adenocarcinoma risk in dominant model (adjusted odds ratio [OR] = 1.329, 95% confidence intervals [CIs] = 1.026-1.723, p = 0.031 and adjusted OR = 1.450, 95% CI = 1.112-1.890, p = 0.006, respectively). The results of crossover analysis revealed that rs3733845 and rs3733846 risk genotypes along with cooking oil exposure increased lung cancer risk by 1.862-fold and 2.260-fold, respectively (adjusted OR = 1.862, 95% CI = 1.105-3.138, p = 0.020 for rs3733845; adjusted OR = 2.260, 95% CI = 1.354-3.769, p = 0.002 for rs3733846). There was positive multiplicative interaction between the two SNPs and cooking oil fume exposure (adjusted OR = 1.362, 95% CI = 1.078-1.719, p = 0.009 for oil × rs3733845; adjusted OR = 1.399, 95% CI = 1.122-1.745, p = 0.003 for oil × rs3733846). In nonsmoking females, rs3733845 and rs3733846 polymorphisms might be associated with lung adenocarcinoma risk. Moreover, the interactions between the two SNPs and cooking oil fume exposure were statistically significant on a multiplicative scale rather than an addictive scale.


Assuntos
Neoplasias Pulmonares/genética , MicroRNAs/genética , Polimorfismo de Nucleotídeo Único , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Idoso , Estudos de Casos e Controles , Culinária , Estudos Cross-Over , Feminino , Interação Gene-Ambiente , Predisposição Genética para Doença , Humanos , Neoplasias Pulmonares/patologia , Pessoa de Meia-Idade , Regiões Promotoras Genéticas , Fumar
12.
J Cardiothorac Surg ; 14(1): 143, 2019 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-31340823

RESUMO

BACKGROUNDS: The pulmonary ciliated muconodular papillary tumor (CMPT) is a very rare tumor with only several case reports in published literatures, and its clinicopathological features, standard treatment methods and prognosis has not been well defined. METHODS: Two cases of CMPT diagnosed and treated in our hospital and 39 cases reported in the published literature were analyzed retrospectively. RESULTS: The cohort of 41 CMPT patients comprised of 20 males and 21 females, aged 9-84 years. The diameter of the primary tumor was 0.3-4.5 cm. Most of these lesions were subsolid nodules, as observed on computed tomography and easily misdiagnosed as early lung adenocarcinoma. Tumors of 26 patients were stained by immunohistochemistry method, which revealed that CK7, CEA, and TTF-1 were positive and CK20 was negative in most patients. The results of gene alternation demonstrated mutations in EGFR, KRAS, and BRAF and ALK rearrangements in CMPT. All the patients underwent surgical treatment and did not receive postoperative adjuvant therapy. The follow-up duration was 0-120 months, and no case of tumor recurrence was found until the final follow-up. CONCLUSIONS: The incidence of CMPT was low and rate of image misdiagnosis high. Immunohistochemistry is helpful for accurate diagnosis of CMPT. Sub-lobectomy may be proper and adjuvant treatment should be avoided since the disease is now prone to benign lesions. Furthermore, since the biological behavior of this tumor is not yet fully elucidated, additional case data are essential for accurate conclusions.


Assuntos
Adenocarcinoma de Pulmão/patologia , Adenocarcinoma Mucinoso/patologia , Neoplasias Pulmonares/patologia , Adenocarcinoma de Pulmão/diagnóstico por imagem , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/cirurgia , Adenocarcinoma Mucinoso/diagnóstico por imagem , Adenocarcinoma Mucinoso/genética , Adenocarcinoma Mucinoso/cirurgia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Cílios/patologia , Feminino , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/cirurgia , Masculino , Pessoa de Meia-Idade , Mutação , Prognóstico , Estudos Retrospectivos , Tomografia Computadorizada por Raios X , Adulto Jovem
13.
Cancer Sci ; 110(9): 3006-3011, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31301084

RESUMO

Decreased cell adhesion has been reported as a significant negative prognostic factor of lung cancer. However, the molecular mechanisms responsible for the cell incohesiveness in lung cancer have not yet been elucidated in detail. We herein describe a rare histological variant of lung adenocarcinoma consisting almost entirely of individual cancer cells spreading in alveolar spaces in an incohesive pattern. A whole exome analysis of this case showed no genomic abnormalities in CDH1 or other genes encoding cell adhesion molecules. However, whole mRNA sequencing revealed that this case had an extremely high expression level of mucin 21 (MUC21), a mucin molecule that was previously shown to inhibit cell-cell and cell-matrix adhesion. The strong membranous expression of MUC21 was found on cancer cells using mAbs recognizing different O-glycosylated forms of MUC21. An immunohistochemical analysis of an unselected series of lung adenocarcinoma confirmed that the strong membranous expression of MUC21 correlated with incohesiveness. Thus, MUC21 could be a promising biomarker with potential diagnostic and therapeutic applications for lung adenocarcinoma showing cell incohesiveness.


Assuntos
Adenocarcinoma de Pulmão/patologia , Neoplasias Pulmonares/patologia , Glicoproteínas de Membrana/metabolismo , Mucinas/metabolismo , Adenocarcinoma de Pulmão/diagnóstico por imagem , Adenocarcinoma de Pulmão/genética , Idoso , Antígenos CD/genética , Caderinas/genética , Feminino , Perfilação da Expressão Gênica , Humanos , Pulmão/diagnóstico por imagem , Pulmão/patologia , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/genética , Tomografia Computadorizada por Raios X , Sequenciamento Completo do Exoma
14.
Cancer Sci ; 110(9): 2960-2972, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31301086

RESUMO

In recent years, circular RNAs (circRNAs) have been revealed to have important roles in carcinogenesis. Metastasis is the leading cause of lung adenocarcinoma (LUAC) death. However, the contributions of circRNA to the metastasis of LUAC remain largely unknown. Based on circBase data and our biobank tissues, we identified circCRIM1 (a circRNA derived from exons 2, 3 and 4 of the CRIM1 gene, hsa_circ_0002346) as having a significantly decreased expression in LUAC samples compared with matched normal control samples. Both in vivo and in vitro experiments revealed that circCRIM1 suppresses the invasion and metastasis of LUAC. In vitro precipitation of circRNAs, luciferase reporter assay, and biotin-coupled microRNA capture were carried out to investigate the Ago2-dependent interaction of circCRIM1 and microRNA (miR)-93/miR-182. Mechanistically, we found that circCRIM1 could promote the expression of leukemia inhibitory factor receptor, a well-known tumor suppressor, by sponging miR-93 and miR-182. In the clinical and pathological analyses, the downregulation of circCRIM1 in LUAC was significantly correlated with lymphatic metastasis and TNM stage, which served as an independent risk factor for the overall survival of patients with LUAC. Our study showed that circCRIM1 inhibits the invasion and metastasis of lung adenocarcinoma cancer cells, which makes it a potential therapeutic target.


Assuntos
Adenocarcinoma de Pulmão/genética , Biomarcadores Tumorais/metabolismo , Subunidade alfa de Receptor de Fator Inibidor de Leucemia/genética , Neoplasias Pulmonares/genética , MicroRNAs/metabolismo , RNA/metabolismo , Adenocarcinoma de Pulmão/mortalidade , Adenocarcinoma de Pulmão/patologia , Animais , Linhagem Celular Tumoral , Proliferação de Células/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Subunidade alfa de Receptor de Fator Inibidor de Leucemia/metabolismo , Pulmão/patologia , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Proteínas de Membrana/genética , Camundongos Nus , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Prognóstico , RNA/genética , RNA Interferente Pequeno/metabolismo , Análise de Sobrevida , Análise Serial de Tecidos , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Life Sci ; 232: 116630, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31279783

RESUMO

AIMS: Lung adenocarcinoma consists of multiple therapeutic targets, however, patients will inevitably progress to later stage diagnosis with Tyrosine Kinase Inhibitor treatment resistance. We aim to investigate the roles of non-coding TUSC7 in ordering the cell division tendency, helping to sensitize the resistance in a miRNA incorporating way. MATERIALS AND METHODS: Online study of bioinformatics analysis, molecular experiments of luciferase test, immunofluorescence staining and qRT-PCR were applied to dig out the mechanistic regulations. KEY FINDINGS: TUSC-7 inhibited the renewal ability of adenocarcinoma stem cells, yielding to asymmetric cell splitting. Informatics analysis and the luciferase testing confirmed the 3'UTR binding site, and revealed the post-transcriptional regulation of NUMB referring to miR-146. TUSC-7 sponged miR-146 and abolished its degradation toward to NUMB, and this integrated cascade made several genes become tangled to full functionality. SIGNIFICANCE: TUSC-7 was proved to be one strong suppressive lnc-RNA in lung adenocarcinoma stem cells, functioning through inactivating NOTCH signaling, and the turbulence on division modes precisely pointed to the key mechanisms of stem cells' renewal. The decreasing of tumor suppressive miR-146 was necessary in TUSC-7 conducted renewal repression, despite it alone could also reduce the renewal efficiency, indicating that more complicated non-coding genes may be involved in its regulation.


Assuntos
Adenocarcinoma de Pulmão/metabolismo , Adenocarcinoma de Pulmão/patologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Células-Tronco Neoplásicas/metabolismo , RNA Longo não Codificante/fisiologia , Regiões 3' não Traduzidas , Adenocarcinoma de Pulmão/genética , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Humanos , Neoplasias Pulmonares/genética , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Células-Tronco Neoplásicas/patologia , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Receptores Notch/genética , Receptores Notch/metabolismo
16.
Life Sci ; 231: 116539, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31176779

RESUMO

OBJECTIVE: Although SET(I2PP2A) and miRNAs are reported to play a pivotal role in lung cancer, the underlying mechanisms have remained obscure. To address this issue, we investigated how miRNAs and SET participate in the progression of lung cancer. METHODS: miRNAs that target SET were predicted from multiple miRNA databases. Three human NSCLC cell lines and two normal lung cell lines were used to evaluate aberrant miRNA and SET expressions. A dual luciferase reporter assay system was employed to verify the interaction between miRNA and SET. Stable miRNA knockdown and SET overexpression in A549 cells were achieved through lentivirus transfection; the corresponding influences on lung cancer progression were also examined. RESULTS: In this study, A549 was the sole cell line to lack SET/TAF-Iα expression, which was inversely correlated with the up-regulation of miR-21-5p. SET was subsequently revealed as the direct target site of miR-21-5p in A549 cells. The stable miR-21-5p knockdown and SET/TAF-Iα overexpression were shown to markedly enhance the expression of SET/TAF-Iα and to inhibit the migration, invasion, proliferation as well as the in vivo tumorigenicity of A549 cells. CONCLUSION: We suggest that SET/TAF-Iα might be a tumor suppressing factor regulated by miR-21-5p in lung adenocarcinoma. This might provide a target for lung adenocarcinoma therapy.


Assuntos
Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/metabolismo , Chaperonas de Histonas/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Fatores de Transcrição/metabolismo , Células A549 , Adenocarcinoma de Pulmão/patologia , Animais , Apoptose/fisiologia , Linhagem Celular , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Progressão da Doença , Feminino , Humanos , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Invasividade Neoplásica
17.
Medicine (Baltimore) ; 98(25): e16119, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31232960

RESUMO

To compare results for radiological prediction of pathological invasiveness in lung adenocarcinoma between radiologists and a deep learning (DL) system.Ninety patients (50 men, 40 women; mean age, 66 years; range, 40-88 years) who underwent pre-operative chest computed tomography (CT) with 0.625-mm slice thickness were included in this retrospective study. Twenty-four cases of adenocarcinoma in situ (AIS), 20 cases of minimally invasive adenocarcinoma (MIA), and 46 cases of invasive adenocarcinoma (IVA) were pathologically diagnosed. Three radiologists of different levels of experience diagnosed each nodule by using previously documented CT findings to predict pathological invasiveness. DL was structured using a 3-dimensional (3D) convolutional neural network (3D-CNN) constructed with 2 successive pairs of convolution and max-pooling layers, and 2 fully connected layers. The output layer comprises 3 nodes to recognize the 3 conditions of adenocarcinoma (AIS, MIA, and IVA) or 2 nodes for 2 conditions (AIS and MIA/IVA). Results from DL and the 3 radiologists were statistically compared.No significant differences in pathological diagnostic accuracy rates were seen between DL and the 3 radiologists (P >.11). Receiver operating characteristic analysis demonstrated that area under the curve for DL (0.712) was almost the same as that for the radiologist with extensive experience (0.714; P = .98). Compared with the consensus results from radiologists, DL offered significantly inferior sensitivity (P = .0005), but significantly superior specificity (P = .02).Despite the small training data set, diagnostic performance of DL was almost the same as the radiologist with extensive experience. In particular, DL provided higher specificity than radiologists.


Assuntos
Adenocarcinoma de Pulmão/diagnóstico , Aprendizado Profundo/normas , Invasividade Neoplásica/patologia , Adenocarcinoma de Pulmão/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Área Sob a Curva , Aprendizado Profundo/tendências , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Curva ROC
18.
J Cancer Res Clin Oncol ; 145(7): 1681-1693, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31175464

RESUMO

OBJECTIVE: To study integrin α6 expression in lung adenocarcinoma tissue through comparison with matching adjacent non-cancerous tissues as well as elucidating the correlation between integrin α6 expression with the clinical parameters of lung adenocarcinoma. We also explore the signal pathways associated with integrin α6 up-regulation. METHODS: The clinical data, cancer tissues, and adjacent non-cancerous tissues of 30 patients diagnosed with lung adenocarcinoma were collected from Taizhou Hospital in Zhejiang Province, China, in 2010. The protein levels of integrin α6 were determined by immunohistochemistry methods. mRNA data of 85 lung adenocarcinoma tissues and 14 normal tissues as well as clinical results were collected from GEO30219. We also collected mRNA data of 533 lung adenocarcinoma tissues and 59 normal tissues as well as the clinical results of 522 patients with lung adenocarcinoma from the Cancer Genome Atlas (TCGA) database. The differences in protein and mRNA levels in cancer tissues and non-cancerous tissues were analyzed, and we subsequently investigated the association between integrin α6 expression and key parameters indicating lung adenocarcinoma progression and overall survival rate. Additionally, the possible pathways involved in the up-regulation of integrin α6 were analyzed by GSEA. RESULTS: The protein levels of integrin α6 in lung adenocarcinoma tissues were significantly higher than those in adjacent tissues (p < 0.01), and were positively correlated with the grade and T stage of lung adenocarcinoma (p < 0.05). Patients with low integrin α6 protein levels had higher survival rates (p < 0.05). The analysis of gene chip data from the TCGA database also showed that the integrin α6 mRNA level was significantly correlated with T stage (p < 0.05), overall survival (OS) rate (p < 0.01), and disease-free survival (DFS) rate (p = 0.005). GSEA gene enrichment analysis identified a series of pathways that may be associated with integrin α6 up-regulation, including the AGR, PYK2, ECM, and PTEN pathways. CONCLUSION: Integrin α6 plays an important role in the occurrence and progression of lung adenocarcinoma and may act as a prognostic predictor of lung adenocarcinoma in patients. Based on the results of the present study, integrin α6 may be a potential target gene for the treatment of lung adenocarcinoma.


Assuntos
Adenocarcinoma de Pulmão/metabolismo , Integrina alfa6/biossíntese , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Biologia Computacional , Humanos , Imuno-Histoquímica , Integrina alfa6/genética , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Prognóstico , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais , Taxa de Sobrevida , Análise Serial de Tecidos , Regulação para Cima
19.
Cancer Imaging ; 19(1): 34, 2019 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-31174617

RESUMO

OBJECTIVE: To identify imaging markers that reflect the epidermal growth factor receptor (EGFR) mutation status by comparing computed tomography (CT) imaging-based histogram features between bone metastases with and without EGFR mutation in patients with primary lung adenocarcinoma. MATERIALS AND METHODS: This retrospective study included 57 patients, with pathologically confirmed bone metastasis of primary lung adenocarcinoma. EGFR mutation status of bone metastases was confirmed by gene detection. The CT imaging of the metastatic bone lesions which were obtained between June 2014 and December 2017 were collected and analyzed. A total of 42 CT imaging-based histogram features were automatically extracted. Feature selection was conducted using Student's t-test, Mann-Whitney U test, single-factor logistic regression analysis and Spearman correlation analysis. A receiver operating characteristic (ROC) curve was plotted to compare the effectiveness of features in distinguishing between EGFR(+) and EGFR(-) groups. DeLong's test was used to analyze the differences between the area under the curve (AUC) values. RESULTS: Three histogram features, namely range, skewness, and quantile 0.975 were significantly associated with EGFR mutation status. After combining these three features and combining range and skewness, we obtained the same AUC values, sensitivity and specificity. Meanwhile, the highest AUC value was achieved (AUC 0.783), which also had a higher sensitivity (0.708) and specificity (0.788). The differences between AUC values of the three features and their various combinations were statistically insignificant. CONCLUSION: CT imaging-based histogram features of bone metastases with and without EGFR mutation in patients with primary lung adenocarcinoma were identified, and they may contribute to diagnosis and prediction of EGFR mutation status.


Assuntos
Adenocarcinoma de Pulmão/diagnóstico por imagem , Neoplasias Ósseas/diagnóstico por imagem , Neoplasias Pulmonares/diagnóstico por imagem , Mutação , Tomografia Computadorizada por Raios X/métodos , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Ósseas/genética , Neoplasias Ósseas/secundário , Receptores ErbB/genética , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade
20.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 35(5): 425-433, 2019 May.
Artigo em Chinês | MEDLINE | ID: mdl-31223112

RESUMO

Objective To investigate the expression and clinical significance of whey acidic protein (WAP) 4-disulfide core domain 2/human epididymis protein 4 (WFDC2/HE4) in lung adenocarcinoma. Methods The expression of WFDC2 in normal lung tissues and lung adenocarcinoma tissues, the correlation between WFDC2 and the prognosis survival in patients with lung adenocarcinoma were analyzed using the BioGPS database, GEPIA database, Oncomine database and Kaplan-Meier Plotter databases. The expression of WFDC2 in cancer tissue T cells and B cells was analyzed using the Cancer Cell Line Encyclopedia (CCLE). The WFDC2-related genes and functional annotations of their gene ontology (GO), the pathway enrichment of Kyoto Gene and Genomic Encyclopedia (KEGG) were analyzed using the STRING database. The co-expression relationship, correlation and significance of WFDC2-related genes in lung adenocarcinoma were analyzed using the cBioPortal database. The expression of WFDC2 in immune infiltrates and its implication to survival prognosis in the patients with lung adenocarcinoma were analyzed using the Tumor Immune Estimation Resource (TIMER) database. Results BioGPS database analysis showed that the expression of WFDC2 was low in normal lung tissues, but none in T cells and B cells of normal human tissues. GEPIA database analysis showed that the expression of WFDC2 was higher in lung adenocarcinoma compared with normal lung tissues. Four hundred and fourteen samples of differential expression of WFDC2 were obtained from Oncomine database. Nineteen of them had increased WFDC2 expression with four in lung adenocarcinoma; fifteen of them had decreased WFDC2 expression with one in lung adenocarcinoma. Meta-analysis of 4 studies meeting the setting conditions showed that the expression level of WFDC2 was high in lung adenocarcinoma tissues. Kaplan-Meier Plotter database results showed that the overall survival (OS) time of patients with lung adenocarcinoma in the high WFDC2 expression group was significantly longer than that in the low WFDC2 expression group. CCLE analysis showed that the expression of WFDC2 in cancer tissue T cells and B cells was significantly higher than that in normal tissues. String database analysis showed that there were 30 genes associated with WFDC2, which were involved in 4 signaling pathways. The classification results from GO annotation indicated the enrichment in 4 cell components, 8 molecular functions, and 27 biological processes. The cBioPortal database showed that the correlation and difference between secretory leukocyte protease inhibitor (SLPI) and WFDC2 in lung adenocarcinoma were markedly significant (Pearson=0.26; Spearman=0.46; P=6.20E-28). TIMER database analysis showed that B cells with high expression of WFDC2 in the immune microenvironment significantly prolonged the survival prognosis of patients with lung adenocarcinoma for 1 year, 3 years, 5 years and 10 years. Conclusion WFDC2 is highly expressed in lung adenocarcinoma tissues with the anti-tumor immunosuppressive effect, which can significantly prolong OS of lung adenocarcinoma patients and be used as a candidate marker for investigating clinical prognosis of lung adenocarcinoma.


Assuntos
Adenocarcinoma de Pulmão/genética , Linfócitos B/metabolismo , Neoplasias Pulmonares/genética , Proteínas/genética , Taxa de Sobrevida , Humanos , Prognóstico , Linfócitos T , Microambiente Tumoral
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