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1.
Nat Commun ; 11(1): 4913, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-33004813

RESUMO

Reprograming of proline metabolism is critical for tumor growth. Here we show that PINCH-1 is highly expressed in lung adenocarcinoma and promotes proline synthesis through regulation of mitochondrial dynamics. Knockout (KO) of PINCH-1 increases dynamin-related protein 1 (DRP1) expression and mitochondrial fragmentation, which suppresses kindlin-2 mitochondrial translocation and interaction with pyrroline-5-carboxylate reductase 1 (PYCR1), resulting in inhibition of proline synthesis and cell proliferation. Depletion of DRP1 reverses PINCH-1 deficiency-induced defects on mitochondrial dynamics, proline synthesis and cell proliferation. Furthermore, overexpression of PYCR1 in PINCH-1 KO cells restores proline synthesis and cell proliferation, and suppresses DRP1 expression and mitochondrial fragmentation. Finally, ablation of PINCH-1 from lung adenocarcinoma in mouse increases DRP1 expression and inhibits PYCR1 expression, proline synthesis, fibrosis and tumor growth. Our results identify a signaling axis consisting of PINCH-1, DRP1 and PYCR1 that regulates mitochondrial dynamics and proline synthesis, and suggest an attractive strategy for alleviation of tumor growth.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adenocarcinoma de Pulmão/patologia , Proteínas com Domínio LIM/metabolismo , Neoplasias Pulmonares/patologia , Proteínas de Membrana/metabolismo , Células A549 , Proteínas Adaptadoras de Transdução de Sinal/genética , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Proliferação de Células/genética , Proteínas do Citoesqueleto/metabolismo , Modelos Animais de Doenças , Dinaminas/metabolismo , Feminino , Técnicas de Inativação de Genes , Humanos , Proteínas com Domínio LIM/genética , Pulmão/citologia , Pulmão/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Masculino , Proteínas de Membrana/genética , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Mitocôndrias/metabolismo , Dinâmica Mitocondrial , Proteínas Musculares/metabolismo , Proteínas de Neoplasias/metabolismo , Prolina/biossíntese , Proteínas Proto-Oncogênicas p21(ras)/genética , Pirrolina Carboxilato Redutases/metabolismo , Análise de Sobrevida
2.
BMC Bioinformatics ; 21(Suppl 14): 368, 2020 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-32998690

RESUMO

BACKGROUND: Lung cancer is the leading cause of the largest number of deaths worldwide and lung adenocarcinoma is the most common form of lung cancer. In order to understand the molecular basis of lung adenocarcinoma, integrative analysis have been performed by using genomics, transcriptomics, epigenomics, proteomics and clinical data. Besides, molecular prognostic signatures have been generated for lung adenocarcinoma by using gene expression levels in tumor samples. However, we need signatures including different types of molecular data, even cohort or patient-based biomarkers which are the candidates of molecular targeting. RESULTS: We built an R pipeline to carry out an integrated meta-analysis of the genomic alterations including single-nucleotide variations and the copy number variations, transcriptomics variations through RNA-seq and clinical data of patients with lung adenocarcinoma in The Cancer Genome Atlas project. We integrated significant genes including single-nucleotide variations or the copy number variations, differentially expressed genes and those in active subnetworks to construct a prognosis signature. Cox proportional hazards model with Lasso penalty and LOOCV was used to identify best gene signature among different gene categories. We determined a 12-gene signature (BCHE, CCNA1, CYP24A1, DEPTOR, MASP2, MGLL, MYO1A, PODXL2, RAPGEF3, SGK2, TNNI2, ZBTB16) for prognostic risk prediction based on overall survival time of the patients with lung adenocarcinoma. The patients in both training and test data were clustered into high-risk and low-risk groups by using risk scores of the patients calculated based on selected gene signature. The overall survival probability of these risk groups was highly significantly different for both training and test datasets. CONCLUSIONS: This 12-gene signature could predict the prognostic risk of the patients with lung adenocarcinoma in TCGA and they are potential predictors for the survival-based risk clustering of the patients with lung adenocarcinoma. These genes can be used to cluster patients based on molecular nature and the best candidates of drugs for the patient clusters can be proposed. These genes also have a high potential for targeted cancer therapy of patients with lung adenocarcinoma.


Assuntos
Adenocarcinoma de Pulmão/patologia , Genômica/métodos , Neoplasias Pulmonares/patologia , Transcriptoma , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/mortalidade , Área Sob a Curva , Análise por Conglomerados , Variações do Número de Cópias de DNA , Bases de Dados Genéticas , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Estadiamento de Neoplasias , Prognóstico , Modelos de Riscos Proporcionais , Mapas de Interação de Proteínas/genética , Curva ROC , Fatores de Risco , Taxa de Sobrevida
3.
Medicine (Baltimore) ; 99(40): e22483, 2020 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-33019442

RESUMO

INTRODUCTION: Epithelial-myoepithelial carcinoma (EMC) is a rare, low-grade malignancy that occurs primarily in the parotid gland and is most common in women aged 60 to 70 years. Cases of parotid EMC have been reported previously. Furthermore, some studies have suggested an increased risk of salivary gland tumors with secondary primary malignancies. There have been few reports of parotid EMC with other primary tumors. PATIENT CONCERNS: A 62-year-old Chinese man visited the hospital with a complaint of a mass on his left cheek that had persisted for 20 years. Routine pulmonary computed tomography showed a local ground glass shadow in the lower lobe of the right lung. DIAGNOSIS: The pathological diagnosis of lung was right lower lobe lung adenocarcinoma (pT1N0). Immunohistochemistry analysis showed that cytokeratin (CK)-7, NapsinA, and thyroid transcription factor-1 tested positive, while CK5/6, P40, and ALKD5F3 tested negative. The pathological diagnosis of left parotid gland: EMC. On immunohistochemistry staining, the outer cells expressed myoepithelial markers, such as CK5/6, P63, smooth muscle actin, while the inner cells expressed glandular epithelial markers, such as low-molecular-weight CK7 and CK8. INTERVENTIONS: The patient underwent resection of the lung and parotid tumors, and received preventive radiotherapy in the parotid gland area. OUTCOMES: The patient is in good condition. No symptom recurrence, distant metastatic spread or significant toxicity occurred during or after the treatment. The patient remains under regular surveillance. CONCLUSION: We report a rare case of parotid EMC with a second primary lung adenocarcinoma. This case is the third case of primary lung cancer associated with parotid EMC reported to date and the first to be reported in nearly 30 years.


Assuntos
Adenocarcinoma de Pulmão/patologia , Neoplasias Pulmonares/patologia , Mioepitelioma/patologia , Segunda Neoplasia Primária/patologia , Neoplasias Parotídeas/patologia , Adenocarcinoma de Pulmão/cirurgia , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/cirurgia , Masculino , Pessoa de Meia-Idade , Mioepitelioma/radioterapia , Mioepitelioma/cirurgia , Segunda Neoplasia Primária/radioterapia , Segunda Neoplasia Primária/cirurgia , Neoplasias Parotídeas/radioterapia , Neoplasias Parotídeas/cirurgia
4.
Anticancer Res ; 40(10): 5659-5666, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988890

RESUMO

BACKGROUND/AIM: Long interspersed nuclear element-1 (LINE-1) methylation status is a marker for global DNA methylation. However, the relationship between LINE-1 methylation and the biology of lung adenocarcinoma remains unclear. Here, we aimed to examine the role of LINE-1 in lung cancer. MATERIALS AND METHODS: LINE-1 methylation levels were quantified by bisulfite pyrosequencing of resected tumor specimens from 162 patients with lung adenocarcinoma. The relationships of LINE-1 methylation with clinicopathological factors, gene mutations, and Ki-67 immunoreactivity were investigated. RESULTS: LINE-1 hypomethylation was associated with tumor invasion and advanced stage. TP53 mutations were more frequently detected in the LINE-1 hypomethylation group than in the hypermethylation group. LINE-1 hypomethylation was associated with poor recurrence-free survival, high maximum standardized uptake value in positron-emission tomography, and high Ki-67 expression in tumors. CONCLUSION: LINE-1 hypomethylation was associated with high-grade malignancy and poor prognosis in lung adenocarcinoma, but was not related to driver mutations.


Assuntos
Adenocarcinoma de Pulmão/genética , Biomarcadores Tumorais/genética , Metilação de DNA/genética , Elementos Nucleotídeos Longos e Dispersos/genética , Adenocarcinoma de Pulmão/patologia , Adulto , Idoso , Núcleo Celular/genética , Proliferação de Células/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Antígeno Ki-67/genética , Masculino , Pessoa de Meia-Idade , Mutação/genética , Prognóstico , Proteína Supressora de Tumor p53/genética
5.
Medicine (Baltimore) ; 99(36): e21453, 2020 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-32898994

RESUMO

To analyze the relationship between pathologic subtype and lymph node metastasis for lung adenocarcinomas of ≤3 cm diameter.We retrospectively studied 384 patients with operable lung adenocarcinomas of ≤3 cm diameter that had been radically resected by lobectomy or anatomic segmentectomy with systematic nodal dissection, at the Fujian Medical University Union Hospital between March 2014 and March 2016.Lymph node metastasis pN1 + pN2 (pN+) was found in 2 of 104 (1.9%) patients with tumor diameter ≤1.0 cm, 12 of 159 (7.5%) patients with tumor diameter >1.0 cm but ≤2.0 cm, and 35 of 121 (28.9%) patients with tumor size >2.0 cm but ≤3.0 cm (P < .01). Lymph node metastasis pN+ was found in 19 of 53 (35.8%) patients with visceral invasion pleural (VIP) and 30 of 331 (9.0%) patients without VIP (P < .05). It was also found in 16 of 51 (31.3%) patients with high serum CEA concentrations and 28 of 297 (9.4%) patients with normal concentrations (P < .05). In a multivariate analysis, tumor diameter, VIP, high serum CEA concentration, and pathologic subtype were significant risk factors. The prevalences of lymph node metastasis pN+ were: 0.0% (0/2), 0.0% (0/89), 3.2% (1/31), 16.2% (34/209), 7.7% (1/13), 46.7% (7/15), 100% (4/4), and 11.8% (2/17) for adenocarcinoma in situ (AIS); minimally invasive adenocarcinoma (MIA); predominantly lepidic (LEP), acinar (ACI), papillary, solid (SOL), and micropapillary (MIP) tumors; and variants of invasive adenocarcinoma, respectively (P < .05). For predominant SOL and MIP tumors, the prevalences of lymph node involvement were significantly higher than for the other subtypes.We have shown that lymph node metastasis in patients with tumor diameter ≤3 cm differs according to lung adenocarcinoma subtype. AIS and MIA were not associated with lymph node metastasis; therefore, systematic nodal dissection may be unnecessary. The prevalence of lymph node metastasis rate was low for LEP, suggesting that systemic lymph node sampling is sufficient. In contrast, for other pathologic subtypes, including SOL and MIP, systematic lymph node dissection should be performed.


Assuntos
Adenocarcinoma de Pulmão/patologia , Neoplasias Pulmonares/patologia , Metástase Linfática/patologia , Adenocarcinoma de Pulmão/cirurgia , Feminino , Humanos , Neoplasias Pulmonares/cirurgia , Excisão de Linfonodo , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
6.
Medicine (Baltimore) ; 99(36): e22128, 2020 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-32899099

RESUMO

RATIONALE: Brain metastasis (BM) is a serious complication in non-small cell lung cancer (NSCLC) patients. Pemetrexed is one of the preferred agents in nonsquamous NSCLC with BM; however, the traditional chemotherapy demonstrated limited efficacy partly due to drug resistance and the blood-brain barrier. PATIENT CONCERNS: A 52-year-old male non-smoker was admitted for irritating cough, chest distress, and back pain. DIAGNOSES: Epidermal growth factor receptor wild-type, anaplastic lymphoma kinase-negative primary lung adenocarcinoma with an asymptomatic solitary BM (cTxNxM1b, IVA). INTERVENTIONS: Pemetrexed (500 mg/m of body surface area) and carboplatin (area under the curve of 5) were firstly administered every 3 weeks for 3 cycles, followed by pemetrexed/carboplatin plus anlotinib (12 mg daily; 2 weeks on and 1 week off) for another 3 cycles. Then maintenance anlotinib monotherapy was continued for a year, without unacceptable adverse events. OUTCOMES: The BM was slightly enlarged after 3 cycles of pemetrexed/carboplatin; however, a complete remission was achieved after the combination therapy. His intracranial progression-free survival was more than 2 years. LESSONS: Pemetrexed/carboplatin plus anlotinib could be considered for the treatment of epidermal growth factor receptor wild-type, anaplastic lymphoma kinase-negative lung adenocarcinoma with BM. Further well-designed trials are warranted to verify this occasional finding.


Assuntos
Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/secundário , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Quinase do Linfoma Anaplásico/metabolismo , Carboplatina/uso terapêutico , Receptores ErbB/genética , Receptores ErbB/metabolismo , Humanos , Indóis/uso terapêutico , Masculino , Pessoa de Meia-Idade , Pemetrexede/uso terapêutico , Quinolinas/uso terapêutico
7.
Nat Commun ; 11(1): 4520, 2020 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-32908154

RESUMO

Tumor extracellular matrix has been associated with drug resistance and immune suppression. Here, proteomic and RNA profiling reveal increased collagen levels in lung tumors resistant to PD-1/PD-L1 blockade. Additionally, elevated collagen correlates with decreased total CD8+ T cells and increased exhausted CD8+ T cell subpopulations in murine and human lung tumors. Collagen-induced T cell exhaustion occurs through the receptor LAIR1, which is upregulated following CD18 interaction with collagen, and induces T cell exhaustion through SHP-1. Reduction in tumor collagen deposition through LOXL2 suppression increases T cell infiltration, diminishes exhausted T cells, and abrogates resistance to anti-PD-L1. Abrogating LAIR1 immunosuppression through LAIR2 overexpression or SHP-1 inhibition sensitizes resistant lung tumors to anti-PD-1. Clinically, increased collagen, LAIR1, and TIM-3 expression in melanoma patients treated with PD-1 blockade predict poorer survival and response. Our study identifies collagen and LAIR1 as potential markers for immunotherapy resistance and validates multiple promising therapeutic combinations.


Assuntos
Adenocarcinoma de Pulmão/tratamento farmacológico , Antineoplásicos Imunológicos/farmacologia , Linfócitos T CD8-Positivos/imunologia , Colágeno/metabolismo , Resistencia a Medicamentos Antineoplásicos/imunologia , Neoplasias Pulmonares/tratamento farmacológico , Receptores Imunológicos/metabolismo , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/imunologia , Adenocarcinoma de Pulmão/patologia , Aminoácido Oxirredutases/genética , Aminoácido Oxirredutases/metabolismo , Animais , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Lewis/tratamento farmacológico , Carcinoma Pulmonar de Lewis/imunologia , Carcinoma Pulmonar de Lewis/patologia , Linhagem Celular Tumoral , Conjuntos de Dados como Assunto , Modelos Animais de Doenças , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/imunologia , Matriz Extracelular/patologia , Feminino , Técnicas de Silenciamento de Genes , Células HEK293 , Receptor Celular 2 do Vírus da Hepatite A/metabolismo , Humanos , Pulmão/imunologia , Pulmão/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Camundongos Transgênicos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Proteína Tirosina Fosfatase não Receptora Tipo 6/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , RNA-Seq , Receptores Imunológicos/genética
8.
Anticancer Res ; 40(10): 5361-5369, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988855

RESUMO

BACKGROUND/AIM: The aim of this study was to evaluate the role of toll-like receptor 2 (TLR2) in the proliferation of human lung cancer cells and identify the signaling pathway that mediates this effect. MATERIALS AND METHODS: Adenocarcinoma (A549 and H1650) and adenosquamous (H125) cells were treated with increasing doses of Pam3CSK4, a TLR2 agonist. Cell proliferation and NF-ĸB activation were evaluated. NF-ĸB was inhibited prior to treatment with Pam3CSK4 and proliferation was assessed. RESULTS: TLR2 expression was significantly higher in A549 and H1650 cells compared to H125 cells (p<0.001). TLR2 stimulation induced proliferation in adenocarcinoma cells only and led to a corresponding increase in NF-ĸB activity (p<0.05). Inhibition of NF-ĸB prior to treatment with Pam3CSK4 attenuated this proliferative response. CONCLUSION: TLR2 activation induced proliferation of lung adenocarcinoma cells through activation of NF-ĸB. Thus, the TLR2 signaling pathway may be a potential therapeutic target in lung adenocarcinoma.


Assuntos
Adenocarcinoma de Pulmão/tratamento farmacológico , Lipopeptídeos/farmacologia , Receptor 2 Toll-Like/genética , Células A549 , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , NF-kappa B/genética , Receptor 2 Toll-Like/agonistas
9.
Medicine (Baltimore) ; 99(31): e20076, 2020 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-32756072

RESUMO

C-terminal binding protein-2 (CtBP2) a transcriptional corepressor, has been reported to involve in tumorigenesis and progression and predict a poor prognosis in several human cancers. However, few studies on CtBP2 in lung cancer tissues have been performed. In the present study, we first explored the CtBP2 gene expression profile from the the cancer genome atlas (TCGA) datasets, then western blot analysis and immunohistochemistry were performed to investigate and verified whether lung adenocarcinoma (LUAD) tissues exhibit deregulated CtBP2 expression. We evaluated the correlations between CtBP2 expression and the clinicopathological characteristics, and Kaplan-Meier survival analyses were performed to estimate the effect of CtBP2 expression on prognosis of LUAD patients. The results revealed that CtBP2 expression was significantly upregulated in LUAD tissues compared with normal lung tissues. Furthermore, increasing CtBP2 expression in LUAD was significantly associated with tumor differentiation (P = .028), tumor node metastasis (TNM) stage (P = .042). CtBP2 expression was significantly correlated with LUAD patients' survival (P = .028). In conclusion, the present study revealed that CtBP2 protein is a novel prognostic marker for LUAD. A further large-scale study is needed to confirm the present results.


Assuntos
Adenocarcinoma de Pulmão/diagnóstico , Oxirredutases do Álcool/análise , Proteínas Correpressoras/análise , Neoplasias Pulmonares/diagnóstico , Adenocarcinoma de Pulmão/química , Adenocarcinoma de Pulmão/mortalidade , Adenocarcinoma de Pulmão/patologia , Biomarcadores Tumorais/análise , Western Blotting , Feminino , Humanos , Pulmão/química , Neoplasias Pulmonares/química , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Prognóstico , Reação em Cadeia da Polimerase em Tempo Real , Análise de Sobrevida
10.
Life Sci ; 259: 118157, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32735888

RESUMO

AIMS: Previous studies have demonstrated that circular RNAs play significant roles in several tumors, including lung adenocarcinoma; however, specific biological functions and molecular mechanisms underlying this process remain unclear. MATERIALS AND METHODS: Here, we conducted real-time quantitative PCR (qRT-PCR) to measure hsa_circ_0001588 expression levels in 60 paired lung adenocarcinoma tissues and cell lines. Furthermore, the association between hsa_circ_0001588 and clinical features of lung adenocarcinoma was analyzed. Functional experiments were conducted to assess the influence of hsa_circ_0001588 on proliferation, migration, and invasion in lung adenocarcinoma cells. We detected possible downstream targets of hsa_circ_0001588 using bioinformatics analysis. Luciferase reporter assays, qRT-PCR, and western blotting assays were performed to verify the molecular mechanism underlying hsa_circ_0001588 functions. KEY FINDINGS: We found that hsa_circ_0001588 was prominently upregulated in lung adenocarcinoma tissues and cell lines; elevated expression of hsa_circ_0001588 was positively correlated with poor clinicopathological features of lung adenocarcinoma. Functional experiments revealed that hsa_circ_0001588 acts as an oncogene to promote the proliferation, migration, and invasion of lung adenocarcinoma in vitro. Mechanistically, hsa_circ_0001588 promoted the proliferation, migration, and metastasis of lung adenocarcinoma by binding to miR-524-3p to promote nucleus accumbens-associated protein 1(NACC1) expression. SIGNIFICANCE: Together, our results revealed that hsa_circ_0001588 upregulated the expression of NACC1 by combining with miR-524-3p to promote the proliferation, migration, and invasion of lung adenocarcinoma cells, suggesting that hsa_circ_0001588 may be an underlying therapeutic target for lung adenocarcinoma.


Assuntos
Adenocarcinoma de Pulmão/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , MicroRNAs/genética , Proteínas de Neoplasias/genética , RNA Circular/genética , RNA Neoplásico/genética , Proteínas Repressoras/genética , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Animais , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Biologia Computacional , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Camundongos , Invasividade Neoplásica/genética , Reação em Cadeia da Polimerase , Prognóstico , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Nat Commun ; 11(1): 3556, 2020 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-32678093

RESUMO

Early cancer detection greatly increases the chances for successful treatment, but available diagnostics for some tumours, including lung adenocarcinoma (LA), are limited. An ideal early-stage diagnosis of LA for large-scale clinical use must address quick detection, low invasiveness, and high performance. Here, we conduct machine learning of serum metabolic patterns to detect early-stage LA. We extract direct metabolic patterns by the optimized ferric particle-assisted laser desorption/ionization mass spectrometry within 1 s using only 50 nL of serum. We define a metabolic range of 100-400 Da with 143 m/z features. We diagnose early-stage LA with sensitivity~70-90% and specificity~90-93% through the sparse regression machine learning of patterns. We identify a biomarker panel of seven metabolites and relevant pathways to distinguish early-stage LA from controls (p < 0.05). Our approach advances the design of metabolic analysis for early cancer detection and holds promise as an efficient test for low-cost rollout to clinics.


Assuntos
Adenocarcinoma de Pulmão/sangue , Biomarcadores Tumorais/sangue , Neoplasias Pulmonares/sangue , Aprendizado de Máquina , Adenocarcinoma de Pulmão/metabolismo , Adenocarcinoma de Pulmão/patologia , Detecção Precoce de Câncer , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Metabolômica , Sensibilidade e Especificidade , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos
13.
J Nat Med ; 74(4): 777-787, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32666278

RESUMO

Lung adenocarcinoma (LUAD) is the top prevalent histological kind of lung cancer worldwide. Recent evidences have demonstrated that Sauchinone plays an anticancer role in tumor cell invasion and migration. Therefore, we performed this investigation to explain the potential role of Sauchinone in LUAD as well as the potential mechanism involved. Cell counting kit 8 (CCK-8) and transwell experiments were implemented to measure the proliferative, invasive and migratory abilities of LUAD cells. qRT-PCR and Western blot were performed to detect the transfection efficiency of si-EIF4EBP1s. Additionally, Western blot was also implemented to evaluate the effect of Sauchinone on EIF4EBP1 expression level as well as cell cycle-related proteins. Our findings showed that Sauchinone remarkably suppressed the proliferative ability of LUAD cells in a dose-dependent and time-dependent manner. EIF4EBP1 was a candidate target gene of Sauchinone. EIF4EBP1 expression was increased in LUAD tissues, and its high expression induced a poorer prognosis of LUAD patients. EIF4EBP1 expression was positively associated with cell cycle in LUAD. Sauchinone treatment attenuated EIF4EBP1 expression and cell cycle-related protein levels. Knockdown of EIF4EBP1 repressed the proliferation, invasion and migration of LUAD cells; furthermore, Sauchinone stimulation enforced its inhibitory effect. Meanwhile, the treatment of Sauchinone intensified the arrest of cell cycle induced by EIF4EBP1 knockdown. To sum up, our discovery indicated that Sauchinone exerts an anticancer role through down-regulating EIF4EBP1 and mediating cell cycle in LUAD.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/uso terapêutico , Adenocarcinoma de Pulmão/tratamento farmacológico , Benzopiranos/uso terapêutico , Proteínas de Ciclo Celular/uso terapêutico , Dioxóis/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Proteínas Adaptadoras de Transdução de Sinal/farmacologia , Adenocarcinoma de Pulmão/patologia , Benzopiranos/farmacologia , Proteínas de Ciclo Celular/farmacologia , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Dioxóis/farmacologia , Regulação para Baixo , Humanos , Neoplasias Pulmonares/patologia , Invasividade Neoplásica , Estudos Prospectivos , Transfecção
14.
Anticancer Res ; 40(8): 4401-4404, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32727769

RESUMO

BACKGROUND: The occurrence of lung adenocarcinoma metastasizing to the pancreas is overall rare and can histologically imitate primary pancreatic ductal carcinoma (PDAC). CASE REPORT: This is a case report of a 70-year-old female with a history of surgically resected right lung adenocarcinoma presenting for routine follow up without symptoms. CT scans revealed a pancreatic cystic mass with ductal dilatation that was sampled via endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) and thought to be a primary pancreatic mucinous neoplasm with high grade dysplasia suspicious for carcinoma based on smear cytology. On repeat EUS-FNA and biopsy (FNB) with additional immunohistochemical testing for lung adenocarcinoma markers thyroid transcription factor (TTF1) and Napsin A and molecular testing, the lesion was identified as a metastasis of lung adenocarcinoma with an epidermal growth factor receptor (EGFR L858R) mutation; subsequently, the patient underwent targeted therapy that yielded an almost complete response. CONCLUSION: To the best of our knowledge, this is the first documented case in English literature of a lung adenocarcinoma metastasis to the pancreas mimicking a pancreatic primary neoplasm and highlights the potential pitfalls of EUS-FNA for the diagnosis of certain metastases to the pancreas.


Assuntos
Adenocarcinoma de Pulmão/diagnóstico por imagem , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pancreáticas/secundário , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/metabolismo , Adenocarcinoma de Pulmão/patologia , Idoso , Biomarcadores/metabolismo , Carcinoma Ductal Pancreático/diagnóstico por imagem , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Diagnóstico Diferencial , Aspiração por Agulha Fina Guiada por Ultrassom Endoscópico , Receptores ErbB/genética , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Mutação , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Tomografia Computadorizada por Raios X
15.
Hosp. domic ; 4(2): 39-44, abr.-jun. 2020.
Artigo em Espanhol | IBECS | ID: ibc-193389

RESUMO

Presentamos el caso de un paciente varón de 67 años diagnosticado de adenocarcinoma de pulmón en estadio IV con dolor irruptivo oncológico (DIO) de difícil control. Durante el transcurso de la enfermedad el paciente necesitó varios ingresos por complicaciones, siendo la más común el mal control del DIO. Tras varios cambios en la pauta analgésica (rotación de opioides, cambios en tratamientos coadyuvantes y vías de administración), se consiguió buen control del dolor a pesar de progresión de la enfermedad de base. Finalmente, el paciente precisó ingreso hospitalario ante deterioro del estado general y claudicación familiar. Ante mal pronóstico, el equipo de Cuidados Paliativos y los familiares decidieron instaurar tratamiento con medidas de confort. De la relevancia del caso clínico que aportamos se concluye que es necesaria la existencia de equipos multidisciplinares formados y entrenados en este ámbito para un buen manejo terapéutico y una mejor calidad de vida en los pacientes


We present the case of a 67-year-old male with stage IV adenocarcinoma lung cancer who presented difficult control of breakthrough cancer pain. During the course of the disease, the patient had to be hospitalized several times due to complications. The most common complication was breakthrough cancer pain. After many changes in the analgesic treatment (opioid rotation, changes in coadjuvant drugs and routes of administration), good control of analgesic pain was achieved despite the progression of this underlying disease. Finally, the patient required being hospitalized due to deterioration of the general condition and family claudication. Faced with a por prognosis, the Palliative Care and Oncology team decided to establish treatment with comfort measures. We can conclude that the existence of multidisciplinary trained team is necessary for good therapeutic management and a better quality of life in patients


Assuntos
Humanos , Masculino , Idoso , Adenocarcinoma de Pulmão/patologia , Neoplasias Pulmonares/patologia , Dor do Câncer/tratamento farmacológico , Dor Irruptiva/tratamento farmacológico , Neoplasias das Glândulas Suprarrenais/secundário , Neoplasias das Glândulas Suprarrenais/diagnóstico por imagem , Adenocarcinoma de Pulmão/diagnóstico por imagem , Neoplasias Pulmonares/diagnóstico por imagem , Estadiamento de Neoplasias
16.
Medicine (Baltimore) ; 99(26): e20594, 2020 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-32590735

RESUMO

The recently published 8th edition of the tumor node and metastasis Classification of Lung Cancer proposes using the maximum dimension of the solid component of a ground glass nodule (GGN) for the T categorization. However, few studies have investigated the collection of this information when using mediastinal window settings. In this study, we evaluated tumor measurement data obtained from computed tomography (CT) scans when using mediastinal window settings.This study included 202 selected patients with persistent, partly solid GGNs detected on thin-slice CT after surgical treatment between 2004 and 2013. We compared the differences in tumor diameters measured by 2 different radiologists using a repeated-measures analysis of variance. We divided the patients into 2 groups based on the clinical T stage (T1a+T1b vs T1c) and estimated the probability of overall survival (OS) and disease-free survival (DFS) using Kaplan-Meier curves.The study included 94 male and 108 female patients. The inter-reviewer differences between tumor diameters were significantly smaller when the consolidation to maximum tumor diameter ratio was ≤0.5. The 2 clinical groups classified by clinical T stage differed significantly with respect to DFS when using the mediastinal window settings. However, no significant differences in OS or DFS were observed when using the lung window setting.Our study yielded 2 major findings. First, the diameters of GGNs could be measured more accurately using the mediastinal window setting. Second, measurements obtained using the mediastinal window setting more clearly depicted the effect of clinical T stage on DFS.


Assuntos
Adenocarcinoma de Pulmão/diagnóstico por imagem , Neoplasias Pulmonares/diagnóstico por imagem , Tomografia Computadorizada por Raios X/métodos , Adenocarcinoma de Pulmão/mortalidade , Adenocarcinoma de Pulmão/patologia , Idoso , Intervalo Livre de Doença , Feminino , Humanos , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Invasividade Neoplásica , Estudos Retrospectivos
17.
Mol Carcinog ; 59(8): 1000-1011, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32511815

RESUMO

Despite an overall decline in the incidence of new cases, lung adenocarcinoma continues to be a leading cause of cancer death worldwide. Due to lack of gene expression signatures for risk and prognosis stratification of lung adenocarcinoma, identifying novel molecular biomarkers and therapeutic targets may potentially improve lung adenocarcinoma prognosis and treatment. In the current study, we investigate the role of USP53 in lung adenocarcinoma. Bioinformatics analysis, quantitative reverse transcription polymerase chain reaction, and Western blot were employed to examine patterns of gene expression in human lung adenocarcinoma database, patient samples, and cancer cell lines. Stable cell lines were produced by transducing with USP53 overexpression vector or short hairpin RNA targeting USP53 in the presence and absence of AKT pathway inhibitor LY294002. Functional assays were carried out to examine the impact of USP53 and AKT pathway on lung adenocarcinoma cell viability, apoptosis, and glycolysis in vitro, as well as tumor growth in vivo. The correlation between USP53 and FKBP51 was measured by coimmunoprecipitation and ubiquitination assay. Decreased USP53 levels are a reliable marker of lung adenocarcinoma across published datasets, clinical samples, and cell culture lines. Low USP53 expression is linked to decreased apoptosis and increased metabolic activity, suggesting it acts as a tumor suppressor. USP53 regulates cell apoptosis and glycolysis through the AKT1 pathway. Mechanistically, USP53 deubiquitinates FKBP51, which in turn dephosphorylates AKT1, and ultimately inhibits tumor growth in lung adenocarcinoma. Taken together, our study establishes USP53 as a novel regulator of AKT1 pathway with an important role in tumorigenesis in lung adenocarcinoma.


Assuntos
Adenocarcinoma de Pulmão/patologia , Apoptose , Glicólise , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas de Ligação a Tacrolimo/metabolismo , Proteases Específicas de Ubiquitina/metabolismo , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/metabolismo , Animais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Estudos de Casos e Controles , Proliferação de Células , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Prognóstico , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas de Ligação a Tacrolimo/genética , Células Tumorais Cultivadas , Proteases Específicas de Ubiquitina/genética , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Am J Surg Pathol ; 44(9): 1259-1265, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32496433

RESUMO

The differential diagnosis of epithelioid mesothelioma from lung adenocarcinoma using immunohistochemistry is improving. However, immunohistochemical markers with high sensitivity and specificity have yet to be identified. In this study, we investigated the utility of sex-determining region Y box 6 (SOX6) as a novel immunohistochemical marker, identified by analyzing previous gene expression data. Immunohistochemically, SOX6 expression was present in 53 of 54 (98%) cases of epithelioid mesothelioma, compared with its expression in only 5 of 69 (7%) cases of lung adenocarcinoma. The sensitivity and specificity of SOX6 expression for differentiating epithelioid mesothelioma and lung adenocarcinoma were 98% and 93%, respectively. SOX6 expression showed similar sensitivity and far better specificity than those of calretinin or podoplanin (D2-40). In addition, SOX6 expression was more sensitive than Wilms' tumor 1 expression. The combination of SOX6 with other markers showed comparable or better sensitivity and specificity relative to other combinations. In particular, the sensitivity of positivity for both SOX6 and calretinin (96%) and the specificity of positivity for both SOX6 and Wilms' tumor 1 (93%) were higher than those of the other combinations. In conclusion, SOX6 is a novel candidate immunohistochemical marker for differentiating epithelioid mesothelioma from lung adenocarcinoma.


Assuntos
Adenocarcinoma de Pulmão/química , Biomarcadores Tumorais/análise , Células Epitelioides/química , Imuno-Histoquímica , Neoplasias Pulmonares/química , Mesotelioma/química , Fatores de Transcrição SOXD/análise , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Biomarcadores Tumorais/genética , Diagnóstico Diferencial , Células Epitelioides/patologia , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Mesotelioma/genética , Mesotelioma/patologia , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Fatores de Transcrição SOXD/genética
19.
J Cancer Res Clin Oncol ; 146(9): 2299-2310, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32556504

RESUMO

BACKGROUND: Although much progress has been made in the diagnosis of early-stage lung adenocarcinoma (ES-LUAD), the prognosis for ES-LUAD patients with rapid recurrence is still poor. Importantly, there is currently no effective and precise method to screen patients who may develop rapid recurrence. Therefore, it is necessary to identify potential differentially expressed genes (DEGs) in ES-LUAD patients with rapid recurrence and non-rapid recurrence. METHODS: Affymetrix GeneChip Human Transcriptome Array was used to identify DEGs between ES-LUAD patients with rapid recurrence and non-rapid recurrence. Rapid recurrence was defined as recurrence-free survival (RFS) â‰¦ 1 year and non-rapid recurrence was defined as RFS â‰§ 3 years. The biological functions of the DEGs were analyzed by GO and KEGG pathway enrichment analyses. The protein-protein interaction (PPI) network of identified DEGs was conducted by STRING and Cytoscape software. The expression level of crucial hub genes and tumor-infiltrating lymphocytes (TILs) was verified by immunohistochemistry (IHC). RESULTS: A total of 416 DEGs were identified between ES-LUAD patients with and without rapid recurrence. The results of GO analysis revealed that 2 of the top 10 categories in the domain of cellular component, 2 of the top 10 in the domain of molecular function, and 9 of the top 10 in the domain of biological process were functionally related to immunity. The results of KEGG analysis showed that 6 of the top 8 pathways were functionally involved in immune regulation and inflammatory response. The PPI network analysis identified ten crucial nodal protein, including EGFR, MMP9, IL-1ß, PTGS2, MMP1, and 5 histone proteins, which constituted 25 key interactions. IL-1ß and PTGS2 expression were closely related to immunity and IHC analysis further revealed that low expression of IL-1ß and PTGS2 is associated with rapid recurrence. Kaplan-Meier analysis further revealed that LUAD patients with lower IL-1ß or PTGS2 expression had a worse RFS. When the TIL density of CD3+, CD4+, CD8+ and CD20+ subsets was less than 20%, ES-LUAD patients have a higher probability of rapid recurrence. CONCLUSION: There were significant differences in the expression of immune-related genes between patients with rapid recurrence and patient with non-rapid recurrence. Immune-related genes such as IL-1ß and PTGS2 and TIL density (20%) play important roles in rapid recurrence of ES-LUAD. This study provided a theoretical basis for distinguishing the two types of patients from an immunological perspective.


Assuntos
Adenocarcinoma de Pulmão/genética , Neoplasias Pulmonares/genética , Recidiva Local de Neoplasia/genética , Adenocarcinoma de Pulmão/patologia , Biomarcadores Tumorais/genética , Biologia Computacional/métodos , Intervalo Livre de Doença , Feminino , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica/genética , Ontologia Genética , Redes Reguladoras de Genes/genética , Humanos , Imuno-Histoquímica/métodos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Prognóstico , Mapas de Interação de Proteínas/genética , Transcriptoma/genética
20.
J Cancer Res Ther ; 16(2): 320-326, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32474519

RESUMO

Context: Increasing evidence has indicated an association between immune cell infiltration in lung adenocarcinoma (LUAD) and clinical outcomes. Aims: This study aimed to investigate the effect of 22 tumor-infiltrating immune cells (TIICs) on the prognosis of patients with LUAD. Settings and Design: This was a case-control study. Materials and Methods: The CIBERSORT algorithm calculated the proportion of cases from the Cancer Genome Atlas (TCGA) cohort. Cox regression analysis evaluated the effect of TIICs on the prognosis of LUAD. The immune risk score model was constructed based on a statistical correlation. Multivariate cox regression analysis investigated independent factors. P < 0.05 was considered to be statistically significant. Results: Certain immune cells had differential infiltration between normal tissues and LUAD. Univariate Cox regression analysis revealed that four immune cell types were statistically correlated with LUAD-related survival risk, and an immune risk scoring model was constructed. The results indicated that patients in the high-risk group were associated with poor outcomes. In addition, the multivariate cox analysis revealed that the immune risk scoring model was an independent factor for LUAD prognosis prediction. Ultimately, a nomogram was established to comprehensively predict the survival of LUAD patients. Conclusions: TIICs played an essential role in the prognosis of LUAD. Furthermore, the immune risk score was a poor predictive factor of LUAD, and the established model was reliable in predicting the prognosis of LUAD.


Assuntos
Adenocarcinoma de Pulmão/imunologia , Biomarcadores Tumorais/genética , Biologia Computacional/métodos , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/imunologia , Linfócitos do Interstício Tumoral/imunologia , Evasão Tumoral/imunologia , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Idoso , Algoritmos , Biomarcadores Tumorais/imunologia , Estudos de Casos e Controles , Estudos de Coortes , Bases de Dados Genéticas , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de Risco , Evasão Tumoral/genética
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