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1.
Heliyon ; 10(2): e24378, 2024 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-38298673

RESUMO

Background: Epidermal growth factor receptor (EGFR) mutations have been identified as promising therapeutic targets for non-small cell lung cancer. Osimertinib, a third-generation EGFR-tyrosine kinase inhibitor-targeting drug, has good anti-tumor ability and excellent intracranial effects. However, management of osimertinib resistance is a clinical challenge. The clinical benefit of osimertinib combined with the antiangiogenic drug, bevacizumab, remains to be determined. Case presentation: A 40-year-old female with right lung adenocarcinoma (cT2aN3M1c, IVb) was confirmed positive for EGFR exon 19 deletion mutation (c.2235_2249del, 1.3%). After receiving 5 months of osimertinib (80 mg, qd) therapy, the patient's disease progressed and she subsequently accepted treatment with osimertinib (80 mg, qd) plus bevacizumab (15 mg/kg, q21d) and achieved notable clinical remission for 23 months until renal impairment occurred, after which bevacizumab was discontinued. The patient had 6 months of remission before progression, after which bevacizumab was added again. To date, the disease has been under control. The brain lesion showed partial response again, and the side effects of bevacizumab were tolerable. The overall survival time exceeded 4 years. Conclusion: This case report describes a treatment strategy for osimertinib-resistant patients with EGFR exon 19 deletion mutations. Metronomic treatment with osimertinib plus bevacizumab was achieved for more than 4 years.

2.
N Engl J Med ; 390(2): 118-131, 2024 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-38197815

RESUMO

BACKGROUND: The early-generation ROS1 tyrosine kinase inhibitors (TKIs) that are approved for the treatment of ROS1 fusion-positive non-small-cell lung cancer (NSCLC) have antitumor activity, but resistance develops in tumors, and intracranial activity is suboptimal. Repotrectinib is a next-generation ROS1 TKI with preclinical activity against ROS1 fusion-positive cancers, including those with resistance mutations such as ROS1 G2032R. METHODS: In this registrational phase 1-2 trial, we assessed the efficacy and safety of repotrectinib in patients with advanced solid tumors, including ROS1 fusion-positive NSCLC. The primary efficacy end point in the phase 2 trial was confirmed objective response; efficacy analyses included patients from phase 1 and phase 2. Duration of response, progression-free survival, and safety were secondary end points in phase 2. RESULTS: On the basis of results from the phase 1 trial, the recommended phase 2 dose of repotrectinib was 160 mg daily for 14 days, followed by 160 mg twice daily. Response occurred in 56 of the 71 patients (79%; 95% confidence interval [CI], 68 to 88) with ROS1 fusion-positive NSCLC who had not previously received a ROS1 TKI; the median duration of response was 34.1 months (95% CI, 25.6 to could not be estimated), and median progression-free survival was 35.7 months (95% CI, 27.4 to could not be estimated). Response occurred in 21 of the 56 patients (38%; 95% CI, 25 to 52) with ROS1 fusion-positive NSCLC who had previously received one ROS1 TKI and had never received chemotherapy; the median duration of response was 14.8 months (95% CI, 7.6 to could not be estimated), and median progression-free survival was 9.0 months (95% CI, 6.8 to 19.6). Ten of the 17 patients (59%; 95% CI, 33 to 82) with the ROS1 G2032R mutation had a response. A total of 426 patients received the phase 2 dose; the most common treatment-related adverse events were dizziness (in 58% of the patients), dysgeusia (in 50%), and paresthesia (in 30%), and 3% discontinued repotrectinib owing to treatment-related adverse events. CONCLUSIONS: Repotrectinib had durable clinical activity in patients with ROS1 fusion-positive NSCLC, regardless of whether they had previously received a ROS1 TKI. Adverse events were mainly of low grade and compatible with long-term administration. (Funded by Turning Point Therapeutics, a wholly owned subsidiary of Bristol Myers Squibb; TRIDENT-1 ClinicalTrials.gov number, NCT03093116.).


Assuntos
Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Proteínas Tirosina Quinases , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/genética , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas/genética , Antineoplásicos/uso terapêutico , Resultado do Tratamento
3.
Arch Environ Contam Toxicol ; 83(3): 242-252, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36121470

RESUMO

Hexachloropentadiene (HCPD) is a highly toxic compound that is mainly used for preparation of organochlorine insecticides. To investigate HCPD contamination of the environment during pesticide processing, 153 air, soil, and biota samples were collected around an agrochemical factory in different seasons of 1 year and analyzed for HCPD. The HCPD concentrations were 0.01-12.7 ng/m3 (average 2.60 ng/m3) in the air samples and 0.14-51.5 ng/g (average 4.11 ng/g) in the soil samples. HCPD concentrations were highest within 1 km north of the production site, which was in the downwind direction of the factory and storage tanks, especially in autumn and winter. Soil-air exchange analysis showed that HCPD was deposited from air to soil with a flux of 0.003 to 0.20 ng/(m2 d) throughout the year. The dismantling of obsolete equipment accelerated the release of HCPD into the air and increased the amount of HCPD deposited in the soil. HPCD concentration ranges were 0.44-55.7 ng/g dry weight [d.w.] (average 22.2 ng/g d.w.) and 6.69-91.4 ng/g d.w. (average 26.2) in locally grown rice and wheat, respectively. The concentration range was 12.1-1596 ng/g lipid weight (average 560 ng/g lipid weight) in local organisms, except for chicken. In tissues from locally raised chicken, the HCPD concentrations decreased in the order of gizzard, liver, heart, and meat. HCPD was amplified through a short food chain (soil, Vigna unguiculata leaves, larvae of Pieris rapae, and chicken), and the bioaccumulation factor gradually increased over a range of 1.19-25.1 (mean 9.81).


Assuntos
Poluentes Atmosféricos , Inseticidas , Praguicidas , Poluentes do Solo , Agroquímicos/análise , Poluentes Atmosféricos/análise , Biota , Monitoramento Ambiental , Inseticidas/análise , Lipídeos , Praguicidas/análise , Solo/química , Poluentes do Solo/análise
4.
Bioengineered ; 13(2): 3183-3193, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-35068336

RESUMO

Dysregulation of calcium-activated nucleotides 1 (CANT1) has been observed in different organs. Thus, its biological function in cancer has increasingly attracted researchers. The current work aims to study the CANT1 role in lung cancer and understand the underlying pathological mechanisms. High amplification of CANT1 was observed in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) tissues compared to normal tissues. The high-CANT1 patients showed a dismal prognosis in comparison with the low-CANT1 patients. Highly expressed CANT1 was significantly associated with the N stage of LUSC patients. Ectopic expression of CANT1 conspicuously increased the proliferation and viability of A549 cells. Conversely, CANT1 depletion resulted in adverse effects in H1299 cells. CANT1 depletion also resulted in the retardation of tumor growth in vivo. Mechanically, we found that CANT1 could elevate NF-ĸB (nuclear factor-k-gene binding) transcriptional activity in a concentration-dependent manner. This regulatory relationship was also established by the Western blot technique. Inhibiting NF-ĸB can significantly blunt the increased NF-κ-B Inhibitor-α (IκBα) expression caused by CANT1 overexpression in A549 cells. In conclusion, highly amplified CANT1 promotes the proliferation and viability of lung cancer cells. We also elucidate a new signaling axis of CANT1-NF-ĸB in lung cancer. This approach might be a promising strategy for lung cancer treatment.


Assuntos
Neoplasias Pulmonares/metabolismo , NF-kappa B/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias Experimentais/metabolismo , Nucleotidases/metabolismo , Transdução de Sinais , Células A549 , Animais , Humanos , Neoplasias Pulmonares/genética , Masculino , Camundongos , Camundongos Nus , NF-kappa B/genética , Proteínas de Neoplasias/genética , Neoplasias Experimentais/genética , Nucleotidases/genética
5.
J Cell Biochem ; 122(9): 969-982, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31742752

RESUMO

Long noncoding RNAs (lncRNAs) are dysregulated in various malignancies and involved in the growth and aggressive phenotypes of cancer cells. Previous studies indicate that lncRNA testis development related 1 (TDRG1) plays critical roles in the development of several malignancies. Nevertheless, the molecular mechanism underlying TDRG1 contributes to non-small cell lung cancer (NSCLC) remains elusive. Here, we demonstrate that TDRG1 is significantly overregulated in NSCLC tissues and cell lines. Knockdown of TDRG1 inhibits the proliferation and metastatic-related traits of NSCLC cell in vitro whereas overexpression of TDRG1 causes opposite results. In addition, TDRG1 silencing inhibits the growth and metastatic ability of NSCLC cell in vivo as demonstrated by xenograft tumor model and lung metastasis model. The binding capacity of TDRG1 with miR-873-5p is demonstrated by bioinformatics prediction tool and luciferase reporter gene assay. Additional, the rescue experiments indicate that TDRG1 interacts with miR-873-5p and its expression is positively associated with the target of miR-873-5p, zinc finger e-box binding homeobox 1 (ZEB1). Altogether, lncRNA TDRG1 facilitates the progression of NSCLC via interacting with miR-873-5p and positively regulates the expression of ZEB1.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , MicroRNAs , RNA Longo não Codificante , Humanos , Masculino , Carcinoma Pulmonar de Células não Pequenas/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/genética , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Longo não Codificante/metabolismo , Homeobox 1 de Ligação a E-box em Dedo de Zinco/genética , Homeobox 1 de Ligação a E-box em Dedo de Zinco/metabolismo
6.
Front Immunol ; 11: 563622, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33240259

RESUMO

Introduction: In murine cancer models, B cells are unnecessary for efficacy of PD-1 inhibitor. However, we do not know whether this applies to clinical settings, especially in patients with non-small-cell lung carcinoma (NSCLC). Case presentation: We report on the case of an advanced lung adenocarcinoma patient without oncogenic driver mutations whose disease progressed on second-line bevacizumab-containing chemotherapy regimens. These previous treatments resulted in profound thrombocytopenia and increased number of B cells; both effects were hard to alleviate. The patient was diagnosed with marginal zone B-cell lymphoma by flow cytometry immunophenotyping. After five cycles of rituximab in combination with lenalidomide treatment, the percentage of B cells rapidly declined to undetectable levels and the lymphoma regressed completely. However, because masses in the lung gradually increased, this patient was subsequently treated with a PD-1 inhibitor. The patient's condition stabilized, and the mass shrank to reach partial response, with progression free survival exceeding 15 months and no serious adverse events. Conclusion: The present case proves the efficacy of PD-1 inhibitor in metastatic lung adenocarcinoma in the absence of B cells. Immune checkpoint inhibitions are thus a choice for patients with B cell deficiencies, such as X-linked agammaglobulinemia, immunoglobulin deficiencies, and common variable immunodeficiency, diseases that have historically been excluded from clinical trials for oncologic drugs.


Assuntos
Adenocarcinoma de Pulmão/tratamento farmacológico , Anticorpos Monoclonais Humanizados/administração & dosagem , Linfócitos B/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Inibidores de Checkpoint Imunológico/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Linfoma de Zona Marginal Tipo Células B/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Idoso , Antineoplásicos Imunológicos/uso terapêutico , Antineoplásicos Fitogênicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/uso terapêutico , Carboplatina/uso terapêutico , Humanos , Fatores Imunológicos/uso terapêutico , Lenalidomida/uso terapêutico , Masculino , Paclitaxel/uso terapêutico , Intervalo Livre de Progressão , Rituximab/uso terapêutico
7.
Aging (Albany NY) ; 12(20): 20308-20331, 2020 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-33091876

RESUMO

The tumor immune microenvironment (TIME) is an important determinant of cancer prognosis and treatment efficacy. To identify immune-related prognostic biomarkers of lung adenocarcinoma, we used the ESTIMATE algorithm to calculate the immune and stromal scores of 517 lung adenocarcinoma patients from The Cancer Genome Atlas (TCGA). We detected 985 differentially expressed genes (DEGs) between patients with high and low immune and stromal scores, and we analyzed their functions and protein-protein interactions. TRIM28 was upregulated in lung adenocarcinoma patients with low immune and stromal scores, and was associated with a poor prognosis. The TISIDB and TIMER databases indicated that TRIM28 expression correlated negatively with immune infiltration. We then explored genes that were co-expressed with TRIM28 in TCGA, and investigated DEGs based on TRIM28 expression in GSE43580 and GSE7670. The 429 common DEGs from these analyses were functionally analyzed. We also performed a Gene Set Enrichment Analysis using TCGA data, and predicted substrates of TRIM28 using UbiBrowser. The results indicated that TRIM28 may negatively regulate the TIME by increasing the SUMOylation of IRF5 and IRF8. Correlation analyses and validations in two lung adenocarcinoma cell lines (PC9 and H1299) confirmed these findings. Thus, TRIM28 may worsen the TIME and prognosis of lung adenocarcinoma.


Assuntos
Adenocarcinoma de Pulmão/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias Pulmonares/metabolismo , Proteína 28 com Motivo Tripartido/metabolismo , Microambiente Tumoral , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/imunologia , Adenocarcinoma de Pulmão/terapia , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Intervalo Livre de Doença , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Fatores Reguladores de Interferon/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/terapia , Masculino , Mapas de Interação de Proteínas , Medição de Risco , Fatores de Risco , Transdução de Sinais , Sumoilação , Transcriptoma , Proteína 28 com Motivo Tripartido/genética
8.
Cell Death Dis ; 11(9): 801, 2020 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-32978367

RESUMO

Exosomes are small endogenous membrane vesicles that can mediate cell communication by transferring genetic materials. Based on that, exosomes have always been discussed as a cargo carrier for microRNA (miRNA) transportation. Accumulating data have reported the inhibitory effects of microRNA-193a (miR-193a) on non-small cell lung cancer (NSCLC) cell progression. However, the mechanisms of miR-193a delivery to cancer cells and miR-193a in exosomes have not been explored clearly in NSCLC. Given that, this work aims to decode exosomal miR-193a in cisplatin (DDP) resistance of NSCLC cells. A549 and H1299 cell lines were screened out and their parent cells and drug-resistant cells were co-cultured with human bone marrow mesenchymal stem cells (BMSCs)-derived exosomes (BMSC-Exo) that had been transfected with miR-193a mimic or si-LRRC1 to detect the colony formation, migration, apoptosis, invasion and proliferation of NSCLC cells. In vivo experiment was conducted to verify the in vitro results. BMSC-Exo with upregulated miR-193a and downregulated LRRC1 suppressed colony formation, invasion, proliferation and migration as well as advanced apoptosis of NSCLC parent cells and drug-resistant cells. BMSC-Exo combined with upregulated miR-193a reduced tumor volume and weight in mice with NSCLC. Functional studies report that BMSC-Exo shuffle miR-193a to suppress the colony formation, invasion, migration, and proliferation as well as advance apoptosis of NSCLC DDP-resistant cells via downregulating LRRC1.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Proteínas de Transporte/metabolismo , Cisplatino/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Pulmonares/genética , Proteínas de Membrana/metabolismo , Células-Tronco Mesenquimais/metabolismo , Adulto , Idoso , Cisplatino/farmacologia , Exossomos/metabolismo , Humanos , MicroRNAs , Pessoa de Meia-Idade , Transfecção
9.
J Cancer ; 11(16): 4724-4735, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32626519

RESUMO

Hypoxia is a common characteristic of solid tumors and is associated with cancer progression and poor outcomes. However, the roles and specific mechanisms of exosomes and hypoxia during cancer progression still remain unclear. Herein, we found that exosomes secreted from hypoxic colorectal cancer (CRC) cells promoted the proliferation, migration, invasion, and metastasis of normoxic CRC cells, and these hypoxic exosomes exerted their biological effects depending on miR-410-3p. We discovered that miR-410-3p was highly enriched in hypoxic CRC-derived exosomes in a HIF1α or HIF2α-dependent manner, and miR-410-3p levels positively associated with poor prognosis of CRC. Moreover, decreased PTEN levels caused by hypoxic CRC cells-derived exosomal miR-410-3p increased activation of PI3K/Akt as well as tumor progression. Conversely, inhibition of miR-410-3p or PI3K/Akt signaling pathway effectively decreased hypoxic CRC cells-derived exosomes-mediated tumor progression. In conclusion, our findings indicate that the hypoxic microenvironment in CRC may promote tumor cells to release miR-410-3p-rich exosomes that are transferred to normoxic cells to enhance tumor progression, revealing a new investigation into the therapeutic targets of exosome for CRC treatment.

10.
Biomed Pharmacother ; 125: 109989, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32062549

RESUMO

Long noncoding RNAs (lncRNAs) play critical roles in the pathogenesis of various diseases, including a variety of tumors. Nevertheless, its functional roles and underlying molecular basis for their dysregulation in lung adenocarcinoma (LUAD) are largely unknown. Herein, in our study, we identified that lncRNA TMPO-AS1 is significantly upregulated in LUAD tissues and cell lines. Knockdown of TMPO-AS1 remarkably suppressed LUAD cell growth, induced apoptosis as well as G1/S arrest, and inhibited LUAD cell invasion, whereas overexpression of TMPO-AS1 exerts the opposite effects. Next, we implemented online database analysis tools to find that mir-383-5p could target TMPO-AS1, and our data showed that TMPO-AS1 was negatively correlated with mir-383-5p in LUAD specimens. We found that inhibiting miR-383-5p expression led to a marked upregulation of TMPO-AS1 level, while overexpression of miR-383-5p markedly suppressed TMPO-AS1's expression and function, suggesting that TMPO-AS1 is negatively regulated by miR-383-5p. In addition, we confirmed that miR-383-5p directly targeted TMPO-AS1 by binding to microRNA binding sites in the TMPO-AS1 sequence with a luciferase reporter and RIP assays. Besides, the inhibition of TMPO-AS1 significantly suppressed the tumorigenesis ability of LUAD cells in vivo. Together, these results demonstrate that TMPO-AS1 could be considered as a potential therapeutic target for LUAD patients.


Assuntos
Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Proteínas Nucleares/genética , RNA Antissenso , RNA Longo não Codificante/genética , Timopoietinas/genética , Animais , Apoptose/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Transformação Celular Neoplásica/genética , Modelos Animais de Doenças , Progressão da Doença , Técnicas de Silenciamento de Genes , Humanos , Imuno-Histoquímica , Camundongos , Interferência de RNA
11.
Pathol Res Pract ; 215(6): 152407, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30962004

RESUMO

OBJECTIVE: Lung adenocarcinoma in young patients is a rare entity, and the targetable genomic alterations (GAs) are poorly studied. In other cancers, it has been demonstrated that young age defines unique disease biology. Here, the association of young age with GAs and prognosis is studied in a large cohort of Chinese patients. METHODS: We retrospectively screened 1000 consecutive patients, and identified 181 patients aged 40 years or younger. GAs were identified by next-generation sequencing (NGS) assay. The clinical and genetic characteristics were analyzed. RESULTS: Among younger group, 167(92.3%) patients were diagnosed with advanced-stage adenocarcinoma, 98(54.1%) were female, 27(14.9%) were smokers, and the median age was 35 years. Targetable GAs which were significantly more common in the younger population (P < 0.001), were associated with young age (P < 0.05). The frequency of ALK translocations, EGFR and KRAS mutations was 37.6%, 34.3% and 6.1%, respectively. Younger patients had a higher prevalence of rare GAs including HER2, ROS1 and MET (P < 0.05). Prognosis for younger patients was similar (median OS of patients with GAs, 23.91 vs 23.67 months, P > 0.05) or better than that for older population (median OS of patients without GAs, 44.28 vs 41.88 months, P < 0.05) according to GAs. Therapy modality was an independent prognostic factor (P < 0.05), and 83% of death rate decreased if given preferred therapy. CONCLUSION: Younger patients with lung adenocarcinoma had unique prevalence of targetable GAs. Comprehensive genotyping including NGS is recommended for personalized therapy and prognosis evaluation in this population.


Assuntos
Adenocarcinoma de Pulmão/genética , Biomarcadores Tumorais/genética , Neoplasias Pulmonares/genética , Adulto , Idade de Início , Povo Asiático/genética , Feminino , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Estudos Retrospectivos
12.
Pathol Res Pract ; 215(3): 427-432, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30455129

RESUMO

Validated serum biomarkers for patients suffering from non-small cell lung cancer (NSCLC) brain metastasis are urgently needed for early diagnosis, treatment monitoring, and prognostic classification in daily clinical practice. Serum S100B was reported to be a marker of leaky blood-brain barrier (BBB), which was often caused by brain tumors. This study aimed to investigate the role of S100B in NSCLC brain metastasis. The results showed that serum S100B correlated significantly with NSCLC brain metastasis (P < 0.001). When evaluated by the ROC curve, at the cutoff point 13.83 pg/ml, the sensitivity and specificity were 94% and 93%, respectively (AUC= 0.938, P < 0.001). High level of serum S100B was significantly correlated with a higher number of brain metastases and significantly worse prognosis (P < 0.05). In addition, S100B was an independent prognostic factor (P < 0.001). In conclusion, serum S100B was a sensitive and specific marker for early detection of brain metastasis in NSCLC and could be used as a surveillance tool for prognosis evaluation.


Assuntos
Biomarcadores Tumorais/sangue , Neoplasias Encefálicas/secundário , Carcinoma Pulmonar de Células não Pequenas/secundário , Neoplasias Pulmonares/patologia , Subunidade beta da Proteína Ligante de Cálcio S100/sangue , Adulto , Idoso , Neoplasias Encefálicas/sangue , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Sensibilidade e Especificidade
13.
Intern Med J ; 49(5): 634-643, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30379408

RESUMO

BACKGROUND: A positive correlation between serum carcinoembryonic antigen (CEA) levels and epidermal growth factor receptor (EGFR) mutations has been reported in lung adenocarcinoma patients. AIM: To investigate retrospectively whether serum CEA levels are also associated with genotypes in a large population of advanced lung adenocarcinoma. METHODS: A large cohort of 701 patients with advanced lung adenocarcinoma was studied retrospectively. RESULTS: EGFR mutations were found in 47.5% (333/701) of advanced lung adenocarcinoma patients, being identified at high frequencies in never-smokers, females, and in patients with abnormal pre-treatment serum CEA levels (53.1% vs 37.5%, P < 0.001). In contrast, anaplastic lymphoma kinase gene rearrangements were found in 7.8% (55/701) of patients, being identified at high frequencies in younger patients, and in patients with normal CEA levels (11.5% vs 5.8%, P = 0.012). Serum CEA levels were divided into four groups: <5, 5-19, 20-99 and ≥100 ng/mL. The rate of EGFR mutations significantly increased as the serum CEA levels increased (37.5%, 49.5%, 53.9% and 57.7%, respectively, P < 0.001). Anaplastic lymphoma kinase gene rearrangements showed the opposite result (11.5%, 7.1%, 5.7% and 4.1%, respectively, P = 0.044). A multivariate analysis revealed that higher pre-treatment serum CEA levels were independently associated with EGFR mutations (95% CI: 1.291-2.487, P < 0.001), but normal serum CEA levels were independently associated with anaplastic lymphoma kinase gene rearrangements (95% CI: 0.275-0.842, P = 0.010). CONCLUSION: Our study demonstrated that a significant association exists between the serum CEA levels and genotypes in patients with advanced lung adenocarcinoma.


Assuntos
Adenocarcinoma de Pulmão/sangue , Povo Asiático , Biomarcadores Tumorais/sangue , Antígeno Carcinoembrionário/sangue , Genótipo , Neoplasias Pulmonares/sangue , Adenocarcinoma de Pulmão/diagnóstico , Adenocarcinoma de Pulmão/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Povo Asiático/genética , Biomarcadores Tumorais/genética , Estudos de Coortes , Receptores ErbB/sangue , Receptores ErbB/genética , Feminino , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade , Vigilância da População/métodos , Estudos Retrospectivos
14.
Mol Med ; 24(1): 52, 2018 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-30285605

RESUMO

BACKGROUND: For the study, we determine the potential biomarkers and uncover the regulatory mechanisms of lncRNA MALAT1 / miR-145 / SOX9 axis on the abilities of cell growth and cell metastasis of colorectal cancer. METHODS: Previously published dataset GSE18105 from GEO database was used for microarray analysis to identify differential-expressed lncRNAs and mRNAs. The miRNA which had targeted relationships with both lncRNA and mRNA was predicted using miRCode and Targetscan. The association between lncRNA and miRNA, miRNA and mRNA was verified using dual-luciferase reporter assay. Expression levels of lncRNA MALAT1, miR-145 and SOX9 were examined by quantitative RT-PCR analysis. The cell viability of two cancer cell lines was compared by CCK-8 assay. Colony formation was hired to detected cell proliferation. The cell cycle distribution and apoptotic cell rate were conducted by flow cytometry assay. Wound healing as well as transwell assay were compare the cell migration and cell invasion respectively among groups. The effect of MALAT1 on colorectal cancer in vivo was constructed by xenograft model. RESULTS: Significantly dysregulated lncRNAs and mRNAs were identified by microarray analysis. By experimental verification, MALAT1 and SOX9 were expressed in a high percentage of colorectal cancer tumors and cells, while miR-145 was in a low expression. We also identified miR-145 as a target of MALAT1 and SOX9. MALAT1 played a role in regulating cancer process by functioning as a competing endogenous RNA. Silencing MALAT1 could effectively decrease the expression level of SOX9, thus suppress cell viability and metastasis. Down-regulated MALAT1 could induce resistance of G1 phase in cell cycle, and facilitation of colorectal cancer cell apoptosis. Nude mice injected with cells transfected with si-MALAT1 had smaller tumor on size and weight. CONCLUSIONS: The regulatory function of lncRNA MALAT1 / miR-145 / SOX9 axis was revealed in colorectal cancer based on bioinformatics analysis. LncRNA MALAT1 could facilitate colorectal cancer cell proliferation, invasion and migration by down-regulating miR-145 and up-regulating SOX9. LncRNA MALAT1 could suppress cell cycle and apoptosis through MALAT1 / miR-145 / SOX9 axis.


Assuntos
Neoplasias Colorretais/genética , MicroRNAs , RNA Longo não Codificante , Fatores de Transcrição SOX9/genética , Animais , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Feminino , Camundongos Endogâmicos BALB C , Camundongos Nus
15.
Cancer Res ; 78(1): 205-215, 2018 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-29263152

RESUMO

The immune checkpoint ligand PD-L1 and the transmembrane mucin MUC1 are upregulated in triple-negative breast cancer (TNBC), where they contribute to its aggressive pathogenesis. Here, we report that genetic or pharmacological targeting of the oncogenic MUC1 subunit MUC1-C is sufficient to suppress PD-L1 expression in TNBC cells. Mechanistic investigations showed that MUC1-C acted to elevate PD-L1 transcription by recruitment of MYC and NF-κB p65 to the PD-L1 promoter. In an immunocompetent model of TNBC in which Eo771/MUC1-C cells were engrafted into MUC1 transgenic mice, we showed that targeting MUC1-C associated with PD-L1 suppression, increases in tumor-infiltrating CD8+ T cells and tumor cell killing. MUC1 expression in TNBCs also correlated inversely with CD8, CD69, and GZMB, and downregulation of these markers associated with decreased survival. Taken together, our findings show how MUC1 contributes to immune escape in TNBC, and they offer a rationale to target MUC1-C as a novel immunotherapeutic approach for TNBC treatment.Significance: These findings show how upregulation of the transmembrane mucin MUC1 contributes to immune escape in an aggressive form of breast cancer, with potential implications for a novel immunotherapeutic approach. Cancer Res; 78(1); 205-15. ©2017 AACR.


Assuntos
Antígeno B7-H1/imunologia , Mucina-1/imunologia , Neoplasias de Mama Triplo Negativas/imunologia , Evasão Tumoral/imunologia , Animais , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Linhagem Celular Tumoral , Epigênese Genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos Transgênicos , Mucina-1/genética , Mucina-1/metabolismo , NF-kappa B/metabolismo , Células-Tronco Neoplásicas/imunologia , Células-Tronco Neoplásicas/patologia , Domínios Proteicos , Subunidades Proteicas , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Oncoimmunology ; 6(9): e1338998, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28932637

RESUMO

The cancer immune microenvironment is of importance for the effectiveness of immunotherapy; however, its dysregulation is poorly understood. The MUC1-C oncoprotein is aberrantly overexpressed in non-small cell lung cancer (NSCLC) and has been linked to the induction of PD-L1. The present work investigated the effects of targeting MUC1-C in an immuno-competent MUC1 transgenic (MUC1.Tg) mouse model. We show that Lewis Lung Carcinoma cells expressing MUC1-C (LLC/MUC1) exhibit upregulation of PD-L1 and suppression of interferon-γ (IFN-γ). In studies of LLC/MUC1 cells growing in vitro and as tumors in MUC1.Tg mice, treatment with the MUC1-C inhibitor, GO-203, was associated with the downregulation of PD-L1 and induction of IFN-γ. The results further demonstrate that targeting MUC1-C results in enhanced effector function of CD8+ tumor-infiltrating lymphocytes (TILs) as evidenced by increased expression of the activation marker CD69, the degranulation marker CD107α, and granzyme B. Notably, targeting MUC1-C was also associated with marked increases in TIL-mediated killing of LLC/MUC1 cells. Analysis of gene expression data sets further showed that overexpression of MUC1 in NSCLCs correlates negatively with CD8, IFNG and GZMB, and that decreases in CD8 and IFNG are associated with poor clinical outcomes. These findings in LLC/MUC1 tumors and in NSCLCs indicate that MUC1-C→PD-L1 signaling promotes the suppression of CD8+ T-cell activation and that MUC1-C is a potential target for reprogramming of the tumor microenvironment.

17.
Onco Targets Ther ; 8: 1259-64, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26064060

RESUMO

OBJECTIVE: The objective of the present investigation was to study the clinical significances of the abnormal expressions of Piwil1 and Piwil2 protein in colonic adenoma and adenocarcinoma. METHODS: This study had applied immunohistochemical method to detect 45 cases of tissues adjacent to carcinoma (distance to cancerous tissue was above 5 cm), 41 cases of colonic adenoma and 92 cases of colon cancer tissues, and their Piwil1 and Piwil2 protein expression levels. ANALYSIS: The correlation of both expression and its relationship with clinicopathological features of colon cancer was analyzed. RESULTS: Positive expression rates of Piwil1 in tissues adjacent to carcinoma, colonic adenoma, and colon cancer were 11.1% (5/45), 53.7% (22/41), and 80.4% (74/92), respectively; the expression rates increased, and the comparisons between each two groups were statistically significant (P<0.05). In each group, the positive expression rates of Piwil2 were 24.4% (11/45 cases), 75.6% (31/41 cases), and 92.4% (85/92 cases); expression rates increased, and the comparisons between each two groups were statistically significant (P<0.05). Piwil1 expression and the correlation of the degree of differentiation, TNM stage, and lymph node metastasis were statistically significant (P<0.05). Piwil2 expression and the correlation of the degree of differentiation, tumor node metastasis (TNM) stage, and lymph node metastasis had no statistical significance (P>0.05). In colon cancer tissue, Piwil1 and Piwil2 expressions were positively correlated (r=0.262, P<0.05). CONCLUSION: The results showed that the abnormal expression of Piwil1 and Piwil2 might play an important role in the process of colon cancer development.

18.
Mol Med Rep ; 10(3): 1409-15, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25017879

RESUMO

The present study aimed to determine whether the expression levels of midkine (MK) and syndecan­1 correlate with the malignant progression and poor prognosis of gastric cardiac adenocarcinoma (GCA). GCA tissue samples (n=72) were obtained from the Department of Pathology of the First Affiliated Hospital of Henan University of Science and Technology (Luoyang, China). The paraffin­embedded samples had been surgically resected and pathologically diagnosed between 2007 and 2009. Normal gastric cardiac biopsy specimens (n=40) were also collected as the control. The expression levels of MK and syndecan­1 were assessed by immunohistochemistry using the high­sensitivity streptavidin­peroxidase method. Statistical analysis was performed on the data obtained using the SPSS 17.0 statistics package. MK expression was detected in 76.4% of GCA samples and 5% of normal gastric cardiac mucosa specimens. A significant positive correlation was observed between the expression levels of MK and the infiltrative depth of the tumor, the presence of lymph node metastasis and the prognosis of the patients (P<0.05). Syndecan­1 expression was detected in 38.9% of GCA samples and 100% of normal gastric cardiac mucosa samples. The expression levels of syndecan­1 were negatively correlated with the grade of differentiation, serosal membrane invasion, lymph node metastasis and the patient's prognosis (P<0.05). Notably, the expression levels of MK and syndecan­1 were inversely correlated (r=­0.352, P<0.01) in the GCA tissue samples. These results suggest that high expression levels of MK in GCA tissues may indicate a differentiation stage that is characteristic of malignancy, a late clinical stage and a poor prognosis, whereas increased syndecan­1 levels may indicate a high degree of differentiation, an early clinical stage and a favorable prognosis. MK and syndecan­1 may serve as important biomarkers for monitoring the development and progression of GCA.


Assuntos
Adenocarcinoma/diagnóstico , Adenocarcinoma/genética , Fatores de Crescimento Neural/metabolismo , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/genética , Sindecana-1/metabolismo , Adenocarcinoma/patologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , China , Progressão da Doença , Feminino , Humanos , Imuno-Histoquímica , Metástase Linfática/genética , Metástase Linfática/patologia , Masculino , Pessoa de Meia-Idade , Midkina , Fatores de Crescimento Neural/genética , Prognóstico , Neoplasias Gástricas/patologia , Sindecana-1/genética
20.
Pathol Res Pract ; 210(3): 176-81, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24370340

RESUMO

This study aimed to explore the association between adenocarcinoma-related morphological and molecular characteristics and EGFR mutations in Chinese lung adenocarcinomas. A total of 139 consecutively resected pulmonary adenocarcinoma patients were screened for EGFR mutations by the amplification refractory mutation system assay. For the resected specimens, histologic subtypes were sub-classified using either the 2004 WHO classification or the 2011 IASLC/ATS/ERS classification. Meanwhile, TITF-1 (thyroid transcription factor 1) and SP-A (surfactant-associated protein A) immunohistochemistry staining was also detected. The results were correlated with EGFR mutations and clinicopathological features mentioned above. Both sub-classification methods reflected differences in frequencies of EGFR mutations in lung adenocarcinoma subtypes. In summary, mixed non-mucinous bronchioloalveolar carcinoma (BAC) or papillary components and papillary predominant adenocarcinoma showed a higher frequency of EGFR mutations than mucinous BAC components; Also, EGFR mutations were significantly more common in tumors with TITF-1 or SP-A expressions than in those without (p=0.002, p=0.026), especially the sensitivity of TITF-1 (96.9%) and the negative predictive value of TITF-1 (88.2%). Our data further showed significant genotype-phenotype correlations between EGFR mutations and adenocarcinoma-related morphological and molecular characteristics, and patients with special histologic and IHC staining features might have higher EGFR mutation rates. In addition, this study, for the first time, indicated the significant relationship between SPA IHC and EGFR mutations, which needed confirmation by further research.


Assuntos
Adenocarcinoma/genética , Povo Asiático/genética , Biomarcadores Tumorais , Receptores ErbB/genética , Predisposição Genética para Doença , Neoplasias Pulmonares/genética , Mutação , Neoplasias Complexas Mistas , Proteínas Nucleares/análise , Proteína A Associada a Surfactante Pulmonar/análise , Fatores de Transcrição/análise , Adenocarcinoma/química , Adenocarcinoma/etnologia , Adenocarcinoma/patologia , Adenocarcinoma de Pulmão , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , China/epidemiologia , Análise Mutacional de DNA , Feminino , Estudos de Associação Genética , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/química , Neoplasias Pulmonares/etnologia , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Fenótipo , Prognóstico , Fator Nuclear 1 de Tireoide
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