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Onco Targets Ther ; 12: 5793-5803, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31410024


Background: ASAP3 was first identified as a protein that promotes cell proliferation in hepatocellular carcinoma and later reported to be an Arf6-specific Arf GTPase-activating protein that regulates cell migration associated with cancer cell invasion. Materials and methods: Patients and tissue samples were from Hubei Cancer Hospital, human lung adenocarcinoma cell lines were obtained from the cell bank of the Chinese Academy of Science, nude mice (BALB/c nu/nu) were obtained from Shanghai SLAC Laboratory Animal Co. Ltd. Our methods contained immunohistochemistry, Western blotting, reverse-transcription polymerase chain reaction (RT-PCR), immunofluorescence staining, stable transfection of lung adenocarcinoma cells, chromatin immunoprecipitation (CHIP) and luciferase assay, wound healing and cell migration assay. Results: In this study, we show that ASAP3 overexpression promotes migration and invasiveness in human lung adenocarcinoma cells and accelerates tumor progression in a xenograft mouse model. In patient tumor samples, ASAP3 overexpression was significantly associated with lymph node metastasis and reduced overall survival. We also show that ASAP3 expression is induced under hypoxic conditions through hypoxia-inducible factor 1α (HIF-1α), which binds directly to HER1 or/and HER2 (hypoxia response element) in the ASAP3 promoter. ASAP3 overexpression counteracts the inhibition of lung adenocarcinoma progression caused by HIF-1α knockdown both in vitro and in vivo. Conclusion: Our results identify ASAP3 as a downstream target of HIF-1α that is critical for metastatic progression in lung adenocarcinoma.

Clin Transl Radiat Oncol ; 17: 17-23, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31080898


Purpose: To analyze associations between heart and lung dose and overall survival (OS) in patients with esophageal cancer who received concurrent chemo-radiotherapy (CCRT) with or without surgery. Patients and methods: Patients received intensity-modulated radiation therapy (median dose 50.4 Gy) from 2004 through 2016. Cutoff points for continuous variables were calculated using the method of Contal and O'Quigley. Kaplan-Meier method with log-rank tests was used to calculate survival. OS was analyzed with both univariate and multivariable Cox models. Results: In all, 560 patients were analyzed; median follow-up time was 29.3 months, and 5-year OS rate was 41.7%. Heart V30 >45% and mean lung dose (MLD) >10 Gy were found to be independently associated with worse survival after adjustment for other clinical and dosimetric factors (P < 0.05). Heart and lung doses were also found to be risk factors for radiation-induced cardiac and pulmonary complications (P < 0.05): 8.5% of patients with heart V30 ≤45% had cardiac complications vs. 15% for V30 >45% (P = 0.046); 18.8% of patients with MLD ≤10 Gy had pulmonary complications vs. 27% for MLD >10 Gy (P = 0.020). Having cardiac complications was associated with worse survival (5-year OS rates 27.6% with vs. 43.2% without, P = 0.012), and having pulmonary complications was associated with worse survival as well (5-year OS rates 23.1% with vs. 47.4% without, P < 0.001). Conclusion: Both heart and lung doses independently predicted worse OS in patients with esophageal cancer, even after adjustment for other clinical and dosimetric factors, and were also risk factors for radiation-induced complications. Both irradiated heart and lung doses should be minimized as a whole.

Medicine (Baltimore) ; 97(21): e10681, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29794744


RATIONALE: This combination of fluticasone propionate (FP) and the long-acting ß2-agonist salmeterol (Salm) can control the symptoms of asthma and COPD better than FP or Salm on their own and better than the combination of inhaled corticosteroids plus montelukast. FP/Salm has been shown to control symptoms of asthma and COPD better than a double dose of inhaled steroids. The patient in our report had a history of COPD, and suffered relapse of RP when given only steroids. It is possible that COPD history helps explain this patient's more difficult treatment course. Therefore, this combination may be more effective than inhaled steroids for patients with a history of COPD. PATIENT CONCERS: This patient suffered adverse reactions triggered by methylprednisolone: weight gain, hyperglycaemia and sleep disturbance after more than two months of intravenous and oral prednisolone. These reactions disappeared when we switched the patients to FP/Salm maintenance therapy. DIAGNOSES: The patient underwent upper right lobectomy in September 2011. Immunohistochemistry indicated low squamous cell differentiation, and he was diagnosed with stage IIB disease (T2N1M0) according to the Union for International Cancer Control (UICC) (7th edition).One month after repeat radiotherapy, the patient experienced fever (37.6°C), cough, chest distress and shortness of breath. We performed serologic tests, laboratory tests for procalcitonin and C-reactive protein, as well as sputum and blood cultures to rule out bacterial infection. Chest CT showed consolidation with air bronchogram in the hilum of the right lung and ground-glass densities in the right lower lobe and left upper lobe. These radiographic signs are typical of RP. Since the patient required oxygen, he was diagnosed with grade III RP. INTERVENTIONS: After the patinet was diagnosed with grade III RP. The patient was immediately prescribed oxygen, anti-infectives for prophylaxis, treatments to facilitate expectoration and prevent asthma, and most importantly, intravenous methylprednisone at an initial dose of 60  per day. And we cut the steroid dose in half every one week when the patient's symptoms improved obviously, and the patchy shadow on the chest radiograph sharply reduced. Then we give him FP (500 mg)/Salm (50 mg) twice daily for two months. Then the dose was halved for an additional two months. OUTCOMES: The patient showed no signs of tumor or RP relapse by the last follow-up in March 2018. LESSONS: This maintenance therapy of FP/Salm for patient with grade III RP may help avoid relapse when steroid therapy is tapered, particularly for patients with a history of COPD. It may also reduce risk of steroid-associated adverse effects. Based on the results observed with our patient, we intend to design a prospective trial to assess the efficacy of FP/Salm when used as preventive treatment for patients at high risk of RP, and when used as maintenance treatment for patients with grade III RP.

Agonistas de Receptores Adrenérgicos beta 2/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Combinação Fluticasona-Salmeterol/uso terapêutico , Neoplasias Pulmonares/terapia , Pneumonite por Radiação/tratamento farmacológico , Glucocorticoides/efeitos adversos , Glucocorticoides/uso terapêutico , Humanos , Pulmão/patologia , Pulmão/efeitos da radiação , Masculino , Metilprednisolona/efeitos adversos , Metilprednisolona/uso terapêutico , Pessoa de Meia-Idade , Pneumonectomia , Doença Pulmonar Obstrutiva Crônica/complicações , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Pneumonite por Radiação/diagnóstico , Tomografia Computadorizada por Raios X , Resultado do Tratamento
Clin Cancer Res ; 24(3): 600-607, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29113987


Purpose: This study examined the potential role of the nuclear deubiquitinating enzyme BRCA1-associated protein-1 (BAP1) in radioresistance in head and neck squamous cell cancer (HNSCC).Experimental Design: We overexpressed, knocked down, and rescued BAP1 expression in six HNSCC cell lines, three human papillomavirus (HPV)-negative and three HPV-positive, and examined the effects on radiosensitivity in vitro and in an HNSCC mouse xenograft model. Radiosensitivity was assessed by clonogenic cell survival and tumor growth delay assays; changes in protein expression were analyzed by immunofluorescence staining and Western blotting. We also analyzed The Cancer Genome Atlas HNSCC database to test for associations between BAP1 expression and outcome in patients.Results: Overexpression of BAP1 induced radioresistance in both cell lines and xenograft models; conversely, BAP1 knockdown led to increased ubiquitination of histone H2A, which has been implicated in DNA repair. We further found that BAP1 depletion suppressed the assembly of constitutive BRCA1 foci, which are associated with homologous recombination (HR), but had minimal effect on γ-H2AX foci and did not affect proteins associated with nonhomologous end joining, suggesting that BAP1 affects radiosensitivity in HNSCC by modifying HR. Finally, in patients with HNSCC, overexpression of BAP1 was associated with higher failure rates after radiotherapy.Conclusions: BAP1 can induce radioresistance in HNSCC cells, possibly via deubiquitination of H2Aub and modulation of HR, and was associated with poor outcomes in patients with HNSCC. BAP1 may be a potential therapeutic target in HNSCC. Clin Cancer Res; 24(3); 600-7. ©2017 AACR.

Biomarcadores Tumorais , Neoplasias de Cabeça e Pescoço/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Ubiquitina Tiolesterase/metabolismo , Animais , Modelos Animais de Doenças , Relação Dose-Resposta à Radiação , Neoplasias de Cabeça e Pescoço/etiologia , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/terapia , Histonas/metabolismo , Recombinação Homóloga , Humanos , Camundongos , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/virologia , Prognóstico , Tolerância a Radiação/genética , Proteínas Supressoras de Tumor/genética , Ubiquitina Tiolesterase/genética , Ubiquitinação , Ensaios Antitumorais Modelo de Xenoenxerto
Oncotarget ; 8(14): 22842-22853, 2017 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-28206964


In order to explore the new mechanism that obesity worsens the prognosis of breast cancer, we reanalyzed the data about gene expression of normal, overweight, and obese breast cancer patients to explore potential genes and validate its function by clinical and experimental data. The fold change of 15-hydroxyprostaglandin dehydrogenate (HPGD) gene which displayed declining trend with BMI increase was 0.46 in obese versus normal weight patients. HPGD protein was highest expressed in normal weight group and lowest expressed in obese group. The rate of positive lymph nodes was 67% in low expression of HPGD group and 35% in high expression of HPGD group. The recurrence-free survival (RFS) rate and overall survival (OS) rate of 5 years had significant difference between low expression of HPGD group and high expression of HPGD group. Obesity dramatically decreased the RFS rate and OS rate of 5 years. Down regulation of HPGD expression could increase the migration and proliferation ability of breast cancer cell line MCF-7. Taken together, our results indicate that low expression of HPGD may be a reason for poor prognosis of obese breast cancer patients.

Neoplasias da Mama/enzimologia , Hidroxiprostaglandina Desidrogenases/metabolismo , Obesidade/enzimologia , Adulto , Neoplasias da Mama/complicações , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Feminino , Humanos , Hidroxiprostaglandina Desidrogenases/genética , Obesidade/complicações , Obesidade/genética , Obesidade/patologia , Prognóstico