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1.  Chronic Lung Injury by Constitutive Expression of Activation-Induced Cytidine Deaminase Leads to Focal Mucous Cell Metaplasia and Cancer 
PLoS ONE  2015;10(2):e0117986.
Activation-induced cytidine deaminase (AID) is an enzyme required for antibody diversification, and it causes DNA mutations and strand breaks. Constitutive AID expression in mice invariably caused lung lesions morphologically similar to human atypical adenomatous hyperplasia (AAH), which can be a precursor of bronchioloalveolar carcinoma. Similar to AAH, mouse AAH-like lesion (MALL) exhibited signs of alveolar differentiation, judging from the expression of alveolar type II (AT2) cell marker surfactant protein C (SP-C). However, electron microscopy indicated that MALL, which possessed certain features of a mucous cell, is distinct from an AAH or AT2 cell. Although MALL developed in all individuals within 30 weeks after birth, lung tumors occurred in only 10%; this suggests that the vast majority of MALLs fail to grow into visible tumors. MALL expressed several recently described markers of lung alveolar regeneration such as p63, keratin 5, keratin 14, leucine-rich repeat containing G protein-coupled receptor 5 (Lgr5), and Lgr6. Increased cell death was observed in the lungs of AID transgenic mice compared with wild-type mice. Based on these observations, we speculate that MALL is a regenerating tissue compensating for cellular loss caused by AID cytotoxicity. AID expression in such regenerating tissue should predispose cells to malignant transformation via its mutagenic activity.
PMCID: PMC4320068  PMID: 25659078
2.  Genes suppressed by DNA methylation in non-small cell lung cancer reveal the epigenetics of epithelial–mesenchymal transition 
BMC Genomics  2014;15(1):1079.
DNA methylation is associated with aberrant gene expression in cancer, and has been shown to correlate with therapeutic response and disease prognosis in some types of cancer. We sought to investigate the biological significance of DNA methylation in lung cancer.
We integrated the gene expression profiles and data of gene promoter methylation for a large panel of non-small cell lung cancer cell lines, and identified 578 candidate genes with expression levels that were inversely correlated to the degree of DNA methylation. We found these candidate genes to be differentially methylated in normal lung tissue versus non-small cell lung cancer tumors, and segregated by histologic and tumor subtypes. We used gene set enrichment analysis of the genes ranked by the degree of correlation between gene expression and DNA methylation to identify gene sets involved in cellular migration and metastasis. Our unsupervised hierarchical clustering of the candidate genes segregated cell lines according to the epithelial-to-mesenchymal transition phenotype. Genes related to the epithelial-to-mesenchymal transition, such as AXL, ESRP1, HoxB4, and SPINT1/2, were among the nearly 20% of the candidate genes that were differentially methylated between epithelial and mesenchymal cells. Greater numbers of genes were methylated in the mesenchymal cells and their expressions were upregulated by 5-azacytidine treatment. Methylation of the candidate genes was associated with erlotinib resistance in wild-type EGFR cell lines. The expression profiles of the candidate genes were associated with 8-week disease control in patients with wild-type EGFR who had unresectable non-small cell lung cancer treated with erlotinib, but not in patients treated with sorafenib.
Our results demonstrate that the underlying biology of genes regulated by DNA methylation may have predictive value in lung cancer that can be exploited therapeutically.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2164-15-1079) contains supplementary material, which is available to authorized users.
PMCID: PMC4298954  PMID: 25486910
DNA methylation; Epithelial-mesenchymal transition; Erlotinib; Lung cancer
3.  Swyer-James syndrome associated with asthma and a giant bulla 
Respirology Case Reports  2014;2(4):150-153.
Swyer-James syndrome was first described in 1953 as unilateral pulmonary emphysema in a 6-year-old boy. The characteristic feature of this syndrome is unilateral pulmonary hyperlucency on a chest X-ray film. Typical symptoms include recurrent chest infections, chronic cough, wheezing, and exertional dyspnea. Although there have been a few reports of pneumothorax in patients with Swyer-James syndrome, there have been no reports about an association with giant bullae. Here, we report a case of Swyer-James syndrome associated with a giant bulla and asthma, in which surgery achieved marked improvement of dyspnea.
PMCID: PMC4263499  PMID: 25530867
Asthma; giant bulla; Swyer-James syndrome
4.  Mediastinal infectious complication after endobronchial ultrasound-guided transbronchial needle aspiration 
We report here a mediastinal infectious complication after endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) that was successfully treated using intravenous antibiotic therapy. EBUS-TBNA was performed for a 59-year old man with mediastinal adenopathy 8 years after left pneumonectomy for squamous cell carcinoma of the lung. A single-needle pass produced an adequate cytology and histology sample, and the lesion was diagnosed as small-cell lung cancer. The procedure itself was uneventful, but the patient developed a nightly fever after the biopsy. Finally, he was readmitted, and intravenous antibiotic therapy was required for 4 weeks to treat a mediastinal infection after EBUS-TBNA before chemotherapy for small-cell lung cancer.
PMCID: PMC3781799  PMID: 23814134
Complication; Endobronchial ultrasonography; Lung cancer; Mediastinal infection
5.  Expression of the GLI family genes is associated with tumor progression in advanced lung adenocarcinoma 
The hedgehog (Hh) signaling pathway is aberrantly activated in various cancers. Expression of the GLI family of genes, which encode for transcriptional factors of the Hh pathway, has not been fully assessed in clinical samples of advanced lung adenocarcinoma. In this study, we retrospectively evaluated the expression of the GLI family of genes in advanced stage lung adenocarcinoma samples and determined their relation to patient survival.
The levels of GLI1, GLI2, and GLI3 mRNA expression were measured by quantitative real-time polymerase chain reaction in surgically obtained tissue samples from stage II-IV lung adenocarcinoma patients (n = 102). Pairwise comparisons between all three GLI mRNA expression were performed, and after dichotomizing the patients into low and high expression groups according to each GLI mRNA expression level, survival curves were calculated and multivariate analyses were conducted.
Significant positive correlation was found between GLI1 and GLI3 mRNA expression (P <0.001). Tumors with higher expression (upper 15%) of GLI1 or GLI3 mRNA were associated with poor survival in stage II-IV (5-year overall survival rates: GLI1 mRNA low, 41.7% vs. high, 20.0%, P = 0.0074; GLI3 mRNA low, 43.1% vs. high, 13.3%, P = 0.0062) and stage III-IV (5-year overall survival rates: GLI1 mRNA low, 34.0% vs. high, 0%, P = 0.0012; GLI3 mRNA low, 33.4% vs. high, 7.7%, P = 0.057) lung adenocarcinoma patients. GLI2 mRNA expression did not appear to have great clinical significance. Multivariate analysis revealed higher GLI1 mRNA expression as an independent factor for unfavorable patient survival (P = 0.0030, hazard ratio = 3.1, 95% confidence interval = 1.5-6.2), as well as tumor differentiation and stage.
Expression of GLI1 and GLI3 mRNA was strongly correlated, and their overexpression, especially that of GLI1, was found to be predictive of aggressive tumor behavior. This study indicates that the Hh pathway may be a key oncogenic signaling network in tumor pathogenesis and, thus, a potential therapeutic target in advanced lung adenocarcinoma.
PMCID: PMC4249769  PMID: 25103784
GLI; Hedgehog signaling; Lung adenocarcinoma; Advanced stage; Expression; Prognosis
6.  Reconstruction of recurrent diaphragmatic eventration with an elongated polytetrafluoroethylene sheet 
We report the case of a 31-year old woman with recurrence of left diaphragmatic eventration 3 years after a previous surgery for this condition. At the initial occurrence, she had experienced dyspnoea on exercise and subsequently underwent laparoscopic plication of the diaphragm with an endo-stapler at a local hospital. Immediately after the operation, the diaphragm was torn and the intestine entered the thorax. Therefore, plication involving sewing was performed. Then, 3 years later, the patient again experienced dyspnoea and was diagnosed as having recurrence of left diaphragmatic eventration. Observation under thoracoscopy revealed that the centre of the left diaphragm was thin but not torn. We reconstructed the left diaphragm with an elongated polytetrafluoroethylene sheet on the naïve diaphragm. The patient was discharged from our hospital 5 days after surgery. Her respiratory function improved and she has not experienced recurrence.
PMCID: PMC3715187  PMID: 23644727
Diaphragmatic eventration; Recurrence; Thoracoscopic surgery; Elongated polytetrafluoroethylene sheet; Pulmonary function
7.  Inspiratory and expiratory computed tomographic volumetry for lung volume reduction surgery 
Three-dimensional (3D) computed tomographic (CT) volumetry has been introduced into the field of thoracic surgery, and a combination of inspiratory and expiratory 3D-CT volumetry provides useful data on regional pulmonary function as well as the volume of individual lung lobes. We report herein a case of a 62-year-old man with severe emphysema who had undergone lung volume reduction surgery (LVRS) to assess this technique as a tool for the evaluation of regional lung function and volume before and after LVRS. His postoperative pulmonary function was maintained in good condition despite a gradual slight decrease 2 years after LVRS. This trend was also confirmed by a combination of inspiratory and expiratory 3D-CT volumetry. We confirm that a combination of inspiratory and expiratory 3D-CT volumetry might be effective for the preoperative assessment of LVRS in order to determine the amount of lung tissue to be resected as well as for postoperative evaluation. This novel technique could, therefore, be used more widely to assess local lung function.
PMCID: PMC3653473  PMID: 23460599
Pulmonary function test; Three-dimensional computed tomographic volumetry; Lung volume reduction surgery
8.  Induction chemoradiotherapy is superior to induction chemotherapy for the survival of non-small-cell lung cancer patients with pathological mediastinal lymph node metastasis 
The purpose of this study was to compare the clinical outcomes of induction chemoradiotherapy and chemotherapy and to identify the prognostic factors for non-small-cell lung cancer patients with mediastinal lymph node metastasis who were treated with induction therapy.
Between August 1995 and December 2010, 50 non-small-cell lung cancer patients with pathological mediastinal lymph node metastasis were scheduled to receive induction therapy followed by surgery. Irinotecan plus cisplatin was used for induction chemotherapy from June 1995 to April 1999, and docetaxel plus cisplatin with concurrent radiation at a dose of 40–46 Gy has been used for induction chemoradiotherapy since May 1999.
Thirty-five patients were treated with induction chemoradiotherapy and 15 were treated with induction chemotherapy. For the entire population, the 3-year and 5-year overall survival rates were 64.1 and 53.9%, respectively, and the 1-year and 2-year disease-free survival rates were 70.0 and 53.1%, respectively. Among the clinicopathological factors, the chemoradiotherapy group exhibited longer overall survival and disease-free survival than the chemotherapy group (overall survival, P = 0.0020; disease-free survival, P = 0.015). Pathological downstaging was also significantly associated with favorable overall survival (P = 0.0042) and disease-free survival (P = 0.021). A multivariate analysis showed that chemoradiotherapy (P = 0.0099) and pathological downstaging (P = 0.039) were independent prognostic factors.
Our results indicated that induction chemoradiotherapy was superior to induction chemotherapy with regard to the outcome of non-small-cell lung cancer patients with mediastinal lymph node metastasis.
PMCID: PMC3501315  PMID: 22976995
Lung cancer; Induction therapy; Chemoradiotherapy; Chemotherapy
9.  Pulmonary function of individual lung lobes after complex living-donor lobar lung transplantation using inspiratory and expiratory three-dimensional computed tomographic volumetry 
A combination of inspiratory and expiratory three-dimensional computed tomographic volumetry provides useful information on pulmonary function and lung volume. We previously reported an early outcome of a patient undergoing living-donor lobar lung transplantation with sparing of the bilateral native upper lobes. Long-term follow-up on such patients had not been reported, and therefore we herein, for the first time, reported the 2-year follow-up of the previously reported case. According to the inspiratory and expiratory three-dimensional computed tomographic volumetric data, we demonstrated that transplanted lower lobe grafts had been working efficiently and spared bilateral native upper lobes had not provided any adverse effects.
PMCID: PMC3501302  PMID: 22945847
Living-donor; Lung transplantation; Size mismatch; Native lung sparing; Three-dimensional computed tomographic volumetry
10.  Protective Effect of Surfactant Inhalation against Warm Ischemic Injury in an Isolated Rat Lung Ventilation Model 
PLoS ONE  2013;8(8):e72574.
Warm ischemia-reperfusion injury remains a crucial issue in transplantation following the cardiac death of donors. Previously, we showed that surfactant inhalation during warm ischemia mitigated ischemia-reperfusion injury. This study investigated the mechanisms of surfactant inhalation protection of the warm ischemic lung after reoxygenation with ventilation alone. In an isolated rat lung ventilation model, cardiac arrest was induced in the CTRL (control) and SURF (surfactant treatment) groups by ventricular fibrillation. Ventilation was restarted 110 min later; the lungs were flushed, and a heart and lung block was procured. In the SURF group, a natural bovine surfactant (Surfacten®) was inhaled for 3 min at the end of warm ischemia. In the Sham (no ischemia) group, lungs were flushed, procured, and ventilated in the same way. Afterwards, the lungs were ventilated with room air without reperfusion for 60 min. Surfactant inhalation significantly improved dynamic compliance and airway resistance. Moreover, surfactant inhalation significantly decreased inducible nitric oxide synthase and caspase-3 transcript levels, and increased those of Bcl-2 and surfactant protein-C. Immunohistochemically, lungs in the SURF group showed weaker staining for 8-hydroxy-2′-deoxyguanosine, inducible nitric oxide synthase, and apoptosis, and stronger staining for Bcl-2 and surfactant protein-C. Our results indicate that surfactant inhalation in the last phase of warm ischemia mitigated the injury resulting from reoxygenation after warm ischemia. The reduction in oxidative damage and the inhibition of apoptosis might contribute to the protection of the warm ischemic lungs.
PMCID: PMC3757025  PMID: 24009692
11.  External fistulous wound with Pseudomonas aeruginosa infection and massive bleeding following rupture of pulmonary suppuration 
We present a 54-year old man with a pulmonary infectious cavity continuing to a cutaneous fistula. Before he was admitted to our hospital, he had undergone open-window surgery for a left thoracic empyema due to the rupture of pulmonary suppuration of the left upper lobe. He had then undergone thoracoplasty with the plombage of the cavity using left pectoralis major muscle. However, this procedure had failed and the external fistulous wound remained infected by Pseudomonas aeruginosa and occasional massive bleeding from the cavity occurred. He underwent en bloc left upper lobectomy for the external fistulous wound. The pedicled left latissimus dorsi muscle flap was transposed to fill the dead space and reinforce the bronchial stump. He remained in good health and did not experience intrathoracic infection or haemoptysis.
PMCID: PMC3352739  PMID: 22419798
Pulmonary suppuration; Thoracic empyema; External fistula; Pseudomonas aeruginosa; Latissimus dorsi muscle flap
12.  Resection of bronchial stricture and destroyed lung after pulmonary tuberculosis 
We present a 53-year old man with destroyed lung syndrome (right upper and middle lobes and S6 of lower lobe with bronchial stricture between the right main and intermediate bronchus) due to tuberculosis 25 years earlier. Aspergillus infection in the destroyed lung was suspected on the basis of antigen positivity. The patient underwent right upper and middle lobectomy, S6 segmentectomy and bronchial resection from the distal end of the right main bronchus to the proximal end of the right basal bronchus. The membranous part of the right main bronchus was cerclaged in order to circularize the flattened bronchus and to match its diameter with that of the basal bronchus. End-to-end anastomosis was then carried out. The postoperative course was uneventful. Pathological examination revealed Aspergillus infection in the cavity of the destroyed lung. Bronchoscopic findings 6 weeks after surgery revealed good healing of the anastomosed portion without stenosis.
PMCID: PMC3329295  PMID: 22361125
Tuberculosis; Bronchial stricture; Destroyed lung; Aspergillus infection; Surgery
13.  Long-term outcome of induction chemoradiotherapy with docetaxel and cisplatin followed by surgery for non-small-cell lung cancer with mediastinal lymph node metastasis 
The purpose of this study was to show the long-term outcome of induction chemoradiotherapy, using docetaxel and cisplatin with concurrent radiotherapy followed by surgery for non-small-cell lung cancer (NSCLC) with mediastinal nodal metastasis. Between January 2000 and July 2006, 22 consecutive NSCLC patients with pathologically proven mediastinal nodal metastasis were treated with tri-modality therapy. The regimen consisted of docetaxel and cisplatin plus concurrent radiation at a dose of 40–46 Gy. The induction therapy was followed by surgery 4–6 weeks later. The pulmonary resections were composed of a lobectomy in 19 patients, including 3 with a sleeve lobectomy, a bilobectomy in 2 patients and a left pneumonectomy in 1 patient. With a median follow-up duration of 8.7 years, the 3-year and 7-year overall survival (OS) rates for the entire population were 72.7 and 63.6%, respectively. Our results suggest that tri-modality therapy is promising for NSCLC patients with mediastinal nodal metastasis.
PMCID: PMC3329306  PMID: 22354091
Non-small-cell lung cancer; Induction chemoradiotherapy; N2
14.  Usefulness of endobronchial ultrasound in patients with previously treated thoracic malignancy 
Diagnosis of mediastinal/hilar lymph nodes and tumours is often challenging for patients with previously treated thoracic malignancy, especially when they have a history of thoracotomy. Endobronchial ultrasound with transbronchial needle aspiration (EBUS-TBNA) has been proposed as a safe, less-invasive modality for such patients. We retrospectively evaluated the role of EBUS-TBNA in the assessment of newly developed mediastinal/hilar abnormalities in patients with previously treated thoracic malignancy. Of 79 patients who underwent EBUS-TBNA between July 2009 and July 2011, 14 patients (18%) had a history of treatment for thoracic malignancy. In all patients, malignancy was confirmed again for the newly developed mediastinal/hilar abnormalities and three of them (21%) presented with a different pathology from the previous malignancy. Out of 14 patients, 12 had a history of thoracotomy and EBUS-TBNA was a useful, less-invasive diagnostic method particularly for these patients. Out of 14 patients, 11 (79%) had a history of lung cancer and 10 of them (91%) had received surgical resection. In conclusion, we confirmed that EBUS-TBNA obtained the pathological diagnosis in a less-invasive manner in all cases. Despite the small number of cases, our results can reveal the usefulness of EBUS-TBNA particularly in patients with previously treated thoracic malignancy.
PMCID: PMC3420288  PMID: 22108942
Endobronchial ultrasound; Endobronchial ultrasound-guided transbronchial needle aspiration; Lung cancer; Malignancy; Recurrence
15.  Higher Expression of Receptor Tyrosine Kinase Axl, and Differential Expression of its Ligand, Gas6, Predict Poor Survival in Lung Adenocarcinoma Patients 
Annals of Surgical Oncology  2012;20(Suppl 3):467-476.
Downstream activation through receptor tyrosine kinases (RTKs) plays important roles in carcinogenesis. In this study, we assessed the clinical involvement of Axl, an RTK, and its ligand, Gas6, in surgically treated lung adenocarcinoma.
Axl and Gas6 mRNA and protein expression levels were quantified using quantitative real-time polymerase chain reaction and immunohistochemistry, respectively, in completely resected lung adenocarcinoma tissues (n = 88) and were evaluated for correlation with clinicopathologic features and patient survival.
Higher expressions of Axl mRNA/protein and Gas6 protein were significantly related to worse clinicopathological features and prognosis (5-year overall survival rates: Axl mRNA low: 72.3 %, high: 49.7 %, P = 0.047; Axl protein low: 77.5 %, high: 38.6 %, P < 0.001; and Gas6 protein low: 70.5 %, high: 48 %, P = 0.042). On the contrary, higher Gas6 mRNA expression was related to better clinicopathological features and prognosis (5-year overall survival rates: Gas6 mRNA low: 59.2 %, high: 81.8 %, P = 0.054). Multivariate analysis suggests that high Axl mRNA expression may be an independent factor for poor patient prognosis (P = 0.04).
In lung adenocarcinoma, Axl and Gas6 expression levels were associated with tumor advancement and patient survival, thus rendering them as reliable biomarkers and potential targets for treatment of lung adenocarcinoma.
PMCID: PMC3853411  PMID: 23242819
16.  Oxidative stress induced Interleukin-32 mRNA expression in human bronchial epithelial cells 
Respiratory Research  2012;13(1):19.
Chronic obstructive pulmonary disease (COPD) is characterized by airflow obstruction and persistent inflammation in the airways and lung parenchyma. Oxidative stress contributes to the pathogenesis of COPD. Interleukin (IL)-32 expression has been reported to increase in the lung tissue of patients with COPD. Here, we show that IFNγ upregulated IL-32 expression and that oxidative stress augmented IFNγ-induced-IL-32 expression in airway epithelial cells. We further investigated transcriptional regulation responsible for IFNγ induced IL-32 expression in human airway epithelial cells.
Human bronchial epithelial (HBE) cells were stimulated with H2O2 and IFNγ, and IL-32 expression was evaluated. The cell viability was confirmed by MTT assay. The intracellular signaling pathways regulating IL-32 expression were investigated by examining the regulatory effects of MAPK inhibitors and JAK inhibitor after treatment with H2O2 and IFNγ, and by using a ChIP assay to identify transcription factors (i.e. c-Jun, CREB) binding to the IL-32 promoter. Promoter activity assays were conducted after mutations were introduced into binding sites of c-Jun and CREB in the IL-32 promoter. IL-32 expression was also examined in HBE cells in which the expression of either c-Jun or CREB was knocked out by siRNA of indicated transcription factors.
There were no significant differences of cell viability among groups. After stimulation with H2O2 or IFNγ for 48 hours, IL-32 expression in HBE cells was increased by IFNγ and synergistically upregulated by the addition of H2O2. The H2O2 augmented IFNγ induced IL-32 mRNA expression was suppressed by a JNK inhibitor, but not by MEK inhibitor, p38 inhibitor, and JAK inhibitor I. Significant binding of c-Jun and CREB to the IL-32 promoter was observed in the IFNγ + H2O2 stimulated HBE cells. Introducing mutations into the c-Jun/CREB binding sites in the IL-32 promoter prominently suppressed its transcriptional activity. Further, knocking down CREB expression by siRNA resulted in significant suppression of IL-32 induction by IFNγ and H2O2 in HBE cells.
IL-32 expression in airway epithelium may be augmented by inflammation and oxidative stress, which may occur in COPD acute exacerbation. c-Jun and CREB are key transcriptional factors in IFNγ and H2O2 induced IL-32 expression.
PMCID: PMC3361495  PMID: 22413812
COPD; acute exacerbation; IFNγ
17.  Intratumoral Wnt2B expression affects tumor proliferation and survival in malignant pleural mesothelioma patients 
Malignant pleural mesothelioma (MPM) is an aggressive thoracic tumor with a poor prognosis. We performed a comprehensive clinical study on the intratumoral expression of Wnt1, Wnt2B and Wnt5A in MPM. One hundred and seven MPM patients were investigated. Immunohistochemistry was performed to evaluate the intratumoral expression of Wnt1, Wnt2B, Wnt5A, survivin and c-Myc, and the Ki-67 proliferation index. The apoptotic index was evaluated by the TUNEL method. Among the 107 MPMs, 23 MPMs (21.5%) were Wnt1-high tumors, 72 MPMs (67.3%) were Wnt2B-high tumors and 54 MPMs (50.5%) were Wnt5A-high tumors. There was no correlation among the levels of Wnt expression. The percentage of Wnt2B-positive tumors was significantly higher compared to that of the other Wnts (p<0.0001). Furthermore, intratumoral Wnt2B expression significantly correlated with the expression of survivin (p<0.001) and c-Myc (p<0.001). Regarding tumor biology, the Ki-67 proliferation index was significantly higher in the Wnt2B-high tumors than in the Wnt2B-low tumors (p=0.0438). In addition, the overall survival was significantly lower in patients with Wnt2B-high tumors than in those with Wnt2B-low tumors (p=0.0238). A Cox multivariate analysis also demonstrated the Wnt2B status to be a significant prognostic factor in MPM patients (p=0.0042). Intratumoral Wnt2B expression was associated with the expression of survivin and c-Myc, tumor proliferation and patient survival in MPM. Wnt2B is a potential molecular target for the treatment of Wnt2B-overexpressing MPMs.
PMCID: PMC3438599  PMID: 22969998
Wnt2B; survivin; c-Myc; proliferation; prognosis; mesothelioma
18.  Induction Chemoradiotherapy Followed by Surgical Resection for Clinical T3 or T4 Locally Advanced Non–Small Cell Lung Cancer 
Annals of Surgical Oncology  2012;19(8):2685-2692.
To examine the usefulness of trimodality therapy in patients with clinical T3 or T4 (cT3–4) locally advanced non–small cell lung cancer (LA-NSCLC).
Between 1997 and 2009, a total of 76 LA-NSCLC patients with cT3–4 underwent surgery. Among them, 36 patients underwent induction chemoradiotherapy with docetaxel and cisplatin plus concurrent radiation followed by surgery (IC group). The other 40 patients initially underwent surgery (IS group). The outcomes of the IC and IS groups were then investigated. To minimize possible biases caused by confounding treatment indications, we performed a retrospective cohort analysis by applying a propensity score (PS). Patients were divided into three groups according to PS tertiles, and comparisons between the IC and IS groups were made by PS tertile-stratified Cox proportional hazard models.
For the entire cohort, which had a median follow-up duration of 48 months, the 3- and 5-year overall survival rates were 83.8 and 78.9%, respectively, in the IC group, versus 66.8 and 56.5%, respectively, in the IS group (P = 0.0092). After adjustments for potentially confounding variables, the IC group continued to have a significantly longer overall survival than the IS group (P = 0.0045). In addition, when the analysis was limited to 52 patients with cT3–4N0 or N1 disease, the IC group had a significantly longer overall survival than the IS group after adjustments for confounding variables (P = 0.019).
Our study indicates that trimodality therapy is highly effective in patients with cT3–4 LA-NSCLC.
Electronic supplementary material
The online version of this article (doi:10.1245/s10434-012-2302-x) contains supplementary material, which is available to authorized users.
PMCID: PMC3404289  PMID: 22396006
19.  Engagement of Overexpressed Her2 with GEP100 Induces Autonomous Invasive Activities and Provides a Biomarker for Metastases of Lung Adenocarcinoma 
PLoS ONE  2011;6(9):e25301.
Overexpression of Her2/ErbB2/Neu in cancer is often correlated with recurrent distant metastasis, although the mechanism still remains largely elusive. We have previously shown that EGFR, when tyrosine-phosphorylated, binds to GEP100/BRAG2 to activate Arf6, which induces cancer invasion and metastasis. We now show that overexpressed Her2 in lung adenocarcinoma cells also employs GEP100. Like EGFR-GEP100 binding, this association is primarily mediated by the pleckstrin homology (PH) domain of GEP100 and Tyr1139/Tyr1196 of Her2. Tyr1139/Tyr1196 are autonomously phosphorylated, when Her2 is overexpressed. Accordingly, invasive activities mediated by the Her2-GEP100 pathway are not dependent on external factors. Blocking Her2-GEP100 binding, as well as its signaling pathway all inhibit cancer invasive activities. Moreover, our clinical study indicates that co-overexpression of Her2 with GEP100 in primary lung adenocarcinomas of patients is correlated with the presence of their node-metastasis with a statistical significance. Since the GEP100 PH domain interacts with both Her2 and EGFR, targeting this domain may provide novel cancer therapeutics.
PMCID: PMC3178645  PMID: 21966491
20.  PIK3CA Mutations and Copy Number Gains in Human Lung Cancers 
Cancer research  2008;68(17):6913-6921.
We investigated the frequency and function of mutations and increased copy number of the PIK3CA gene in lung cancers. PIK3CA mutations are one of the most common gene changes present in human cancers. We analyzed the mutational status of exons 9 and 20 and gene copy number of PIK3CA using 86 non–small cell lung cancer (NSCLC) cell lines, 43 small cell lung cancer (SCLC) cell lines, 3 extrapulmonary small cell cancer (ExPuSC) cell lines, and 691 resected NSCLC tumors and studied the relationship between PIK3CA alterations and mutational status of epidermal growth factor receptor (EGFR) signaling pathway genes (EGFR, KRAS, HER2, and BRAF). We also determined PIK3CA expression and activity and correlated the findings with effects on cell growth. We identified mutations in 4.7% of NSCLC cell lines and 1.6% of tumors of all major histologic types. Mutations in cell lines of small cell origin were limited to two ExPuSC cell lines. PIK3CA copy number gains were more frequent in squamous cell carcinoma (33.1%) than in adenocarcinoma (6.2%) or SCLC lines (4.7%). Mutational status of PIK3CA was not mutually exclusive to EGFR or KRAS. PIK3CA alterations were associated with increased phosphatidylinositol 3-kinase activity and phosphorylated Akt expression. RNA interference–mediated knockdown of PIK3CA inhibited colony formation of cell lines with PIK3CA mutations or gains but was not effective in PIK3CA wild-type cells. PIK3CA mutations or gains are present in a subset of lung cancers and are of functional importance.
PMCID: PMC2874836  PMID: 18757405
21.  MET gene amplification or EGFR mutation activate MET in lung cancers untreated with EGFR tyrosine kinase inhibitors 
We analyzed MET protein and copy number in NSCLC with or without EGFR mutations untreated with EGFR tyrosine kinase inhibitors (TKIs). MET copy number was examined in 28 NSCLC and 4 human bronchial epithelial cell lines (HBEC) and 100 primary tumors using quantitative real-time PCR. Positive results were confirmed by array comparative genomic hybridization and fluorescence in-situ hybridization. Total and phospho-MET protein expression was determined in 24 NSCLC and 2 HBEC cell lines using Western blot. EGFR mutations were examined for exon 19 deletions, T790M, and L858R. Knockdown of EGFR with siRNA was performed to examine the relation between EGFR and MET activation. High-level MET amplification was observed in 3 of 28 NSCLC cell lines and in 2 of 100 primary lung tumors that had not been treated with EGFR-TKIs. MET protein was highly expressed and phosphorylated in all the 3 cell lines with high MET amplification. In contrast, 6 NSCLC cell lines showed phospho-MET among 21 NSCLC cell lines without MET amplification (p = 0.042). Furthermore, those 6 cell lines harboring phospho-MET expression without MET amplification were all EGFR mutant (p = 0.0039). siRNA-mediated knockdown of EGFR abolished phospho-MET expression in examined 3 EGFR mutant cell lines of which MET gene copy number was not amplified. By contrast, phospho-MET expression in 2 cell lines with amplified MET gene was not down-regulated by knockdown of EGFR. Our results indicated that MET amplification was present in untreated NSCLC and EGFR mutation or MET amplification activated MET protein in NSCLC.
PMCID: PMC2767331  PMID: 19117057
MET; amplification; EGFR; gefitinib; lung cancer
22.  Sequential Molecular Changes during Multistage Pathogenesis of Small Peripheral Adenocarcinomas of the Lung 
We investigated EGFR and KRAS alterations among atypical adenomatous hyperplasia and small lung adenocarcinomas with bronchioloalveolar features to understand their role during multistage pathogenesis.
Sixty lesions measuring 2 cm or less were studied, including 38 noninvasive lesions (4 atypical adenomatous hyperplasias, 19 Noguchi type A and 15 type B) and 22 invasive lesions (type C) based on the World Health Organization classification and Noguchi’s criteria. EGFR and KRAS mutations were examined using PCR-based assays. EGFR copy number was evaluated using fluorescence in situ hybridization.
EGFR and KRAS mutations were found in 26 (43.3%) and 5 (8.3%) lesions, respectively. Increased EGFR copy number status was identified in 10 lesions (16.7%), both mutant and wild type. EGFR or KRAS mutations were present in 39.5% and 7.9% (respectively) of noninvasive lesions and 50% or 9.1% (respectively) of invasive lesions. EGFR copy number was increased in 7.9% and 31.8% of noninvasive and invasive lesions (P = 0.029). Multivariate analysis revealed that increased EGFR copy number was the only significant factor to associate with invasive lesions (P = 0.035).
EGFR and KRAS mutations occur early during the multistage pathogenesis of peripheral lung adenocarcinomas. By contrast, increased EGFR copy number is a late event during tumor development and plays a role in the progression of lung adenocarcinoma independent of the initiating molecular events.
PMCID: PMC2758162  PMID: 18379350
Multistage pathogenesis; EGFR; KRAS; Mutation; Amplification
23.  Anti-tumor effect of bisphosphonate (YM529) on non-small cell lung cancer cell lines 
BMC Cancer  2007;7:8.
YM529 is a newly developed nitrogen-containing bisphosphonate (BP) classified as a third-generation BP that shows a 100-fold greater potency against bone resorption than pamidronate, a second-generation BP. This agent is, therefore expected to be extremely useful clinically for the treatment of osteoporosis and hypercalcemia. Recently, YM529 as well as other third-generation BPs have also been shown to exert anti-tumor effects against various types of cancer cells both in vitro or/and in vivo. In this study, we investigate the anti-tumor effect of YM529 on non-small cell lung cancer (NSCLC).
Direct anti-tumor effect of YM529 against 8 NSCLC cell lines (adenocarcinoma: H23, H1299, NCI-H1819, NCI-H2009, H44, A549, adenosquamous cell carcinoma: NCI-H125, squamous cell carcinoma: NCI-H157) were measured by MTS assay and calculated inhibition concentration 50 % (IC50) values. YM529 induced apoptosis of NCI-H1819 was examined by DNA fragmentation of 2 % agarose gel electrophoresis and flowcytometric analysis (sub-G1 method). We examined where YM529 given effect to apoptosis of NSCLC cells in signaling pathway of the mevalonate pathway by western blotting analysis.
We found that there was direct anti-tumor effect of YM529 on 8 NSCLC cell lines in a dose-dependent manner and their IC50 values were 2.1 to 7.9 μM and YM529 induced apoptosis and G1 arrest cell cycle with dose-dependent manner and YM529 caused down regulation of phospholyration of ERK1/2 in signaling pathways of NSCLC cell line (NCI-H1819).
Our study demonstrate that YM529 showed direct anti-tumor effect on NSCLC cell lines in vitro, which supports the possibility that third-generation BPs including YM529 can be one of therapeutic options for NSCLC.
PMCID: PMC1781945  PMID: 17222343
24.  UCHL1 provides diagnostic and antimetastatic strategies due to its deubiquitinating effect on HIF-1α 
Nature Communications  2015;6:6153.
Hypoxia-inducible factor 1 (HIF-1) plays a role in tumour metastases; however, the genes that activate HIF-1 and subsequently promote metastases have yet to be identified. Here we show that Ubiquitin C-terminal hydrolase-L1 (UCHL1) abrogates the von Hippel–Lindau-mediated ubiquitination of HIF-1α, the regulatory subunit of HIF-1, and consequently promotes metastasis. The aberrant overexpression of UCHL1 facilitates distant tumour metastases in a HIF-1-dependent manner in murine models of pulmonary metastasis. Meanwhile, blockade of the UCHL1–HIF-1 axis suppresses the formation of metastatic tumours. The expression levels of UCHL1 correlate with those of HIF-1α and are strongly associated with the poor prognosis of breast and lung cancer patients. These results indicate that UCHL1 promotes metastases as a deubiquitinating enzyme for HIF-1α, which justifies exploiting it as a prognostic marker and therapeutic target of cancers.
When stabilized, HIF-1 can activate adaptation to hypoxia and metastasis. Here the authors show that upregulation of Ubiquitin C-terminal hydrolase-L1 in human cancers promotes metastasis and correlates with poor prognosis because of its role in opposing ubiquitin-mediated degradation of HIF-1.
PMCID: PMC4317501  PMID: 25615526

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