Objective To investigate whether the Notch-1 signaling pathway is involved in the acquisition of the epithelial-mesenchymal transition (EMT) phenotype of gefitinib-acquired resistant lung cancer cells.Methods The PC9 cell line (harboring EGFR exon 19 deletion) and PC9/AB2 cells (gefitinibacquired resistant PC9 cells) were used.siRNA targeting Notch-1 eukaryotic expression vector (siNotch-1) was constructed and PC9/AB2 cells were transfected with siNotch-1.The protein expression of EGFR,Akt,Erk,Notch receptors and ligands,TGF-β receptors,E-cadherin,Vimentin,and Snail were detected by Western blot assay.DNA sequencing and fluorescence in situ hybridization (FISH) analysis were processed to detect mutation of EGFR exon 20 and MET amplification,respectively.For cytotoxicity assay,cell viability was assessed by Cell Counting Kit 8.Results Gefitinib resistant cell line PC9/AB2 had no evidence of MET amplification or EGFR T790M mutation.The expression of Notch-1 was upregulated in gefitinib resistant PC9/AB2 cells compared with that in gefitinib-sensitive PC9 cells.There were no significant protein expression differences of other Notch receptors,Notch ligands or TGF-β receptors between both paired cell lines.Western blot results showed that protein expression of E-cadherin was greatly reduced in PC9/AB2 cells,while elevated levels of Vimentin and Snail were observed.A significant reduction of the expression of Snail and Vimentin in Notch-1 siRNA transfected PC9/AB2 cells with increased E-cadherin expression was found by Western blot assay.PC9/AB2 cells displayed a round like cell morphology after Notch-1 siRNA transfection.Silence of Notch-1 decreased colony-formation ability but enhanced sensitivity of gefitinib on PC9/AB2 cells.Conclusion Notch-1 might play a novel role in acquired resistance to gefitinib,which could be reversed by inhibiting Notch-l.

PURPOSE: Adenoid cystic carcinoma (ACC) of the trachea and bronchus is a rare tumor. Although MYB-NFIB oncogene fusion and Notch1 mutation have been identified in ACC, little is known about the expression and clinical significance of Notch1 and its target gene fatty acid binding protein 7 (FABP7) in tracheobronchial ACC. MATERIALS AND METHODS: Primary tracheobronchial ACC that were resected between 1998 and 2014 were identified through the pathology and oncology database from five thoracic oncology centers in China. A tissue array was constructed from the patients’ samples and the expressions of Notch1 and FABP7 were evaluated by immunohistochemistry. The association between the expression of both markers and survival was determined. RESULTS: Overexpression of Notch1 and FABP7, detected in 37.8% and 38.3% of 368 patients with tracheobronchial ACC, respectively, was an independent prognostic indicator for recurrencefree survival (RFS) by multivariable Cox proportional hazard model (p=0.032 and p=0.048, respectively). Overexpression of Notch1, but not of FABP7, predicted overall survival (OS) (p=0.018). When categorized into four groups according to coexpression of Notch1 and FABP7, patients with overexpression of both Notch1 and FABP7 belonged to the group with the shortest RFS and OS (p=0.01 and p=0.048, respectively). CONCLUSION: Expression of Notch1 and FABP7, and coexpression of Notch1 and FABP7, is strongly associated with poor survival in resected tracheobronchial ACC. These data are consistent with the hypothesis that poor differentiation of tracheobronchial ACC correlates with the activation of Notch signaling.
Adenoids* ; Bronchi ; Carcinoma, Adenoid Cystic* ; Carrier Proteins* ; China ; Humans ; Immunohistochemistry ; Oncogene Fusion ; Pathology ; Prognosis ; Proportional Hazards Models ; Retrospective Studies* ; Trachea

Background and objective It has been proven that any changes of transforming growth factorβ(TGF-β)-Smad signal transduction pathway will lead to abnormalities of signal transmission and the out of control during cell growth and differentiation, resulting in cancer development. hTe aim of this study is to investigate the prognostic values of TGF-β1, Smad2 and Smad4 in resected non-small cell lung cancer (NSCLC). Methods hTe expression of TGF-β1, Smad2, and Smad4 was evaluated by immunohistochemistry in 85 patients with NSCLC. hTe relationships among the expression of these proteins, clinicopathological factors, and prognosis were also analyzed. Results TGF-β1 positive expression was signiif-cantly correlated with the late stage and lymph node involvement. No signiifcant association existed between the expression of Smad2 and the clinicopathological characteristics. hTe lack of Smad4 expression was associated with the advanced tumor stage (P=0.014). Multivariate analysis indicated that lymph node involvement (P=0.001) was an independent prognostic factor in the 85 NSCLC patients. hTe positive expression levels of TGF-β1 (P=0.032) and N stage (P=0.028) were demonstrated to be independent risk factors for survival among 47 lung adenocarcinoma patients. Adenocarcinoma patients with TGF-β1 positive expression demonstrated an unfavorable survival outcome (P=0.0376). Conclusion TGF-β1 may be an independent predic-tor of survival in resected lung adenocarcinoma patients.

BACKGROUND: The purpose of this study is to compare the survival time of non-small cell lung cancer (NSCLC) patients with different organ metastasis. Among all cancers, the morbidity and mortality of lung cancer is the highest worldwide, which may caused by local recurrence and distant metastasis, and the location of metastasis may predict the prognosis of patients. METHODS: A total of 117,542 patients with NSCLC diagnosed between 2010 and 2014 were enrolled from Surveillance, Epidemiology, and End Result (SEER) databases, and the relationship between distant metastasis and survival time was retrospectively analyzed. RESULTS: Of all the 117,542 patients diagnosed with non-small cell lung cancer, 42,071 (35.8%) patients had different degrees of distant metastasis during their medical history, including 26,932 single organ metastases and 15,139 multiple organ metastases, accounting for 64.0% and 36.0% of the metastatic patients respectively. Compared with patients with no metastasis, whose median survival time was 21 months, the median survival time of patients with metastases was 7 months (lung), 6 months (brain), 5 months (bone), 4 months (liver), and 3 months (multiple organ) respectively, and the difference was significant (P<0.001, except liver vs multiple organ P=0.650); Most patients with NSCLC (88.4%) eventually died of lung cancer. CONCLUSIONS Distant metastasis of NSCLC patients indicates poor prognosis. In NSCLC patients with single organ metastasis, the prognosis of lung metastasis is the best, and liver metastasis is the worst, and multiple organ metastasis is worse than single organ metastasis.
Aged ; Aged, 80 and over ; Bone Neoplasms ; mortality ; secondary ; Brain Neoplasms ; mortality ; secondary ; Carcinoma, Non-Small-Cell Lung ; mortality ; pathology ; Female ; Humans ; Liver Neoplasms ; mortality ; secondary ; Lung Neoplasms ; mortality ; pathology ; Male ; Middle Aged ; Neoplasm Metastasis ; Neoplasm Staging ; Prognosis ; Retrospective Studies