To develop sero-diagnostic markers for lung cancer, we generated monoclonal antibodies using lung adenocarcinoma (AC)-derived A549 cells as antigens by employing the random immunization method. Hybridoma supernatants were immunohistochemically screened for antibodies with AMeX-fixed and paraffin-embedded A549 cell preparations. Positive clones were monocloned twice through limiting dilutions. From the obtained monoclonal antibodies, one designated as KU-Lad-001 was recognized as calnexin (CANX) based on immunoprecipitation and MADLI TOF/TOF-MS analysis. To evaluate the utility of this antibody as a sero-diagnostic marker for lung cancer, we performed reverse-phase protein array analysis with samples of 195 lung cancer patients and 100 healthy controls. The CANX expression levels were significantly higher in lung cancer patients than in healthy controls (P<0.0001), and the area under the curve of ROC was 0.980, with 96.9% specificity and 99.0% sensitivity. Furthermore, since CANX was also detected in stage I disease, the serum CANX levels should be applicable markers discriminating lung cancer patients from healthy controls and possibly used in the detection of early lung cancer. To our knowledge, the present results provide evidence that CANX may be a novel sero-diagnostic marker for lung cancer.
To investigate the relationships between the expression of MUC5B and clinicopathological parameters, the expression of MUC5B was immunohistochemically studied. MUC5B expression was observed in 129 of 198 (65.2%) adenocarcinomas and in 4 of 49 (8.2%) squamous cell carcinomas (P < 0.00001). MUC5B expression was significantly associated with poorer differentiation (P = 0.0303), higher pathological TNM stage (p = 0.0153) and poorer prognosis of adenocarcinoma patients (P = 0.0017). Multivariable analysis with Cox proportional hazards models confirmed that MUC5B expression increased the hazard of death after adjusting for other clinicopathological factors (HR = 2.66; 95%CI, 1.26–5.61). We also immunohistochemically evaluated TTF-1 expression and found that the combination of MUC5B with TTF-1 is a useful marker for adenocarcinomas. The diagnostic accuracies of TTF-1 and MUC5B for adenocarcinoma were 83.8% and 70.4%, respectively. The accuracy increased to 94.3% when the two factors were combined. In survival analysis, the MUC5B(High)/TTF-1(−) group was significantly associated with a poorer outcome compared with the MUC5B(Low)/TTF-1(+) group (p < 0.0001). The present study suggested that the combination of MUC5B and TTF-1 expression is useful for discriminating adenocarcinomas from squamous cell carcinomas, yielding prognostic significance in patients with lung adenocarcinoma.
Background: Many functional molecules controlling diverse cellular function are included in low-molecular weight proteins and peptides. Materials and Methods: To identify proteins controlling function in lung adenocarcinomas (AC), we performed two-dimensional gel electrophoresis employing tricine-SDS polyacrylamide in the second dimension (tricine 2-DE). This system was able to detect proteins under 1 kDa even with posttranslational modifications. To confirm the utility of detected proteins as novel tumor markers for AC, we performed immunohistochemical analysis using 170 formalin-fixed and paraffin-embedded lung AC tissues. Results: Tricine 2-DE revealed that five proteins including S100A16 were overexpressed in lung AC-derived cells compared with lung squamous cell carcinoma, small cell carcinoma, and large cell neuroendocrine carcinomaderived cells. Immunohistochemically, S100A16 showed various subcellular localization in lung cancer tissues and a membranous staining status was correlated with the T-factor (P=0.0008), pathological stage (P=0.0015), differentiation extent (P=0.0001), lymphatic invasion (P=0.0007), vascular invasion (P=0.0001), pleural invasion (P=0.0087), and gender (P=0.039), but not with the age or smoking history. More importantly, membranous staining of S100A16 was significantly correlated with a poorer overall survival of either stage I (P=0.0088) or stage II / III (P=0.0003) lung AC patients, and multivariate analysis confirmed that membranous expression of S100A16 was an independent adverse prognostic indicator (P=0.0001). Conclusions: The present results suggest that S100A16 protein is a novel prognostic marker for lung AC.
Background: Immunotherapy can become a crucial therapeutic option to improve the prognosis of patients with non-small-cell lung cancer (NSCLC). Here, we evaluated the impact of programmed cell death ligand-1 (PD-L1) expression in surgically resected NSCLCs. Methods: We estimated PD-L1 expression in 229 consecutive NSCLC specimens using rabbit polyclonal antibodies to human PD-L1 in a SP263 immunohistochemical assay and evaluated PD-L1 expression for potential associations with clinicopathological parameters and survival time. Results: PD-L1 expression was significantly higher in tumors from men or current smokers. Squamous cell carcinoma histology was independently associated with high PD-L1 expression according to multivariate analysis (p = 0.015). The 5-year survival rate of patients was 70%, and the difference in the 5-year survival rate according to PD-L1 expression was not statistically significant (high expression group [67%] vs. low expression group [68%]); however, the squamous cell carcinoma group exhibited significantly lower 5-year survival rates as compared to the non-squamous cell carcinoma group (53 and 71%, respectively; p = 0.026). Conclusion: Here, we revealed high PD-L1 expression and poor prognosis observed in patients with surgically resected squamous NSCLC as compared with non-squamous NSCLC. Our results support the identification of patient subsets that most likely respond to anti-PD-1 therapy as the first step in precision medicine.
Background: Several studies have reported that S100A14 plays important roles during different steps of the tumorigenic process and tumor progression of several types of cancer. The aim of the present study was to investigate the clinicopathological and prognostic significance and functional roles of S100A14 in lung adenocarcinoma. Patients and Methods: S100A14 expression was immunohistochemically studied in 166 consecutive resected lung adenocarcinomas, and its correlation with clinicopathological parameters was evaluated. Functional roles of S100A14 in lung adenocarcinoma were investigated based on invasion and migration assays on a small interfering (si)RNA-treated lung adenocarcinoma cell line. Results: S100A14 expression was detected in 82 of the 166 (49.4%) lung adenocarcinomas. S100A14 expression was significantly correlated with sex, poorer tumor differentiation, higher disease stages, larger tumor size, lymph node metastasis, intratumoral vascular invasion, intratumoral lymphatic invasion, pleural invasion, and poorer prognosis. Invasion and wound healing assays showed that S100A14 siRNA knockdown cells had significantly decreased invasion and migration abilities compared with siRNA control cells. Conclusion: S100A14 is expressed in a subset of lung adenocarcinoma, and its expression is related to certain clinicopathological parameters. Furthermore, S100A14 expression was strongly correlated with migration and invasion in lung adenocarcinoma cells.
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