• Asian Pacific Journal of Cancer Prevention
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• v.14 no.11
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• pp.6321-6326
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• 2013

Introduction: Lung cancer is extremely harmful to human health and has one of the highest worldwide incidences of all malignant tumors. Approximately 80% of lung cancers are classified as non-small cell lung cancers (NSCLCs). Cisplatin-based multidrug chemotherapy regimen is standard for such lesions, but drug resistance is an increasing problem. F-box/WD repeat-containing protein 7 (FBW7) is a member of the F-box protein family that regulates cell cycle progression, and cell growth and differentiation. FBW7 also functions as a tumor suppressor. Methods: We used cell viability assays, Western blotting, and immunofluorescence combined with siRNA interference or plasmid transfection to investigate the underlying mechanism of cisplatin resistance in NSCLC cells. Results: We found that FBW7 upregulation significantly increased cisplatin chemosensitivity and that cells expressing low levels of FBW7, such as NCI-H1299 cells, have a mesenchymal phenotype. Furthermore, siRNA-mediated silencing or plasmid-mediated upregulation of FBW7 resulted in altered epithelial-mesenchymal transition (EMT) patterns in NSCLC cells. These data support a role for FBW7 in regulating the EMT in NSCLC cells. Conclusion: FBW7 is a potential drug target for combating drug resistance and regulating the EMT in NSCLC cells.

• Tuberculosis and Respiratory Diseases
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• v.48 no.3
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• pp.324-330
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• 2000

Objective : Lung cancer arises after a series of morphological changes, which take several years to progress from normal epithelium to invasive cancer. Multiple molecular changes and growth factor production have been documented in lung cancers, both small cell and non-small cell types. Insulin-like growth factors(IGFs) are important mitogenic and anabolic peptides, both in vivo and in vitro, and are thought to be significant autocrine-paracrine factors involved in normal and malignant cell proliferation. In this study, the degree of expression of IGF-1 on the immunohistochemical staining in human non-small cell lung cancer(NSCLC) cells and small cell lung cancer (SCLC) cells were investigated. Methods : Immunohistochemical staining for IGF-1 was performed in 15 cases of small cell carcinoma, 15 cases of squamous cell carcinoma, 15 cases of adenocarcinoma, and 12 cases of bronchoalveolar carcinoma. Results : The expression of IGF-1 on the immunohistochemical staining significantly increased in NSCLC cells than in SCLC cells. Conclusion : These results suggest the expression of IGF-1 in human lung cancer cells. The immunohistochemical staining of IGF-1 in lung cancer cell lines may assist in the differentiation of NSCLC and SCLC.

• Tuberculosis and Respiratory Diseases
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• v.40 no.4
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• pp.395-403
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• 1993

Background: The cell cycle is composed of a series of steps which can be negatively or positively regulated by various factors. Alteration or inactivation of p53 by mutations, or by its interactions with oncogene products of DNA tumor viruses, can lead to cancer. Mutations of the p53 gene occur frequently in human primary lung cancers and the wild-type p 53 allele is often concomitantly deleted. These suggest that deprivation of suppressive role of the wild-type p53 may ensure tumor cell growth presumable by the mutant p53 gene. Methods: In an attempt to investigate this hypothesis, a mutant p53 gene was immunohistochemically demonstrated in the formalin-fixed paraffin-embedded tissue sections of lung cancers by using a monoclonal antibody p53 (Ab-3 and clone DO7). Results: The expression of p53 (DO7) was found in all four normal lung tissues, four small cell carcinomas, and four non small cell carcinomas in histologic types of lung cancer. In the six normal lung tissues the expressions of p53 (Ab-3) were not found. Contrarily, the expression of p53 (Ab-3) was found in the nuclei of lung cancers among fifteen (46.9%) of thirty-two cases studied. The expression of p53 (Ab-3) was disclosed in three case (37.5%) of eight small cell carcinomas and twelve cases (50.0%) of twenty-four non small cell carcinomas in histologic types of lung cancer. Conclusion: These findings suggest that expression of the mutant p53 is related to the one of events in the pathogenesis of human lung cancer and the role of the other oncogenes might be also related to the development of lung cancers.

• Journal of Chest Surgery
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• v.39 no.5 s.262
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• pp.376-381
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• 2006

Background: The Ki-67 protein is a biomarker associated with cell proliferation and a valuable negative prognostic factor in non-small cell lung cancer. We investigated the Ki-67 protein expression in resected non-small cell lung cancer to evaluate the impact on clinicopathological characteristics and postoperative prognosis. Material and Method: Using monoclonal antibody Ki-67, we immunohistochemically examined 38 surgically resected non-small ceil lung cancers to determine Ki-67 Labeling Index (LI). We analysed the differences of clinicopathological characteristics and postoperative recurrence and survival between High Ki-67 Group $(LI{\ge}20%)$ and Low Ki-67 Group (LI<20%). Result: The Ki-67 LIs were heterogenous and a mean values was $20.0{\pm}20.05%$. There were no significant differences in age, sex, smoking, TNM stage, and vascular invasion between High Ki-67 Group and Low Ki-67 Group. A High Ki-67 Group was significantly associated with squamous cell type, poor differentiation, and lymphatic invasion $(p{\le}0.05)$. High Ki-67 Group showed a trend of lower survival (median 47.2 vs. 90.5 months, p=0.312) and lower disease-free survival (median 18.2 vs. 72.3 months, p=0.327) than Low Ki-67 Group. Conclusion: These results indicate that increased Ki-67 protein expression may be a negative prognostic factor and showed a trend of shortened survival and disease-free survival. To evaluate the pivotal role of Ki-67 protein expression, a long-term follow-up and further study are required.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.24
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• pp.10591-10596
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• 2015

Background: Tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) has been reported to be associated with the development of various cancers. However, the role of TRAF6 in lung cancer remains unclear. Objective: To explore the expression and clinicopathological significance of TRAF6 protein in lung cancer tissues. Materials and Methods: Three hundred and sixty-five lung cancer samples and thirty normal lung tissues were constructed into 3 microarrays. The expression of TRAF6 protein was determined using immunohistochemistry (IHC). Furthermore, correlations between the expression of TRAF6 and clinicopathological parameters were investigated. Results: The expression of TRAF6 in total lung cancer tissues (365 cases), as well as in small cell lung cancer (SCLC, 26 cases) and non-small cell lung cancer (NSCLC, 339 cases) was significantly higher compared with that in normal lung tissues. The ROC curve showed that the area under curve of TRAF6 was 0.663 (95%CI 0.570~0.756) for lung cancer. The diagnostic sensitivity and specificity of TRAF6 were 52.6% and 80%, respectively. In addition, the expression of TRAF6 was correlated with clinical TNM stage, tumor size and lymph node metastasis in all lung cancers. Consistent correlations were also observed for NSCLCs. Conclusions: TRAF6 might be an oncogene and the expression of TRAF6 protein is related to the progression of lung cancer. Thus, TRAF6 might become a target for diagnosis and gene therapy for lung cancer patients.

• Tuberculosis and Respiratory Diseases
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• v.56 no.5
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• pp.514-522
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• 2004

Background : Non-steroidal anti-inflammatory drugs (NSAID) are useful in chemoprevention of colorectal cancers. Continuous NSAID administation causes 40% to 50% reduction in relative risk for colorectal cancer. Sulindac possesses an antiproliferative effect and induces apoptosis and tumor regression on colon cancer and other types of cancers. We intended to analyze the effects of sulindac in three non-small cell lung cancer cell lines. Materials and Methods : The human lung cancer cell lines, A549, NCI-H157 and NCI-H460 were used for this study. Viability was tested by MTT assay, and cell death rate was measured by lactate dehydrogenase(LDH) release. Apoptosis was estimated by flow cytometric analysis and nuclear staining. Results: Sulindac was able to decrease the viability of non-small cell lung cancer cells in a dose- and time- dependent manner. In a parallel effect of sulindac on cell death rate, LDH release was increased in sulindac-treated lung cancer cells. Sulindac significantly increased apoptosis characterized by an increase of $sub-G_0/G_1$ fraction and morphological change of nuclei. The rate of apoptotic cells after sulindac treatment in lung cancer cells increased in a time- and dose- dependent manner in flow cytometric analysis. Apoptotic cells were defined as nuclear shrinkage, chromatin condensation and nuclear fragmentation of cells. Conclusion : Sulindac decreases viability and induces the apoptosis of lung cancer cells. Further studies will be needed to elucidate the potential mechanism of sulindac-induced apoptosis in lung cancer cells.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.2
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• pp.639-643
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• 2013

Aim: Connexin 43 (Cx43) and E-cadherin are important biomarkers related with cancer. Their expression at protein and mRNA levels was here investigated in 50 primary lung carcinoma tissues and 20 samples of adjacent normal tissue of Chinese patients with non-small cell lung cancer (NSCLC). Methods: Protein and mRNA expression were evaluated by ABC immunohistochemistry and RT-PCR. Results: (1) The positive expression rates of Cx43 and E-cadherin protein were higher in the adjacent normal tissues than those in the primary lung carcinoma tissues; (2) the positive expression rates of Cx43 and E-cadherin protein decreased with NSCLC progression; (3) the expression of E-cadherin protein was not related with the pathological type of NSCLC; and (4) the relative quantity of the Cx43 or E-cadherin mRNA expression was correlated with the the histological type, clinical stage, cancer cell differentiation and the lymph node metastasis. Conclusion: The data suggested that the Cx43 and E-cadherin are reduced with NSCLC progression, and might be important biomarkers for judging the metastasis and prognosis.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.1
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• pp.453-456
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• 2013

Introduction: Lung cancer, the leading cause of cancer deaths, is divided into 2 main classes based on its biology, therapy and prognosis: non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). Many cases are at an advanced stage at diagnosis, which is a major obstacle to improving outcomes. It is important to define the high risk group patients for early diagnosis and chance of cure. Blood group antigens are chemical components on erythrocyte membranes but they are also expressed on a variety of epithelial cells. Links between ABO blood groups with benign or malignant diseases, such as gastric and pancreas cancers, have been observed for a long time. In this study, we aimed to investigate any possible relationship between lung cancer histological subtypes and ABO-Rh blood groups. Materials and Methods: The files of 307 pathologically confirmed lung cancer patients were reviewed retrospectively. Cases with a serologically determined blood group and Rh factor were included and those with a history of another primary cancer were excluded, leaving a total of 221. The distribution of blood groups of the lung cancer patients were compared with the distribution of blood groups of healthy donors admitted to the Turkish Red Crescent Blood Service in our city in the year 2012. Results: There was no significant difference between patients with lung cancer of either type and the control group in terms of distribution of ABO blood groups and Rh factor (p: 0.073). There was also no relationship with non small cell cancer histological subtypes. Conclusions: In this study, we found no relationship between the ABO-Rhesus blood groups and NSCLC and SCLC groups. To our knowledge this is the first analysis of ABO blood groups in SCLC patients.

• Biomedical Science Letters
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• v.14 no.4
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• pp.243-248
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• 2008

The Forkhead box M1 (FoxM1) has been shown to regulate transcription of cell cycle genes essential for $G_1$-S and $G_2$-M progression, including $p27^{kip1}$. The $p27^{kip1}$ gene is a member of the universal cyclin-dependent kinase inhibitor family. Immunohistochemical studies for FoxM1 and $p27^{kip1}$ were performed in 154 lung cancers (69 squamous cell carcinomas (SCC) and 85 adenocarcinomas (ADC)). Immunoreactivity for FoxM1 and $p27^{kip1}$ were found in 79 (51.3%) and 49 (31.8%) out of 154 cases, respectively. Forty-six (58.2%) of the 79 cases with a positive FoxM1 immunoreactivity showed a negative $p27^{kip1}$ expression in 154 lung cancers. According to histologic type, 22 (53.7%) of the 41 SCC cases with a positive FoxM1 immunoreactivity showed a negative $p27^{kip1}$ expression and 24 (63.2%) of the 38 ADC cases with a positive FoxM1 immunoreactivity showed a negative $p27^{kip1}$ expression. The expression of $p27^{kip1}$ was significantly higher in the SCC than in the ADC (P=0.050). There were no significant associations between the FoxM1 and $p27^{kip1}$ expressions and other clinicopathologic factors. These findings suggest that FoxM1 overexpression may diminish the expression of $p27^{kip1}$ protein in lung cancers. Further studies are needed to define the relation between FoxM1 and $p27^{kip1}$ for examining the mechanisms of tissue-specific FoxM1 expression.

• Development and Reproduction
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• v.24 no.2
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• pp.113-123
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• 2020

Metformin has been widely used as an antidiabetic drug, and reported to inhibit cell proliferation in many cancers including non-small cell lung cancer (NSCLC). In NSCLC cells, metformin suppresses PI3K/AKT/mTOR signaling pathway, but effect of metformin on RAS/RAF/MEK/ERK signaling pathway is controversial; several studies showed the inhibition of ERK activity, while others demonstrated the activation of ERK in response to metformin exposure. Metformin-induced activation of ERK is therapeutically important, since metformin could enhance cell proliferation through RAS/RAF/MEK/ERK pathway and lead to impairment of its anticancer activity suppressing PI3K/AKT/mTOR pathway, requiring blockade of both signaling pathways for more efficient antitumor effect. The present study tested the combination therapy of metformin and trametinib by monitoring the alterations of regulatory effector proteins of cell signaling pathways and the effect of the combination on cell viability in NCI-H2087 NSCLC cells with NRAS and BRAF mutations. We show that metformin alone blocks PI3K/AKT/mTOR signaling pathway but induces the activation and phosphorylation of ERK. The combination therapy synergistically decreased cell viability in treatment with low doses of two drugs, while it gave antagonistic effect with high doses. These findings suggest that the efficacy of metformin and trametinib combination therapy may depend on the alteration of ERK activity induced by metformin and specific cellular context of cancer cells.