• Tuberculosis and Respiratory Diseases
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• 제70권4호
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• pp.301-306
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• 2011

Background: It is well-known that cell-free nucleic acids rise in patients with many types of malignancies. Several recent experimental studies using cancer cell lines have shown that changes in cell-free RNA are predictive of the response to chemotherapy. The objective of this study was to determine whether quantification of free RNA can be used as a biomarker for clinical responses to chemotherapy in patients with lung cancer. Methods: Thirty-two patients with lung cancer (non-small cell lung cancer, n=24; small cell lung cancer, n=8) were divided into 2 groups according to their responses to chemotherapy (response group, n=19; non-response group, n=13). Blood samples were collected before and after two cycles of chemotherapy. Real-time quantitative RT-PCR was used for transcript quantification of the glyceraldehyde-3-phosphate dehydrogenase gene. Results: The pre chemotherapy values (Response group $41.36{\pm}1.72$ vs. Non-response group $41.33{\pm}1.54$, p=0.78) and post chemotherapy values (Response group $39.92{\pm}1.81$ vs. Non-response group $40.41{\pm}1.47$, p=0.40) for cell free RNA concentrations, expressed as Ct GAPDH (threshold cycle glyceraldehyde-3-phosphate dehydrogenase gene) levels, was not different between the two groups. There was no significant relationship between changes in the cell free RNA level clinical responses after chemotherapy (p=0.43). Conclusion: We did not find a correlation between quantification of serum cell free RNA levels and clinical responses to chemotherapy in patients with lung cancer. Further investigations are needed to determine whether the cell free RNA level is a useful predictor of responses to chemotherapy in patients with lung cancer.

• 대한의생명과학회지
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• 제20권2호
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• pp.49-55
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• 2014

RalBP1 is an ATP-dependent non-ABC transporter, responsible for the major transport function in many cells including many cancer cell lines, causing efflux of glutathione-electrophile conjugates of both endogenous metabolites and environmental toxins. RalBP1 is expressed in most human tissues, and is over-expressed in non-small cell lung cancer cell lines and in many other tumor types. Blockade of RalBP1 by various approaches has been shown to increase sensitivity to radiation and chemotherapeutic drugs, leading to cell apoptosis. In xenograft tumor models in mice, RalBP1 blockade or depletion results in complete and sustained regression across many cancer cell types including lung cancer cells. In addition to its transport function, RalBP1 has many other cellular and physiological functions, based on its domain structure which includes a unique Ral-binding domain and a RhoGAP catalytic domain, as well as docking sites for multiple signaling proteins. Additionally, RalBP1 is also important for stromal cell function in tumors, as it was recently shown to be required for efficient endothelial cell function and angiogenesis in solid tumors. In this review, we discuss the cellular and physiological functions of RalBP1 in normal and lung cancer cells.

• Asian Pacific Journal of Cancer Prevention
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• 제15권1호
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• pp.139-143
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• 2014

Although correlations between platelets and lung cancer has been recognized, effects on non-small cell lung cancer (NSCLC) metastasis remain to be determined in detail. In the present study, wound healing assays revealed a role of platelets in NSCLC cell migration. Thus the mean migration rate of lung adenocarcinoma A549 cells was significantly elevated after co-culture with platelets ($81.7{\pm}0.45%$ vs $41.0{\pm}3.50%$, P<0.01). Expression of GAPDH was examined by reverse transcription-polymerase chain reaction to study the effect of platelets on NSCLC cell proliferation. The result showed that the proliferation of A549 and SPC-A1 cells was not affected. Mouse models were established by transfusing A549 cells and SPC-A1 cells into mice lateral tail veins. We found tumor metastasis nodules in lungs to be increased significantly after co-transfusion with platelets (in A549, $4.33{\pm}0.33$ vs $0.33{\pm}0.33$, P=0.01; in SPC-A1, $2.67{\pm}0.33$ vs $0.00{\pm}0.00$, P=0.01). In addition, consecutive inoperable patients with newly diagnosed NSCLC (TNM stage III or IV) between January 2009 and December 2011 were retrospectively reviewed. Using the Kaplan-Meier method, NSCLC patients with a high platelet counts demonstrated a significantly shorter progression free survival compared with those with a low platelet count (> $200{\times}10^9/L$, 3 months versus ${\leq}200{\times}10^9/L$, 5 months, P=0.001). An elevated platelet count was also identified as an independent prognostic factor by Cox regression analysis for prgression free survival (adjusted hazard ratio: 1.69; 95% CI: 1.16, 2.46; P=0.006). This study suggested that platelets might contribute to the hematogenous metastatic process by promoting cancer cell migration, which eventually affects the prognosis of NSCLC.

• Journal of Chest Surgery
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• 제31권12호
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• pp.1200-1205
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• 1998

연구목적: 폐암은 protooncogene의 활성화와 종양억제유전인자(tumor suppressor gene)의 비활성화 등 다단 과정에 의하여 발생한다. 치료목적의 완전 절제가 가능하였던 제 IIIA기 비소세포폐암 환자에서 cyclin D1, p53, bcl-2 gene의 변이가 폐암에 미치는 영향을 조사하고자 하였다. 대상 및 방법: 1990년부터 1995년까지 연세의료원에서 치료목적의 완전절제가 가능하였던 stageIIIA 비소세포폐암 환자 100명의 paraffin block과 임상기록을 이용하였다. 각 환자의 조직절편을 labelled streptavidin-biotin method로 immunohistochemical 염색하였고 cyclin D1, p53, Bcl-2 immunostaining을 위한 조직절편들은 immunostaining하기 전 citrate buffer 내에서 10분에서 20분간 microwave oven으로 전처치한 후 cyclin D1은 NCL-cyclin D1-GM으로 p53는 lone DO-7으로 bcl-2는 clone 124로 overnight incubation하였다. 수술 후 평균 추적조사기간은 24.1 개월(range; 2∼84 개월)이었다. 결과: 100예의 폐암 중 56예가 편평상피세포암, 37예가 선암, 5예가 adenosquamous cell carcinoma, 2예가 대세포암이었고 수술 후 5년 생존율은 32.1%이었다. cyclin D1의 양성율은 35 %, p53는 56 %, bcl-2는 17 %였으나 cyclin D1, p53, Bcl-2 단백질 양성 발현과 생존율과의 상관관계는 없었다. 결론: 연구결과 cyclin D1, p53, Bcl-2 단백질 양성 발현이 비소세포폐암 발생기전과 연관되어 있으나 수술 후 예후인자로서는 부적당한 것으로 판단되었다.

• Asian Pacific Journal of Cancer Prevention
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• 제15권17호
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• pp.7097-7103
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• 2014

Over-expression of de novo lipogenesis (DNL) genes is associated with the prognosis of various types of cancers. However, the effects of single nucleotide polymorphisms (SNPs) in these genes on recurrence and survival of non-small cell lung cancer (NSCLC) patients after surgery are still unknown. In this study, a total of 500 NSCLC patients who underwent surgery treatment were included. Eight SNPs in 3 genes (ACACA, FASN and ACLY) of the DNL pathway were examined using the Sequenom iPLEX genotyping system. Multivariate Cox proportional hazards regression and Kaplan-Meier curves were used to analyze the association of SNPs with patient survival and tumour recurrence. We found that two SNPs in the FASN gene were significantly associated with the recurrence of NSCLC. SNP rs4246444 had a significant association with lung cancer recurrence under additive model (hazard ratio [HR], 0.82; 95% confidence interval [95%CI], 0.67-1.00; p=0.05). Under the dominant model, rs4485435 exhibited a significant association with recurrence (HR, 0.75; 95%CI, 0.56-1.01; p=0.05). Additionally, SNP rs9912300 in ACLY gene was significantly associated with overall survival in lung cancer patients (HR, 1.41; 95%CI, 1.02-1.94, p=0.04) under the dominant model. Further cumulative effect analysis showed moderate dose-dependent effects of unfavorable SNPs on both survival and recurrence. Our data suggest that the SNPs in DNL genes may serve as independent prognostic markers for NSCLC patients after surgery.

• Asian Pacific Journal of Cancer Prevention
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• 제16권8호
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• pp.3301-3306
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• 2015

Nucleolin (C23) is an important anti-apoptotic protein that is ubiquitously expressed in exponentially growing eukaryotic cells. In order to understand the impact of C23 in radiation therapy, we attempted to investigate the relationship of C23 expression with the radiosensitivity of human non-small cell lung cancer (NSCLC) cells. We investigated the role of C23 in activating the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs), which is a critical protein for DNA double-strand breaks (DSBs) repair. As a result, we found that the expression of C23 was negatively correlated with the radiosensitivity of NSCLC cell lines. In vitro clonogenic survival assays revealed that C23 knockdown increased the radiosensitivity of a human lung adenocarcinoma cell line, potentially through the promotion of radiation-induced apoptosis and adjusting the cell cycle to a more radiosensitive stage. Immunofluorescence data revealed an increasing quantity of ${gamma}$-H2AX foci and decreasing radiation-induced DNA damage repair following knockdown of C23. To further clarify the mechanism of C23 in DNA DSBs repair, we detected the expression of DNA-PKcs and C23 proteins in NSCLC cell lines. C23 might participate in DNA DSBs repair for the reason that the expression of DNA-PKcs decreased at 30, 60, 120 and 360 minutes after irradiation in C23 knockdown cells. Especially, the activity of DNA-PKcs phosphorylation sites at the S2056 and T2609 was significantly suppressed. Therefore we concluded that C23 knockdown can inhibit DNA-PKcs phosphorylation activity at the S2056 and T2609 sites, thus reducing the radiation damage repair and increasing the radiosensitivity of NSCLC cells. Taken together, the inhibition of C23 expression was shown to increase the radiosensitivity of NSCLC cells, as implied by the relevance to the notably decreased DNA-PKcs phosphorylation activity at the S2056 and T2609 clusters. Further research on targeted C23 treatment may promote effectiveness of radiotherapy and provide new targets for NSCLC patients.

• Asian Pacific Journal of Cancer Prevention
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• 제15권24호
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• pp.10937-10941
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• 2015

Pathogenesis of lung cancer is a complicated biological process including multiple genetic and epigenetic changes. Since cigarette smoking is confirmed as the most main risk factor of non-small cell lung cancer (NSCLC), the aim of this study was to determine whether tobacco exposure plays a role in gene methylation. Methylation of the RAR-${\beta}$ gene were detected using methylation-specific polymerase chain reaction in DNA from 167 newly diagnosed cases with NSCLC and corresponding 105 controls. A significant statistical association was found in the detection rate of the promoter methylation of RAR-${\beta}$ gene between NSCLC and controls ($x^2$=166.01; p<0.01), and hypermethylation of the RAR-${\beta}$ gene was significantly associated with smoking status (p=0.038, p<0.05). No relationship was found between RAR-${\beta}$ gene methylation and pathologic staging including clinical stage, cell type, gender and drinking (p>0.05), and the methylation of RAR-${\beta}$ gene rate of NSCLC was slightly higher in stages III+IV (80.0%) than in I+II (70.8%). Similar results were obtained for methylation of the RAR-${\beta}$ gene between squamous cell carcinoma (77.9%) and other cell type lung cancer (73.9%). These results showed that the frequency of methylation increased gradually with the development of clinical stage in smoking-associated lung cancer patients, and tobacco smoke may be play a potential role in RAR-${\beta}$ gene methylation in the early pathogenesis and process in lung cancer, particularly squamous cell carcinoma. Aberrant promoter methylation is considered to be a promising marker of previous carcinogen exposure and cancer risk.

• Molecules and Cells
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• 제45권10호
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• pp.718-728
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• 2022

Splicing factor B subunit 4 (SF3B4), a component of the U2-pre-mRNA spliceosomal complex, contributes to tumorigenesis in several types of tumors. However, the oncogenic potential of SF3B4 in lung cancer has not yet been determined. The in vivo expression profiles of SF3B4 in non-small cell lung cancer (NSCLC) from publicly available data revealed a significant increase in SF3B4 expression in tumor tissues compared to that in normal tissues. The impact of SF3B4 deletion on the growth of NSCLC cells was determined using a siRNA strategy in A549 lung adenocarcinoma cells. SF3B4 silencing resulted in marked retardation of the A549 cell proliferation, accompanied by the accumulation of cells at the G0/G1 phase and increased expression of p27, p21, and p53. Double knockdown of SF3B4 and p53 resulted in the restoration of p21 expression and partial recovery of cell proliferation, indicating that the p53/p21 axis is involved, at least in part, in the SF3B4-mediated regulation of A549 cell proliferation. We also provided ubiquitination factor E4B (UBE4B) is essential for p53 accumulation after SF3B4 depletion based on followings. First, co-immunoprecipitation showed that SF3B4 interacts with UBE4B. Furthermore, UBE4B levels were decreased by SF3B4 depletion. UBE4B depletion, in turn, reproduced the outcome of SF3B4 depletion, including reduction of polyubiquitinated p53 levels, subsequent induction of p53/p21 and p27, and proliferation retardation. Collectively, our findings indicate the important role of SF3B4 in the regulation of A549 cell proliferation through the UBE4B/p53/p21 axis and p27, implicating the therapeutic strategies for NSCLC targeting SF3B4 and UBE4B.

• Tuberculosis and Respiratory Diseases
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• 제67권3호
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• pp.191-198
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• 2009

Background: Pemetrexed, a multi-targeted antifolate has been used as a second line treatment against non-small cell lung cancer (NSCLC). We aimed to clarify the efficacy and survival according to line of treatment, histologic type, and expression of thymidylate synthase (TS). Methods: Ninety-eight patients were treated with pemetrexed as a second line treatment (n=43) or as an additional course of treatment (n=55). TS expression was studied with immunohistochemistry and graded as 0 to 3 based on the extent of expression. Results: The response rate (RR) in 98 subjects was 10.2% and the disease control rate (DCR=PR+SD) was 30.6%. RR and DCR were 12.7% and 32.7% in non-squamous cell carcinoma (NSQC) compared to 7.0% and 27.9% in squamous cell carcinoma (SQC) (p>.05). No significant differences in RR and DCR were observed between a second line group (4.7%, 20.9%) and a further line group (14.5%, 38.2%). A similar trend was observed in the 88 response evaluable subjects. TS was expressed in 28.6% (grade 1), 24.5% (grade 2) and 7.1% (grade 3), respectively, and it was not expressed in 39.8% of subjects. TS expression rate was significantly higher in the SQC (72.1%) compared to NSQC (50.9%, p=0.033). However, the efficacy of pemetrexed was not significantly different by the extent of TS expression. Conclusion: Pemetrexed showed efficacy, not only in a second-line setting, but also in further lines of treatment for NSCLC. The efficacy of pemetrexed tended to be higher in patients with NSQC compared to SQC. TS expression rate was significantly higher in SQC compared to NSQC.

• Radiation Oncology Journal
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• 제24권4호
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• pp.237-242
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• 2006

목 적: 국소적으로 진행된 비소세포성 폐암에서 예후영향인자를 찾기 위하여 근치적 방사선 치료에 대한 성적을 후향적으로 평가하였다. 대상 및 방법: $1991{\sim}2002$년에 걸쳐 본원에서 방사선치료를 받은 stage IIIB 비소세포성 폐암 환자 216명의 의무기록을 후향적으로 분석하였다. 완전관해와 부분관해를 반응군(response group), 불변 및 진행성질환을 무반응군(non-response group)으로 묶어 분류하였다. 결 과: 근치목적의 방사선치료를 시행한 총 140명의 환자 중 방사선단독치료를 받은 환자는 68명, 항암화학제와 병용요법을 시행한 환자는 72명이었다. 계획된 방사선치료가 완료된 것은 단독에서는 30예, 병용요법에서는 39예였다. 중앙생존기간은 방사선 단독치료군에서는 4.6개월, 병용요법군에서는 9.9개월이었다. 1년, 2년 및 3년 생존율이 방사선 단독치료군에서는 13.3%, 3.3%, 0%였으며, 항암화학제 병용요법군에서는 각각 35.9%, 20.5%, 15.4%였다(p<0.001). 반응군에서 방사선 단독으로 치료한 환자는 중앙생존기간 7.2개월, 항암화학제 병용치료환자는 16.5개월이었고, 무반응군에서 단독치료 환자는 4.4개월, 병용치료환자는 6.7개월이었다(p=0.001). 치료반응과 항암화학요법의 병용이 전체생존율에 영향을 주었다(p<0.001). Grade 3 이상의 심한 합병증은 방사선 단독요법에서 2예(6.7%), 항암화학 병용요법에서 7예(17.9%)였다. 결 론: Stage IIIB 비소세포성 폐암에서 방사선치료와 더불어 항암화학치료를 병용했을 때, 방사선단독요법에 비해 치료반응률과 생존율이 더 높았다.