Common genetic variants at 1q22 and 10q23 and gastric cancer susceptibility in a Korean population.

Song, Hye-Rim,Kim, Hee Nam,Kweon, Sun-Seog,Choi, Jin-Su,Shim, Hyun Jeong,Cho, Sang Hee,Chung, Ik Joo,Park, Young-Kyu,Kim, Soo Hyun,Choi, Yoo-Duk,Joo, Kyung Woong,Shin, Min-Ho Saikon Pub. Co 2014 TUMOR BIOLOGY Vol.35 No.4

<P>Genetic variants at 1q22 and 10q23 were identified as genetic markers of both gastric cancer and esophageal squamous cell carcinoma susceptibility by two genome-wide association studies. The aim of this study was to determine whether rs4072037A > G in MUC1 at 1q22 and rs2274223A > G in PLCE1 at 10q23 are associated with a risk of gastric cancer in a Korean population. We conducted a large-scale case-control study of 3,245 patients with gastric cancer and 1,700 controls. The allele frequencies of rs4072037G and rs2274223G were 11.2 and 25.5% among patients with gastric cancer, compared with 12.8 and 26.4%, respectively, among controls. We found that the rs4072037 AG genotype was significantly associated with a reduced risk of gastric cancer [odds ratios (OR)?= 0.78; 95% confidence interval (CI)?= 0.67-0.91 for AG vs AA]. Compared with the rs2274223 AA genotype, we found a significant association between the rs2274223 AG genotype and a weakly reduced risk of gastric cancer (OR = 0.87; 95% CI = 0.76-0.99 for AG vs AA). Our data suggest that genetic variants at 1q22 and 10q23 play a role in gastric carcinogenesis.</P>

The relevance of serum carcinoembryonic antigen as an indicator of brain metastasis detection in advanced non-small cell lung cancer.

Lee, Dong-Soo,Kim, Yeon-Sil,Jung, So-Lyoung,Lee, Kyo-Young,Kang, Jin-Hyoung,Park, Sarah,Kim, Young-Kyoon,Yoo, Ie-Ryung,Choi, Byung-Ock,Jang, Hong-Seok,Yoon, Sei-Chul Saikon Pub. Co 2012 TUMOR BIOLOGY Vol.33 No.4

<P>Although many biomarkers have emerged in non-small cell lung cancer (NSCLC), the predictive value of site-specific spread is not fully defined. We designed this study to determine if there is an association between serum biomarkers and brain metastasis in advanced NSCLC. We evaluated 227 eligible advanced NSCLC patients between May 2005 and March 2010. Patients who had been newly diagnosed with stage IV NSCLC but had not received treatment previously, and had available information on at least one of the following pretreatment serum biomarkers were enrolled: carcinoembryonic antigen (CEA), cytokeratin 19 fragments (CYFRA 21-1), cancer antigen 125 (CA 125), cancer antigen 19-9, and squamous cancer cell antigen. Whole body imaging studies and magnetic resonance imaging of the brain were reviewed, and the total number of metastatic regions was scored. Brain metastasis was detected in 66 (29.1%) patients. Although serum CEA, CYFRA 21-1, and CA 125 levels were significantly different between low total metastatic score group (score 1-3) and high total metastatic score group (score 4-7), only CEA level was significantly different between patients with brain metastasis and those without brain metastasis (p < 0.0001). The area under the receiver operating curve of serum CEA for the prediction of brain metastasis was 0.724 (p = 0.0001). The present study demonstrated that the pretreatment serum CEA level was significantly correlated with brain metastasis in advanced NSCLC. These findings suggested the possible role of CEA in the pathogenesis of brain invasion. More vigilant surveillance would be warranted in the high-risk group of patients with high serum CEA level and multiple synchronous metastasis.</P>

The expression of glutamine-metabolism-related proteins in breast phyllodes tumors.

Kim, Sewha,Jung, Woo Hee,Koo, Ja Seung Saikon Pub. Co 2013 Tumour biology Vol.34 No.5

<P>The aim of this study was to investigate the expression of glutamine-metabolism-related proteins according to the histologic grade of phyllodes tumors (PTs) and to assess its clinical implication. We generated tissue microarrays of 224 PTs and performed immunohistochemical staining and western blot analysis of glutamine-metabolism-related molecules, including GLS1, GDH, and ASCT2. The associations between immunohistochemical results and clinicopathologic parameters were evaluated. The expression of GLS1 (p < 0.001), GDH (p < 0.001), and ASCT2 (p = 0.005) in stromal components significantly increased with worsening PT histological grade. GDH expression in epithelial components significantly increased in high-grade PT (p = 0.026). In western blot, stromal expression of GLS1, GDH, and ASCT2 increased as histologic grade increased. By univariate analysis, stromal GLS1 expression (p = 0.022) and stromal GDH expression (p = 0.009) were independent predictors of shorter DFS. Stromal GLS1 expression (p < 0.001) and stromal GDH expression (p < 0.001) were independent predictors of shorter OS. This study demonstrated that the stromal expression of the glutamine-metabolism-related proteins GLS1, GDH, ASCT2 increases with worsening histological PT grade.</P>

Involvement of heme oxygenase-1 in Korean colon cancer.

Kang, Kyoung Ah,Maeng, Young Hee,Zhang, Rui,Yang, Young Ro,Piao, Mei Jing,Kim, Ki Cheon,Kim, Gi Young,Kim, Young Ree,Koh, Young Sang,Kang, Hee Kyoung,Hyun, Chang Lim,Chang, Weon Young,Hyun, Jin Won Saikon Pub. Co 2012 TUMOR BIOLOGY Vol.33 No.4

<P>Heme oxygenase-1 (HO-1) catabolizes heme into carbon monoxide, biliverdin, and free iron which mediate its protective effect against oxidative stress. The aim of the present study was to determine the expression level and activity of HO-1 in Korean colon cancer tissues and cell lines. HO-1 protein expression was higher (>1.5-fold) in tumor tissues than in adjacent normal tissues in 14 of 20 colon cancer patients, and HO-1 protein expression was closely correlated with HO-1 enzyme activity in cancer tissues. Immunohistochemical data confirmed that HO-1 protein was expressed at a higher level in colon cancer tissues than in normal mucosa. Furthermore, HO-1 mRNA and protein expression and enzyme activity were higher in the colon cancer cell lines Caco-2, SNU-407, SNU-1033, HT-29, and SW-403 than in the normal fetal human colon cell line FHC. Treatment with the HO-1 inhibitor zinc protoporphyrin decreased the viability of colon cancer cell lines. These data indicate that HO-1 may serve as a clinically useful biomarker of colon cancer and as a target for anticolon cancer drugs.</P>

Zebularine-induced apoptosis in Calu-6 lung cancer cells is influenced by ROS and GSH level changes.

You, Bo Ra,Park, Woo Hyun Saikon Pub. Co 2013 Tumour biology Vol.34 No.2

<P>Zebularine (Zeb) is a DNA methyltransferase (DNMT) inhibitor that has various biological properties including anti-cancer effect. In the present study, we evaluated the effects of Zeb on the growth and death of Calu-6 lung cancer cells in relation to reactive oxygen species (ROS) and glutathione (GSH) levels. Zeb inhibited the growth of Calu-6 cells with an IC50 of approximately 150 μM at 72 h in a dose-dependent manner. Zeb induced an S phase arrest of the cell cycle and apoptosis in Calu-6 cells. Pan-caspase inhibitor (Z-VAD) and caspase-8 inhibitor (Z-IETD) significantly rescued some cells from Zeb-induced Calu-6 cell death. In relation to ROS and GSH levels, O2 (?-) level was significantly increased in Zeb-treated Calu-6 cells and caspase inhibitors reduced O2 (?-) level in these cells. Zeb induced GSH depletion in HeLa cells, which was attenuated by caspase inhibitors. L-buthionine sulfoximine (BSO), a GSH synthesis inhibitor, intensified the apoptotic cell death, ROS level, and GSH depletion in Zeb-treated Calu-6 cells. In addition, BSO increased Bax protein and decreased Bcl-2 protein in Zeb-treated Calu-6 cells. In conclusion, Zeb inhibited the growth of Calu-6 lung cancer cells via cell cycle arrest and caspase-dependent apoptosis and its cell death was influenced by ROS and GSH level changes.</P>

The accumulation of DNA repair defects is the molecular origin of carcinogenesis.

Cha, Hyuk-Jin,Yim, Hyungshin Saikon Pub. Co 2013 Tumour biology Vol.34 No.6

<P>Genomic instability has been considered to be one of the prominent factors for carcinogenesis and the development of a number of degenerative disorders, predominantly related to the aging. The cellular machineries involved in the maintenance of genomic integrity such as DNA repair and DNA damage responses are extensively characterized by a large number of studies. The failure of proper actions of such cellular machineries may lead to the devastating effects mostly inducing cancer or premature aging, even with no acute exogenous DNA damage stimuli. In this review, we especially focus on the pathophysiological aspects of the defective DNA damage responses in carcinogenesis and premature aging. Clear understanding the causes of carcinogenesis and age-related degenerative diseases will provide novel and efficient approaches for prevention and rational treatment of cancer and premature aging.</P>

Upregulation and secretion of kallikrein-related peptidase 6 (KLK6) in gastric cancer.

Kim, Jin Ju,Kim, Jong-Tae,Yoon, Hyo Ran,Kang, Min Ah,Kim, Joo Heon,Lee, Young-Ha,Kim, Jae Wha,Lee, Seon-Jin,Song, Eun Young,Myung, Pyung Keun,Lee, Hee Gu Saikon Pub. Co 2012 Tumour biology Vol.33 No.3

<P>KLK6 encoding kallikrein-related peptidase 6, a trypsin-like serine protease, has been shown to be upregulated in several cancers, although the tumorigenic role of KLK6 has not been elucidated. In this study, KLK6 was identified as a highly upregulated gene in gastric cancer; therefore, the possibility that KLK6 might be a suitable candidate tumor marker was examined. RT-PCR and immunohistochemical analysis showed overexpression of KLK6 in gastric cancer tissues compared to nontumor regions. Sera from gastric cancer patients had a 1.7-fold increase in KLK6 (373.1 μg/L, P = 0.048) compared to healthy individuals (214.2 μg/L), although there was no significant difference among patients with various tumor stages. Cellular invasiveness decreased by 45% in cells transfected with KLK6-specific small interfering RNA. Exogenous overexpression of KLK6 led to decreased activity of the E-cadherin promoter. This study shows that KLK6 is significantly upregulated and secreted in gastric cancer tissues and sera, suggesting that KLK6 might be used as a potential biomarker and therapeutic target for gastric cancer.</P>

The expression of metabolism-related proteins in phyllodes tumors.

Kwon, Ji Eun,Jung, Woo-Hee,Koo, Ja Seung Saikon Pub. Co 2013 Tumour biology Vol.34 No.1

<P>The purpose of this study was to investigate the association between the expression of hypoxia-inducible factor (HIF)-1α, insulin-like growth factor (IGF)-1, glucose transporter 1 (Glut-1), carbonic anhydrase IX (CAIX), and monocarboxylate transporter (MCT)4, which are metabolism-related proteins in phyllodes tumors (PTs), and clinicopathologic factors and its implication. We used tissue microarrays to analyze 207 PTs and performed immunohistochemical staining against the glycolysis-related molecules HIF-1α, IGF-1, Glut-1, CAIX, and MCT4. We then compared the immunohistochemical results and clinicopathologic parameters. The expressions of HIF-1α, Glut-1, CAIX, and MCT4 in the stromal component of PTs increased (P?=?0.019, P?<?0.001, P?=?0.045, and P?<?0.001, respectively) with increasing tumor grade. According to univariate analysis, factors associated with shorter disease-free survival were Glut-1 expression (P?=?0.001) and MCT4 expression (P?<?0.001) in the stromal component, and the factors associated with shorter overall survival were IGF-1 expression (P?=?0.012), Glut-1 expression (P?<?0.001), CAIX expression (P?=?0.039), and MCT4 expression (P?<?0.001) in the stromal component. Our investigation of stromal expression of the metabolism-related proteins HIF-1α, IGF-1, Glut-1, CAIX, and MCT4 revealed that, as the PT grade increased, the stromal expression of HIF-1α, Glut-1, CAIX, and MCT4 significantly increased. This result suggested that increasing PT grade is associated with increased glycolysis in the stromal component.</P>

IRF7 promotes glioma cell invasion by inhibiting AGO2 expression.

Kim, Jun-Kyum,Jin, Xiong,Ham, Seok Won,Lee, Seon Yong,Seo, Sunyoung,Kim, Sung-Chan,Kim, Sung-Hak,Kim, Hyunggee Saikon Pub. Co 2015 TUMOR BIOLOGY Vol.36 No.7

<P>Interferon regulatory factor 7 (IRF7) is the master transcription factor that plays a pivotal role in the transcriptional activation of type I interferon genes in the inflammatory response. Our previous study revealed that IRF7 is an important regulator of tumor progression via the expression of inflammatory cytokines in glioma. Here, we report that IRF7 promotes glioma invasion and confers resistance to both chemotherapy and radiotherapy by inhibiting expression of argonaute 2 (AGO2), a regulator of microRNA biogenesis. We found that IRF7 and AGO2 expression levels were negatively correlated in patients with glioblastoma multiforme. Ectopic IRF7 expression led to a reduction in AGO2 expression, while depletion of IRF7 resulted in increased AGO2 expression in the LN-229 glioma cell line. In an in vitro invasion assay, IRF7 overexpression enhanced glioma cell invasion. Furthermore, reconstitution of AGO2 expression in IRF7-overexpressing cells led to decreased cell invasion, whereas the reduced invasion due to IRF7 depletion was rescued by AGO2 depletion. In addition, IRF7 induced chemoresistance and radioresistance of glioma cells by diminishing AGO2 expression. Finally, AGO2 depletion alone was sufficient to accelerate glioma cell invasion in vitro and in vivo, indicating that AGO2 regulates cancer cell invasion. Taken together, our results indicate that IRF7 promotes glioma cell invasion and both chemoresistance and radioresistance through AGO2 inhibition.</P>

CCAR2 deficiency augments genotoxic stress-induced apoptosis in the presence of melatonin in non-small cell lung cancer cells.

Kim, Wootae,Jeong, Joo-Won,Kim, Ja-Eun Saikon Pub. Co 2014 TUMOR BIOLOGY Vol.35 No.11

<P>Melatonin exhibits oncostatic activity in several cancers but does not lead to cytotoxicity in estrogen receptor (ER)-negative non-small cell lung cancers (NSCLCs). In an effort to overcome the melatonin resistance of these cancers, we investigated whether cell cycle and apoptosis regulator 2 (CCAR2) depletion would promote apoptosis following genotoxic stress in melatonin-resistant cancer cells. Ordinarily, the NSCLC cell lines A549 and A427 did not undergo cell death following melatonin treatment for short period. These cell lines were irradiated with UV, a source of genotoxic damage, to trigger apoptotic signaling. Treatment with melatonin prior to irradiation did not produce any significant change in apoptosis. By contrast, in CCAR2-deficient cells, melatonin treatment increased apoptosis induced by genotoxic stress; this effect was dependent on the dose of melatonin. The increase in apoptosis in CCAR2-deficient cells was not dependent on SIRT1. The results indicate that CCAR2 is critical for maintaining cell survival in the presence of melatonin under genotoxic stress. Furthermore, CCAR2 is overexpressed in NSCLC; therefore, melatonin could be used as a potential supplement to classical anticancer drugs in therapies against CCAR2-deficient cancers.</P>