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ABSTRACT: PURPOSE: IL-10 determines virus persistent infection and promotes viral-associated tumor progression via tumor immune escape. However, the role of IL-10 in tumor progression and prognosis in lung adenocarcinoma remains controversial. EXPERIMENTAL DESIGN: To investigate how IL-10 is regulated by HPV E6, IL-10 promoter was constructed to understand which transcriptional factor could be responsible for its transcription. To verify which molecule could be responsible for IL-10-mediated soft agar growth and invasion capability, PCR array and mechanistic strategies were performed. IL-10 and CIP2A mRNA levels in lung tumors from lung cancer patients were determined by real-time RT-PCR. The prognostic value of both molecules on survival was estimated by Cox regression model. RESULTS: Mechanistic studies showed that IL-10 protein and mRNA expression was decreased in E6-knockdown TL1 cells and increased in E6-overexpressing TL4 cells. In addition, IL-10 transcription was predominantly regulated by E6-mediated phosphorylation of CREB and C/EBPβ via PI3K signaling pathway. IL-10-mediated tumor aggressiveness in vitro and in vivo occurs through increased CIP2A expression via PI3K signaling pathway. Among patients, IL-10 mRNA expression in lung tumors was positively correlated with CIP2A mRNA expression. Cox-regression analysis showed that IL-10 and CIP2A mRNA levels may independently predict survival in patients with lung adenocarcinoma, especially in patients with E6-positive tumors. CONCLUSIONS: IL-10 production from lung tumors and immune cells promotes lung adenocarcinoma aggressiveness and patients with poor survival. We thus suggest that PI3K inhibitor combined with chemotherapy may potentially enhance tumor regression and improve patients' outcome and life quality.
Clinical Cancer Research 06/2013; · 7.74 Impact Factor
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ABSTRACT: Polymorphisms (1082A>G, - 819C>T, and -592G>A) in the interleukin-10 (IL10) promoter are associated with its transcriptional activity. IL10 induction by cigarette smoking plays a role in smoking-related lung tumor progression. We therefore expected to find a difference in impact of IL10 haplotypes on overall survival (OS) and relapse-free survival (RFS) between squamous cell carcinomas (SCC) and adenocarcinomas (ADC) of lung.
Normal lung tissues adjacent to resected tumors from 439 lung cancer patients were collected to determine IL10 haplotypes (ATA and non-ATA) by direct sequencing and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Kaplan-Meier and multivariate Cox regression models were used to assess the impact of IL10 haplotype on OS and RFS. Resluts: The non-ATA haplotype was more prevalent in patients with nodal metastatic tumors (N1 and N2) than in those with non-nodal metastatic tumors (N0). This observation was only made for patients with SCC and not ADC. Patients with SCC with the non-ATA haplotype had poorer OS and RFS when compared to those with the ATA haplotype, whereas IL10 haplotype was not associated with the clinical outcome of patients with ADC.
The IL10 haplotype may independently predict survival and relapse in patients with surgically resected SCC, but not ADC.
Anticancer research 06/2013; 33(6):2729-35. · 1.73 Impact Factor
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ABSTRACT: We recently reported that high-risk human papillomavirus (HPV) 16/18 E6 protein was associated with p53 protein degradation in lung cancer. The present study addressed the relationship between the different p53 genotypes and HPV oncoprotein expression with respect to p53 protein degradation and clinical outcome in primary lung cancer patients.
We examined whether p53 codon 72 polymorphism and HPV oncoprotein expression could be associated with patients' outcome by collecting 319 lung tumors from patients with non-small cell lung cancer to determine p53 codon 72 polymorphisms, HPV 16/18 infection, and HPV 16/18 E6 and p53 protein expression by polymerase chain reaction (PCR)-restriction fragment length polymorphism, nested-PCR, and immunohistochemical analysis.
The presence of HPV 16/18 DNA and E6 protein was inversely associated with p53 expression. The frequency of p53 protein degradation was also much higher in HPV 16/18 E6-positive/Arg/Arg lung tumors than in the other 3 groups. After adjusting gender and tumor type, the major contributors to p53 degradation in lung cancer patients were determined to be p53 codon72 polymorphism and HPV 16/18 E6 oncoprotein expression. This association was not found for HPV 16/18 DNA infection. Survival was significantly longer in patients with HPV 16/18 E6-negative/Arg/Arg tumors (median 32.7 months) than in patients with HPV-positive and p53 genetic variant tumors (p = 0.008).
The HPV 16/18 E6 protein, which is involved in the p53 inactivation that contributes to HPV-infected lung tumorigenesis, is associated with the p53 codon 72 genotype. The combination of HPV 16/18 E6 status and p53 codon72 polymorphism in lung tumors is an important biologic and prognostic parameter.
The Annals of thoracic surgery 04/2013; 95(4):1196-203. · 3.74 Impact Factor
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ABSTRACT: P53 inactivation by p53 mutation and E6 oncoprotein plays a crucial role in human
carcinogenesis. DDX3 has been shown to be a target of p53. In this study, we
hypothesized that DDX3 loss by p53 inactivation may promote tumor malignancy and
poor patients’ outcome. Mechanically, DDX3 loss by p53-knockdown and
E6-overexpression was observed in A549 lung cancer cells. Conversely, DDX3
expression was markedly elevated by wild-type p53 ectopic expression in p53-null
H1299 cells, E6-knockdown TL-1 lung cancer and SiHa cervical cancer cells.
Interestingly, DDX3 loss promotes soft-agar growth and invasive capability; however,
both capabilities were suppressed by DDX3 overexpression. We next expected that
DDX3 loss might result in Slug-suppressed E-cadherin expression via decreased
MDM2-mediated Slug degradation. As expected, MDM2 transcription is suppressed
by DDX3 loss via decreased SP1 binding activity onto MDM2 promoter.
Consequently, Slug expression was elevated by the reduction of MDM2 due to DDX3
loss, and E-cadherin expression was suppressed by Slug. Consistent observations in
the correlation of DDX3 loss with MDM2, Slug, and E-cadherin were seen in lung
tumors from lung cancer patients. In addition, patients with low-DDX3 tumors had
poorer survival and relapse than patients with high-DDX3 tumors. In conclusion, we
suggest that DDX3 loss by p53 inactivation via MDM2/Slug/E-cadherin pathway
promotes tumor malignancy and poor patient outcome
Oncogene 02/2013; · 6.37 Impact Factor
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ABSTRACT: BACKGROUND: Chronic cough related to eosinophilic inflammation has become an important cause of cough in recent years. Although fractional exhaled nitrogen oxide (FeNO) measurement is an important monitoring tool, its lack of reference level may limit its usefulness. This study aimed to determine the optimal FeNO level to guide inhaled corticosteroid (ICS) management in patients with chronic cough. METHODS: This retrospective study reviewed the medical records of patients with chronic cough for more than 8 weeks. Based on the selection criteria, data were recalculated to determine the optimal cut-off value of FeNO for initiating ICS treatment in such patients. RESULTS: The medical records of 81 eligible patients were reviewed. Cough improved completely in 38 (Group A) of 44 patients who were treated with ICS but not in the other six patients (Group B). In the 37 patients without ICS treatment, cough improved in 32 (Group C) by specific treatment aimed at the possible causes of the cough, whereas the remaining five (Group D) had persistent cough. The patients were further subdivided into Category 1 (all patients in Group A) and Category 2 (all patients in Groups B and C). Receiver operating characteristic analysis showed that an FeNO of 33.9 ppb was the best cut-off value for using ICS (sensitivity 94.7%, specificity 76.3%) in patients with chronic cough. In fourteen of 15 patients with bronchial hyperresponsiveness (BHR) or borderline BHR, the FeNO values were equal or higher than 33.9 ppb. Obstructive ventilatory impairment was only seen in two patients. CONCLUSION: Using FeNO measurement as a rapid, noninvasive diagnostic tool for patients with chronic cough, ICS can be prescribed if the FeNO is 33.9 ppb or more.
Journal of the Chinese Medical Association 01/2013; 76(1):15-19. · 0.79 Impact Factor
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ABSTRACT: Human papillomavirus (HPV) infection is associated with non-smoking female lung cancer. Our previous report demonstrated that HPV 16 promotes lung tumor cell progression by up-regulating interleukin-17 (IL-17). IL-17 and its downstream signaling mediator, interleukin-8 (IL-8), have been implicated to modulate a variety of pro-angiogenic factors and play important roles in tumor angiogenesis and metastasis. Accordingly, we hypothesized that HPV infection may potentiate tumorigenic and metastatic characteristics of the infected cells through IL-8. The goal of the present study was to determine whether HPV infection in lung adenocarcinoma cells can promote the expression of IL-8 and metalloproteinases (MMPs) to make the transformed cells equipped with angiogenic and metastatic characteristics. The expression of IL-8 and MMPs in HPV 16 E6-transfected H1299 cells was analyzed to examine the hypothesis. HPV 16 E6 up-regulates pro-angiogenic MMP-2 and MMP-9 through inducing IL-8 expression in lung cancer cells. The results indicate that, in addition to cell proliferation-related machinery, HPV infection promotes the expression and activities of angiogenic and metastatic molecules in lung adenocarcinoma cells. The cytokines induced by HPV infection may work together to confer the malignant and tumorigenic potentials on the infected cells by promoting machineries of growth, angiogenic and metastatic characteristics.
PLoS ONE 01/2013; 8(1):e54423. · 4.09 Impact Factor
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ABSTRACT: Background & objectives: Hypoxia inducible factor-1α (HIF-1α) has been shown to play a role in the pathogenesis of renal interstitial fibrosis. However, the relationship of HIF-1α expression intensity in human renal tissue with the degree of renal function or renal fibrosis has not been investigated. We therefore, undertook this study to assess the relationship between HIF-1α expression and degree of renal impairment and renal fibrosis using renal tissue from nephrectomized kidneys from patients with chronic kidney disease. Methods: This retrospective study was performed with 70 patients undergoing unilateral or bilateral nephrectomy because of renal cell carcinoma, urothelial cell carcinoma, or renal abscess. Immunohistochemical analysis of HIF-1α expression in non-tumourous or non-abscess renal parenchyma was performed. The patients were divided into two groups: group 1 (n=37) with low intensity HIF-1α expression and group 2 (n=33) with high intensity HIF-1α expression. Results: The intensity of renal HIF-1α expression was significantly associated with serum creatinine level (P =0.005), estimated glomerular filtration rate (P=0.02), fibrosis score of the interstitium (P=0.004) and glomerular sclerosis (P=0.013). A high intensity of HIF-1α expression tended to be associated with lower serum creatinine, higher estimated glomerular filtration rate, low interstitial fibrosis score and low glomerular sclerosis. In addition, multivariate analysis by step-wise logistic regression demonstrated that interstitial fibrosis was the only independent factor associated with the intensity of renal HIF-1α expression (OR 4.107, CI 1.535-11.313, P=0.005). Interpretation & conclusions: This study demonstrated a correlation between intensity of HIF-1α expression and degree of renal interstitial fibrosis. The association demonstrated an elevated HIF-1α expression in less severe kidney disease. The intensity of HIF-1α renal expression plays a role in the pathogenesis of chronic kidney disease.
The Indian journal of medical research 01/2013; 137(1):102-110. · 1.84 Impact Factor
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ABSTRACT: Manganese superoxide dismutase (MnSOD) is an antioxidant enzyme responsible for the elimination of superoxide radical. The role of MnSOD in tumor progression in different human cancers is still controversial. In the present study, MnSOD expression in lung cancer cells was explored by knockdown or overexpression using transfection of a small hairpin RNA or an expression vector, respectively, to determine whether MnSOD expression mediates lung cancer cell invasion, and oncogenic potential by increasing FoxM1 and MMP2 expression. Western blotting showed that FoxM1 and MMP2 expression was dependent on MnSOD expression, suggesting that FoxM1 could be upregulated by MnSOD. Three FoxM1 promoters were constructed to verify this activation of FoxM1 by MnSOD and to determine the transcription factors responsible. Luciferase reporter and chromatin immunoprecipitation assays indicated that MnSOD overexpression in lung cancer cells promoted binding of E2F1 and Sp1 to their putative FoxM1 promoter binding sites and activated FoxM1 reporter activity. MnSOD also enhanced the potential for cell invasion, and anchorage-independent colony growth on soft-agar plates, again via upregulation of FoxM1 and MMP2 expression. In lung cancer patients, evaluation of MnSOD expression in lung tumors by immunohistochemistry indicated a positive correlation between FoxM1 and MMP2 mRNA expressions. Kaplan-Meier and Cox regression analysis revealed a poorer overall survival (OS) and relapse free survival (RFS) in patients with MnSOD-positive tumors than with MnSOD-negative tumors. We conclude that MnSOD may promote tumor aggressiveness via upregulation of the FoxM1-MMP2 axis, and that MnSOD expression can independently predict survival and relapse in resected lung adenocarcinoma patients.
Molecular Cancer Research 12/2012; · 4.29 Impact Factor
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Zhongguo fei ai za zhi = Chinese journal of lung cancer 10/2012;
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ABSTRACT: Background: The hOGG1 Ser326Cys polymorphism is associated with lung cancer risk, but there are limited data regarding an association between the APE1 Asp148Glu polymorphism and lung cancer. Biological evidence shows that the hOGG1-Cys allele results in less DNA repair activity; however, this is not associated with p53 mutation in lung cancer. Therefore, we investigated whether an interaction between hOGG1 and APE1 is associated with the frequency of p53 mutation in lung cancer.Methods: We studied 217 Taiwanese adults with primary lung cancer. DNA polymorphisms of hOGG1 and APE1 were determined by polymerase chain reaction (PCR)-based restriction fragment length polymorphism. Mutations in p53 exons 5-8 were detected by direct sequencing. Multiple logistic regression was used to estimate odds ratios (ORs) and 95% CIs for the risk of p53 mutation associated with polymorphisms of hOGG1 and APE1 in lung cancer.Results: As expected, no association between hOGG1 polymorphism and p53 mutation was observed in this population. However, a higher risk of p53 mutation was found in participants with the APE1 Asp/Asp genotype than in those with the APE1-Glu allele (OR, 2.15; 95% CI, 1.19-3.87; P = 0.011). The risk of p53 mutation was also higher in participants with APE1 Asp/Asp plus hOGG1-Cys than in those with APE1-Glu plus hOGG1 Ser/Ser (OR, 3.72; 95% CI, 1.33-10.40; P = 0.012).Conclusions: These results suggest that the APE1 Asp/Asp genotype and the combination of the APE1 Asp/Asp and hOGG1-Cys variants are associated with increased risk of p53 mutation in non-small cell lung cancer.
Journal of Epidemiology 09/2012; · 1.86 Impact Factor
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ABSTRACT: Human papillomavirus (HPV) 16/18 E6 oncoprotein is expressed in lung tumors and is associated with p53 inactivation. The tissue inhibitor of metalloproteinase 3 (TIMP-3) is essential for limiting inflammation; therefore, we expected that TIMP-3 loss might induce chronic inflammation, thereby promoting tumor malignancy as well as poor survival and relapse in patients with HPV-infected non-small cell lung cancer. In this study, the loss of TIMP-3 by loss of heterozygosity and/or promoter hypermethylation was more frequent in HPV16/18 E6-positive tumors than in E6-negative tumors. To explore the possible underlying mechanism, E6-negative TL4 and CL1-0 cells were transfected with an E6 cDNA plasmid. A marked decrease in TIMP-3 expression was caused by promoter hypermethylation via increased DNA (cytosine-5-)-methyltransferase 1 (DNMT1) expression. Mechanistic studies indicated that TIMP-3 loss promoted interleukin-6 (IL-6) production, which led to cell invasion and anchorage-independent growth on soft agar plates. Kaplan-Meier and Cox regression models showed that patients with low-TIMP-3/high-IL-6 tumors had shorter overall survival and relapse-free survival periods when compared with patients with high-TIMP-3/low-IL-6 tumors. In summary, loss of TIMP-3 may increase IL-6 production via the tumor necrosis factor α/nuclear factor κB axis, thereby promoting tumor malignancy and subsequent relapse and poor survival in patients with HPV-infected non-small cell lung cancer.
American Journal Of Pathology 09/2012; 181(5):1796-806. · 4.89 Impact Factor
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ABSTRACT: To investigate the association between human papilloma virus (HPV) infection and colorectal cancer.
Sixty-nine patients with pathologically confirmed primary colorectal cancer including 6 stage I, 24 stage II, 21 stage III, and 18 stage IV patients were enrolled in this study to investigate whether HPV 16 could be involved in colorectal tumorigenesis. Nested-polymerase chain reaction (nested-PCR) was used to detect HPV16 DNA in colorectal tumor tissues and further confirmed by in situ hybridization (ISH). In addition, immunohistochemistry analysis was performed to examine the E6 oncoprotein in colorectal tumors. To verify whether E6 could inactivate the p53 transcriptional function, the levels of p21 and Mdm2 mRNA expression were evaluated by real-time reverse transcription (RT)-PCR.
Of the 69 colorectal tumors, HPV16 DNA was detected in 11 (16%) by nested-PCR, and HPV16 DNA was present in 8 of the 11 (73%) tumors which was confirmed by ISH. The presence of HPV16 DNA in colorectal tumors was not associated with patients' clinical parameters including age, gender, smoking status, tumor site; however, HPV16 infection was more common in stage I patients than in late-stages patients (II, III and IV). We next asked whether HPV16 infection could be linked with colorectal cancer development. Immunohistochemical data indicated that 8 of the 11 HPV16 DNA-positive tumors had E6 oncoprotein expression. Moreover, we also observed that the adjacent normal tissues including endothelial cells, lymphocytes, fibroblasts, and gland cells in E6-positive tumors had E6 oncoprotein expression. In addition, 3 of the 4 (75%) E6-positive tumors carrying p53 wild-type had negative immunostaining, but one tumor had less p53 immunostaining. We further examined whether E6-positive and/or p53 mutated tumors reduce p53 transcriptional activity. Real-time RT-PCR analysis indicated that p21 and mdm2 mRNA expression levels in E6/p53-wildtype tumors were significantly lower than in their adjacent normal tissues; as expected, E6-positive/p53-mutated tumors had lower p21 and mdm2 mRNA expression levels compared with their adjacent normal tissues. These results clearly indicate that the E6 oncoprotein expressed in p53 wildtype tumors may reduce p21 and mdm2 expression via p53 inactivation.
These results suggest that HPV16 infection may be involved in a subset of colorectal cancer, and we suggest that the transmission of HPV to the colon and rectum might occur through peripheral blood lymphocytes.
World Journal of Gastroenterology 08/2012; 18(30):4051-8. · 2.47 Impact Factor
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ABSTRACT: OBJECTIVE: Most reports have shown that PAH-related DNA adducts are positively correlated with the smoking status of oral cancer patients. However, these reports did not focus on a specific carcinogen in cigarette smoke. The purpose of this study was to elucidate the role of the BPDE (7,8-dihydroxy-anti-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene)-DNA adduct in the development of oral cancer in Taiwanese patients. DESIGN: We enrolled 158 oral cancer patients and 64 non-cancer controls to investigate whether there were differences in susceptibility to cigarette smoke exposure in the formation of DNA adducts between cancer patients and controls. Immunohistochemistry and ELISA (enzyme-linked immunosorbent assay) were used to evaluate BPDE-DNA adduct levels in this study. RESULTS: Our data showed that the BPDE-DNA adduct levels were positively correlated with gender, smoking status, betel nut chewing and alcohol consumption. The difference in DNA adduct levels could be explained by genetic polymorphisms of glutathione S-transferase M1 (GSTM1), but not by cytochrome P-4501A1 (CYP1A1). Patients with high DNA adduct levels (≧34.03 adducts/10(8) nucleotides) had an approximately 9.936-fold risk of oral cancer compared with those with low DNA adduct levels (<34.03 adducts/10(8) nucleotides) (p<0.001). CONCLUSIONS: We suggest that genetic background and carcinogen exposure may increase the risk of developing oral cancer.
Archives of oral biology 07/2012; · 1.65 Impact Factor
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ABSTRACT: BACKGROUND: Subcellular localization of apurinic/apyrimidinic endonuclease-1/redox factor-1 (Ape1) has been demonstrated to promote lung tumor malignancy via NF-κB activation. We hypothesized that increased cytoplasmic Ape1 expression might cause NF-κB activation by p53 aberration, and result in poor outcome in non-small cell lung cancer (NSCLC). METHODS: Herein, knockdown of E6 or p53 and overexpression of E6 were performed in various lung cancer cells to test whether cytoplasmic Ape1 expression could be elevated by p53 aberration. To examine whether cytoplasmic Ape1 could be associated with patients' outcome, 125 lung tumors from patients with NSCLC were collected to determine Ape1 protein and mRNA expression by immunohistochemistry and real-time RT-PCR. RESULTS: Our data showed that cytoplasmic Ape1 decreased in E6-knockdown TL-1 cells and increased in E6-overexpressed TL-4 and p53-knockdown H520 cells; and cell invasion capability was dependent on the presence of cytoplasmic Ape1. Increases in cytoplasmic Ape1 by p53 aberration may be through activation of Ape1 transcription and S-nitrosation of Ape1 protein. Kaplan-Meier and Cox models showed that patients with high cytoplasmic Ape1 had shorter cancer-specific survival (CSS) and relapse-free survival (RFS) periods than did those with low cytoplasmic Ape1. CONCLUSIONS: We suggest that cytoplasmic Ape1 expression elevated by p53 aberration may be used to predict poor survival and relapse in patients with NSCLC.
Annals of Surgical Oncology 06/2012; · 4.17 Impact Factor
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ABSTRACT: IL-10 is associated with tumor malignancy via immune escape. We hypothesized that IL-10 haplotypes categorized by IL-10 promoter polymorphisms at -1082A>G, -819C>T, and -592C>A might influence IL-10 expression and give rise to non-small cell lung cancer (NSCLC) patients with poor outcomes and relapse. We collected adjacent normal tissues from 385 NSCLC patients to determine IL-10 haplotypes by direct sequencing and polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). Of the 385 tumors, 241 were available to evaluate IL-10 mRNA expression levels by real-time RT-PCR. The influence of IL-10 haplotypes on overall survival (OS) and relapse free survival (RFS) were determined by Kaplan-Meier and multivariate Cox regression analysis. The results showed that IL-10 mRNA levels were significantly higher in tumors with the non-ATA haplotype than with the ATA haplotype (P = 0.004). Patients with the non-ATA haplotype had shorter OS and RFS periods than did patients with the ATA haplotype. This may be associated with the observation that the number of tumor-infiltrating lymphocytes was decreased in the tumors with higher levels of IL-10. Consistently, T cells from the peripheral blood of the patients with non-ATA haplotype were more susceptible to apoptosis and less cytotoxic to tumor cells, compared to those from the patients with ATA haplotype. The results suggest that IL-10 can promote tumor malignancy via promoting T cell apoptosis and tumor cell survival, and IL-10 haplotype evaluated by PCR-RFLP or direct sequencing may be used to predict survival and relapse in resected NSCLC, helping clinicians to make appropriate decisions on treatment of the patients.
PLoS ONE 01/2012; 7(7):e39525. · 4.09 Impact Factor
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ABSTRACT: A thymine/cytosine point mutation in the MSP I restriction site of cytochrome P450 1A1 (CYP1A1) has been linked to susceptibility to smoking-related cancers and is reported to result in increased enzyme activity. Therefore, we sought to determine whether allelic variation of CYP1A1 is associated with protein expression and protein activity in pterygium.
We collected 150 pterygium samples and 50 normal conjunctiva samples, which served as controls. DNA samples were extracted from blood cells and then subjected to real-time ploymerase chain reaction (PCR) to determine CYP1A1 genotype. CYP1A1 protein expression was determined by immunohistochemical staining with a monoclonal antibody for CYP1A1. Pterygium epithelial cells (PECs), cultured in a serum-free culture medium, real-time PCR, western blot and enzyme-linked immunosorbent assay (ELISA) were used to understand the effect of CYP1A1 allelic variation in protein expression and activity.
Forty-eight (33.3%) pterygium specimens tested positive for CYP1A1 protein expression. CYP1A1 protein expression was significantly greater in the pterygium group than in the control group (p<0.0001). In addition, CYP1A1 protein expression was associated with allelic variation. CYP1A1 protein expression was significantly greater in the m2/m2 group than in the m1/m1and m1/m2 groups (p=0.006). In the cell model, CYP1A1 protein expression and b[a]P 7,8-diol 9,10-epoxide (BPDE)-like DNA adducts increased in CYP1A1 m2/m2 (genotype T/T) PEC cells as compared with m1/m2 (genotype C/T) and m1/m1 (genotype C/C) cells.
CYP1A1 expression in pterygium correlates with allelic variation and can be used as an independent risk marker.
Molecular vision 01/2012; 18:1937-43. · 2.20 Impact Factor
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Chun-Yi Chuang,
Wen-Wei Sung,
Lee Wang,
Wea-Long Lin,
Kun-Tu Yeh,
Mao-Chang Su,
Chun-Han Hsin,
Shiann-Yann Lee,
Buor-Chang Wu, Ya-Wen Cheng,
Huei Lee
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ABSTRACT: Human papillomavirus (HPV) is a risk factor in a subset of oropharyngeal cancer; however, the contribution of HPV in the malignancy of oral squamous cell carcinomas (OSCC) is not fully understood in Taiwanese. Herein, 61 patients with no risk factors and 117 patients with one or more risk factors were enrolled in this study. HPV16/18 infection rate in non-smokers, non-drinkers and non-betel quid chewers was higher than their counterparts. The development of HPV-infected cancer has been shown to be associated with interleukin-10 (IL-10) expression. To this end, IL-10 mRNA expression in OSCC tumors was evaluated by real-time RT-PCR. Data showed that HPV-positive patients had higher IL-10 mRNA levels than in HPV-negative patients. Kaplan-Meier and Cox-regression analysis indicated that the prognostic significance of IL-10 mRNA on overall survival and relapse free survival was only observed in HPV-positive OSCC, but not in HPV-negative OSCC. Mechanistically, the elevation of IL-10 by E6 was responsible for increased colony formation and migration capability in OSCC cells. Therefore, we suggest that IL-10 induced by E6 promotes cell growth and migration capability and consequent poor survival and relapse in HPV-positive OSCC.
PLoS ONE 01/2012; 7(10):e47541. · 4.09 Impact Factor
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ABSTRACT: Glycolic acid (GA) has been widely used in cosmetic agents and superficial chemical peeling in recent years. It has long been concerned that UV irradiation would enhance the photosensitivity of GA on human skin. Therefore, it is mandatory to explore the biologic effects of concomitant exposure of GA and UV irradiation in human keratinocytes.
The aim of the study is to explore the effects of concomitant exposure of GA and UVB in a human keratinocyte cell line (HaCaT).
We used HaCaT to investigate the effects of GA (5mM), UVB (50mJ/cm(2)), and co-treatment with GA and UVB (GA+UVB) in human keratinocytes. We used a phase contrast microscope to observe morphological changes of the cells, and employed flow cytometry to detect cell viability, cell cycle, and mitochondrial membrane potential (MMP), and intracellular reactive oxygen species (ROS) levels. Cell damage was detected by DAPI stain, and Western blot was used to detect the activities of apoptosis- related and cycle checkpoint-related proteins such as Bax, Bcl-2, caspases-3, -4, -9, Endo G, AIF, and p21, p27, p53, cdk2, cyclin E, cyclin A.
We found that either GA or UVB alone had inhibitory effect on cell proliferation, and co-treatment with GA and UVB had synergistic anti-proliferative effect. GA alone did not affect the cell cycle, and UVB induced HaCaT cells accumulated at S phase, and co-treatment with GA and UVB arrested cells at S phase more prominently. Moreover, all the treatment with GA, UVB, and GA+UVB in HaCaT cells induced apoptosis. We further demonstrated that GA had synergistic apoptotic effect in human keratinocytes. GA and UVB both had effects on the decline of MMP and increase of ROS release, and GA had synergistic increase in the level of ROS in UVB-treated HaCaT cells. Besides, co-treatment with GA and UVB had synergistic effect on apoptosis through the over-expressions of Bax, p21, p53, caspases-3, -4, -9, Endo G and AIF, and confocal microscopy disclosed translocation of AIF and Endo G from cytoplasm to the nucleus. Therefore, apoptosis induced by co-treatment by GA+UVB was initiated and executed by multiple pathways including mitochondria- and ER-dependent, and caspase-dependent and caspase-independent pathways.
We demonstrated that GA, UVB, GA+UVB inhibited proliferation and induced apoptosis in HaCaT cells. The mechanisms of apoptosis induced by co-treatment of GA and UVB involve multiple pathways. The synergistic photo-toxicity may be related to cell cycle arrest and apoptosis in UVB-treated HaCaT cells. These results highlight the potential adverse effects of GA-containing cosmetic agents on human skin.
Journal of dermatological science 12/2011; 64(3):191-8. · 3.71 Impact Factor
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ABSTRACT: Overexpression of ribonucleotide reductase M2 (hRRM2) and p53-dependent RR small subunit (p53R2) has been correlated with tumor malignancy and progression in several types of cancer. The aim of this study was to determine the association of p53R2/hRRM2 expression with clinicopathological characteristics of stage I and II non-small cell lung cancer (NSCLC). Immunohistochemistry was conducted on a tissue array that included 92 samples. Correlations between hRRM2 and p53R2 expression and clinicopathological factors, recurrence/metastasis, and outcomes were analyzed. The analyses revealed that there was no correlation between p53R2 expression and clinicopathological factors; hRRM2 was only positively related to poor tumor differentiation (p=0.006). Regarding overall survival during the follow-up period, patients with p53R2+/hRRM2- tumors had the best outcomes (p<0.01). Multivariant Cox analysis revealed that p53R2 (risk=0.232, 95% CI=0.086-0.626, p=0.004) not only served as a prognostic biomarker to predict survival, but also as an independent biomarker to predict disease-free survival (risk=0.545, 95% CI=0.301-0.987, p=0.045) of patients with NSCLC. Therefore, we consider that the expression of p53R2 can be used not only as a biomarker for overall survival, but also as an indicator for tumor recurrence. Based on our finding, p53R2 expression seems more important than that of hRRM2 in prognosis of early-stage lung cancer.
Anticancer research 10/2011; 31(10):3475-81. · 1.73 Impact Factor
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ABSTRACT: Fas ligand (FasL) -844T/C polymorphism (rs763110) has a demonstrated association with lung cancer risk. FasL -844CC with higher FasL expression has been suggested to contribute to tumor progression via immune escape. However, the impact of FasL -844T/C polymorphism on the clinical outcome of non-small cell lung cancer (NSCLC) remains to be identified.
A total of 385 adjacent normal lung tissues from patients with NSCLC were collected to determine FasL -844T/C polymorphism by PCR-based restriction fragment length polymorphism. FasL mRNA and protein expression in lung tumors were evaluated by real-time PCR and immunohistochemistry. The prognostic value of FasL -844T/C polymorphism on survival and relapse was determined by Kaplan-Meier analysis and Cox proportional hazards models.
The FasL -844CC genotype had higher prevalence in those with advanced tumors than in those with early tumors (P = 0.008). In addition, patients with the FasL -844CC genotype were more prone to tumor relapse than those with the FasL -844TT+TC genotype (62.1% vs. 37.9%, P = 0.001). Multivariate Cox regression analysis showed that patients with the FasL -844CC genotype had poorer survival in terms of overall survival (OS) and relapse-free survival (RFS) than those with the FasL -844TT+TC genotype (24.1 vs. 42.8 months for OS, HR = 1.455, P = 0.004; 15.4 vs. 31.4 months for RFS, HR = 1.710, P < 0.001).
FasL -844T/C polymorphism may predict survival and relapse in NSCLC. We suggest that FasL may be a molecular target for immunotherapeutic interventions to improve the clinical outcome of patients with NSCLC. This finding should be validated by another investigative group.
Clinical Cancer Research 08/2011; 17(18):5991-9. · 7.74 Impact Factor
