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1.  Trastuzumab-Related Cardiotoxicity Among Older Patients With Breast Cancer 
Journal of Clinical Oncology  2013;31(33):4222-4228.
Purpose
The use of trastuzumab in the adjuvant setting improves outcomes but is associated with cardiotoxicity manifested as congestive heart failure (CHF). The rates and risk factors associated with trastuzumab-related CHF among older patients are unknown.
Patients and Methods
Breast cancer patients at least 66 years old with full Medicare coverage, diagnosed with stage I-III breast cancer between 2005 and 2009, and treated with chemotherapy were identified in the SEER-Medicare and in the Texas Cancer Registry–Medicare databases. The rates and risk factors associated with CHF were evaluated. Chemotherapy, trastuzumab use, comorbidities, and CHF were identified using International Classification of Diseases, version 9, and Healthcare Common Procedure Coding System codes. Analyses included descriptive statistics and Cox proportional hazards models.
Results
In total, 9,535 patients were included, of whom 2,203 (23.1%) received trastuzumab. Median age of the entire cohort was 71 years old. Among trastuzumab users, the rate of CHF was 29.4% compared with 18.9% in nontrastuzumab users (P < .001). Trastuzumab users were more likely to develop CHF than nontrastuzumab users (hazard ratio [HR], 1.95; 95% CI, 1.75 to 2.17). Among trastuzumab-treated patients, older age (age > 80 years; HR, 1.53; 95% CI, 1.16 to 2.10), coronary artery disease (HR, 1.82; 95% CI, 1.34 to 2.48), hypertension (HR, 1.24; 95% CI, 1.02 to 1.50), and weekly trastuzumab administration (HR, 1.33; 95% CI, 1.05 to 1.68) increased the risk of CHF.
Conclusion
In this large cohort of older breast cancer patients, the rates of trastuzumb-related CHF are higher than those reported in clinical trials. Among patients treated with trastuzumab, those with cardiac comorbidities and older age may be at higher risk. Further studies need to confirm the role that the frequency of administration plays in the development of trastuzumab-related CHF.
doi:10.1200/JCO.2013.48.7884
PMCID: PMC3821011  PMID: 24127446
2.  Muddy Water? Variation in reporting receipt of breast cancer radiation therapy by population-based tumor registries 
International journal of radiation oncology, biology, physics  2013;86(4):10.1016/j.ijrobp.2013.03.016.
Purpose
Receipt of radiation therapy (RT) is a key quality indicator in breast cancer treatment. Prior analyses using population-based tumor registry data have demonstrated substantial underuse of RT for breast cancer, but the validity of such findings remains debated. To address this controversy, we evaluated accuracy of registry RT coding compared to the gold standard of Medicare claims.
Methods and Materials
Using SEER-Medicare data, we identified 73,077 patients age ≥ 66 diagnosed with breast cancer from 2001-2007. Underascertainment (1-sensitivity), sensitivity, specificity, kappa, and chi-square were calculated for RT receipt determined by registry data vs. claims. Multivariate logistic regression characterized patient, treatment, and geographic factors associated with underascertainment of RT. Findings in the SEER-Medicare registries were compared to three non-SEER registries (Florida, New York, and Texas).
Results
In the SEER-Medicare registries, 41.6% (n=30,386) of patients received RT according to registry coding versus 49.3% (n=36,047) according to Medicare claims (P<0.001). Underascertainment of RT was more likely if patients resided in a newer SEER registry (OR 1.70, 95%CI 1.60-1.80;P<0.001), rural county (OR 1.34, 95%CI 1.21-1.48;P<0.001) or if RT was delayed (OR 1.006/day, 95%CI 1.006-1.007,P<0.001). Underascertainment of RT receipt in SEER registries was 18.7% (95% CI 18.6-18.8%), compared to 44.3% (95% CI 44.0-44.5%) in non-SEER registries.
Discussion
Population-based tumor registries are highly variable in ascertainment of RT receipt and should be augmented with other data sources when evaluating quality of breast cancer care. Future work should identify opportunities for the radiation oncology community to partner with registries to improve accuracy of treatment data.
doi:10.1016/j.ijrobp.2013.03.016
PMCID: PMC3836610  PMID: 23773392
Breast Cancer; radiation therapy utilization; SEER
3.  Small sample properties of rare variant analysis methods 
BMC Proceedings  2014;8(Suppl 1):S13.
We are now well into the sequencing era of genetic analysis, and methods to investigate rare variants associated with disease remain in high demand. Currently, the more common rare variant analysis methods are burden tests and variance component tests. This report introduces a burden test known as the modified replication based sum statistic and evaluates its performance, and the performance of other common burden and variance component tests under the setting of a small sample size (103 total cases and controls) using the Genetic Analysis Workshop 18 simulated data with complete knowledge of the simulation model. Specifically we look at the variable threshold sum statistic, replication-based sum statistics, the C-alpha, and sequence kernel association test. Using minor allele frequency thresholds of less than 0.05, we find that the modified replication based sum statistic is competitive with all methods and that using 103 individuals leads to all methods being vastly underpowered. Much larger sample sizes are needed to confidently find truly associated genes.
doi:10.1186/1753-6561-8-S1-S13
PMCID: PMC4143716  PMID: 25519366
4.  Variants in melanocortin 1 receptor gene contribute to risk of melanoma – a direct sequencing analysis in a Texas population 
Pigment cell & melanoma research  2013;26(3):10.1111/pcmr.12070.
Summary
In this study, we directly sequenced the Melanocortin 1 Receptor (MC1R) gene in 2,212 individuals to detect all variants and assessed their associations with cutaneous melanoma (CM) risk in a hospital-based study of 1,106 CM patients and 1,106 control subjects. Of 61 MC1R variants identified, 16 rare variants have not been previously reported by others; three MC1R variants were associated with a significant CM risk [c.451C>T (OR = 1.78, 95% CI = 1.44–2.20), c.478C>T (OR = 1.31, 95% CI = 1.05–1.63), and c.880G>C (OR = 1.69, 95% CI = 1.15–2.48)]; and two with borderline CM risk [c.942A>G (OR =1.23, 95% CI =1.00–1.51, and c.274G>A (OR = 1.23,95% CI = 0.99–1.53)] under a dominant model. When combined these five MC1R variants for cumulative effect analysis, we found that subjects with an increased number of variant genotypes from any of these five variants had significantly increased risk of CM with ORs of 1.68 (95% CI = 1.39–2.04), 1.61 (95% CI = 1.27–2.04), and 2.64 (95% CI = 1.72–4.05) for one, two, and three or more variant genotypes, respectively (trend test: P <0.001). Further haplotype and diplotype analyses based on the above-mentioned five SNPs suggested that the c.451T allele contributed to the high risk of CM and that the five variants may have joint effects on the risk of CM. Additional analysis suggests that the three most significant SNPs may be the molecular mechanisms underlying the known risk factors of the colors of the eyes, skin and hair in this study population. In conclusion, our study provided confirmatory evidence that both common and rare variants in the MC1R coding region may be biomarkers for susceptibility to CM in US populations.
doi:10.1111/pcmr.12070
PMCID: PMC3721512  PMID: 23360207
melanocortin 1 receptor gene; direct sequencing; interaction; melanoma; case-control
5.  Deciphering the Mechanisms of Tumorigenesis in Human Pancreatic Ductal Epithelial Cells 
Purpose
The most common genetic lesions in pancreatic ductal adenocarcinoma (PDAC) have been identified. However, significant gaps still exist in our understanding of how such genetic alterations act in concert to induce PDAC development. In this study, we investigated the mechanism of tumorigenic transformation in the immortalized human pancreatic ductal epithelial (HPDE) cell line by sequentially introducing PDAC signature alterations into this cell line.
Experimental Design
The phenotype for stable expression of mutant K-ras, Her2, p16/p14shRNA, and Smad4shRNA in HPDE cells was examined by assays for cell proliferation, migration, invasion; soft agar; and orthotopic tumorigenesis. The mechanisms of tumorigenic transformation were further explored by gene expression profiling and pathway analyses.
Results
The transformed cells exhibited enhanced proliferation, migration, and invasion; displayed anchorage-independent growth in soft agar; and grew orthotopic tumors with some histopathological features of PDAC. We found that Smad4 played key roles in the tumorigenic transformation of HPDE cells. We further found that MDM2 and Bmi-1 were overexpressed in the tumorigenic HPDE cells and that Bmi-1 overexpression was regulated by Smad4. Ingenuity Pathway Analysis software analysis of microarray data revealed that dysregulation of integrin-linked kinase (ILK) signaling and the cell cycle were the most significant changes involved in tumorigenic transformation. Altogether, this cell culture model closely recapitulated human pancreatic carcinogenesis from gene lesions, activation of specific signaling pathways, and some histopathological features.
Conclusion
The combination of activated K-ras and Her2 with inactivated p16/p14 and Smad4 was sufficient and essential to transform HPDE cells, thus revealing the potential tumorigenic mechanism.
doi:10.1158/1078-0432.CCR-12-0032
PMCID: PMC3576034  PMID: 23340292
human pancreatic ductal adenocarcinoma; tumorigenic transformation; human pancreatic ductal epithelial cell line; Smad4
6.  Association between a Functional Polymorphism (-1195T>C) in the IGFBP5 Promoter and Head and Neck Cancer Risk 
Head & neck  2010;33(5):650-660.
Background
No studies have evaluated roles of insulin-like growth factor binding protein 5 (IGFBP-5) polymorphisms in risk of squamous cell carcinoma of the head and neck (SCCHN).
Methods
A hospital-based study of 1082 SCCHN patients and 1120 cancer-free controls was performed to investigate associations between two functional polymorphisms -1195T>C and -709G>C in the IGFBP5 promoter region and SCCHN risk.
Results
We demonstrated that the transcription factor AP-1 differentially bound to T or C variants at -1195 in the promoter to regulate the IGFBP5 promoter activity and that the C variant genotypes were associated with deferential risk of late-stage SCCHN, compared with the TT genotype, particularly for HPV-unrelated sites (adjusted OR, 2.21; 95% CI, 1.19-4.11 for CC vs. TT).
Conclusion
The IGFBP5 -1195T>C polymorphism is functional and may potentially be a biomarker for susceptibility to late-stage SCCHN.
doi:10.1002/hed.21514
PMCID: PMC3023825  PMID: 20949447
IGFBP5; head neck cancer; TNM stage; polymorphism; association
7.  Association of a novel functional promoter variant (rs2075533 C>T) in the apoptosis gene TNFSF8 with risk of lung cancer—a finding from Texas lung cancer genome-wide association study 
Carcinogenesis  2011;32(4):507-515.
Published genome-wide association studies (GWASs) have identified few variants in the known biological pathways involved in lung cancer etiology. To mine the possibly hidden causal single nucleotide polymorphisms (SNPs), we explored all SNPs in the extrinsic apoptosis pathway from our published GWAS dataset for 1154 lung cancer cases and 1137 cancer-free controls. In an initial association analysis of 611 tagSNPs in 41 apoptosis-related genes, we identified only 10 tagSNPs associated with lung cancer risk with a P value <10−2, including four tagSNPs in DAPK1 and three tagSNPs in TNFSF8. Unlike DAPK1 SNPs, TNFSF8 rs2181033 tagged other four predicted functional but untyped SNPs (rs776576, rs776577, rs31813148 and rs2075533) in the promoter region. Therefore, we further tested binding affinity of these four SNPs by performing the electrophoretic mobility shift assay. We found that only rs2075533T allele modified levels of nuclear proteins bound to DNA, leading to significantly decreased expression of luciferase reporter constructs by 5- to –10-fold in H1299, HeLa and HCT116 cell lines compared with the C allele. We also performed a replication study of the untyped rs2075533 in an independent Texas population but did not confirm the protective effect. We further performed a mini meta-analysis for SNPs of TNFSF8 obtained from other four published lung cancer GWASs with 12  214 cases and 47  721 controls, and we found that only rs3181366 (r2 = 0.69 with the untyped rs2075533) was associated to lung cancer risk (P = 0.008). Our findings suggest a possible role of novel TNFSF8 variants in susceptibility to lung cancer.
doi:10.1093/carcin/bgr014
PMCID: PMC3066422  PMID: 21292647
8.  A novel functional DEC1 promoter polymorphism −249T>C reduces risk of squamous cell carcinoma of the head and neck 
Carcinogenesis  2010;31(12):2082-2090.
Human DEC1 (deleted in esophageal cancer 1) gene is located on chromosome 9q, a region frequently deleted in various types of human cancers, including squamous cell carcinoma of the head and neck (SCCHN). However, only one epidemiological study has evaluated the association between DEC1 polymorphisms and cancer risk. In this hospital-based case–control study, four potentially functional single-nucleotide polymorphisms −1628 G>A (rs1591420), −606 T>C [rs4978620, in complete linkage disequilibrium with −249T>C (rs2012775) and −122 G>A(rs2012566)], c.179 C>T p.Ala60Val (rs2269700) and 3′ untranslated region-rs3750505 as well as the TP53 tumor suppressor gene codon 72 (Arg72Pro, rs1042522) polymorphism were genotyped in 1111 non-Hispanic Whites SCCHN patients and 1130 age-and sex-matched cancer-free controls. After adjustment for age, sex and smoking and drinking status, the variant −606CC (i.e. −249CC) homozygotes had a significantly reduced SCCHN risk (adjusted odds ratio = 0.71, 95% confidence interval = 0.52–0.99) compared with the −606TT homozygotes. Stratification analyses showed that a reduced risk associated with the −606CC genotype was more pronounced in subgroups of non-smokers, non-drinkers, younger subjects (defined as ≤57 years), carriers of the TP53 Arg/Arg (rs1042522) genotype, patients with oropharyngeal cancer or late-stage SCCHN. Further in silico analysis revealed that the −249 T-to-C change led to a gain of a transcription factor-binding site. Additional functional analysis showed that the −249T-to-C change significantly enhanced transcriptional activity of the DEC1 promoter and the DNA–protein-binding activity. We conclude that the DEC1 promoter −249 T>C (rs2012775) polymorphism is functional, modulating susceptibility to SCCHN among non-Hispanic Whites.
doi:10.1093/carcin/bgq198
PMCID: PMC2994282  PMID: 20935061
9.  Genetic variations in TERT–CLPTM1L genes and risk of squamous cell carcinoma of the head and neck 
Carcinogenesis  2010;31(11):1977-1981.
Single-nucleotide polymorphisms (SNPs) of TERT-rs2736098 (C > T) and CLPTM1L-rs401681(C > T) at the 5p15.33 locus are significantly associated with cancer risk as reported in genome-wide association studies (GWAS), but there are no reported studies for squamous cell carcinoma of the head and neck (SCCHN). In a case–control study of 1079 SCCHN cases and 1115 cancer-free controls of non-Hispanic whites who were frequency matched by age and sex, we genotyped for these two SNPs and assessed their associations with SCCHN risk. Compared with the CC genotypes of each polymorphism, the associations of a slightly reduced risk of SCCHN with the variant genotypes of CT + TT of both polymorphisms were approaching statistical significance [Odds ratio (OR) = 0.90, 95% confidence interval (CI) = 0.76–1.08 for TERT-rs2736098 and OR = 0.86, 95% CI = 0.71–1.04 for CLPTM1L-rs401681, respectively]. When the two SNPs were combined, the variant genotypes of the two SNPs were significantly associated a moderately reduced risk of SCCHN (OR = 0.82, 95% CI = 0.67–0.99), and the number of variant genotypes was associated with a significantly reduced risk in a dose–response manner (P = 0.028). Furthermore, the reduced risk was more pronounced in ever smokers, ever drinkers and patients with oropharyngeal cancer. Our results suggested that these two SNPs at the 5p15.33 locus may be associated with a reduced risk of SCCHN, particularly for their combined effect. Although we added additional evidence for the association of the two SNPs with cancer risk as reported in GWAS, additional studies are needed to replicate our findings.
doi:10.1093/carcin/bgq179
PMCID: PMC2966556  PMID: 20802237
10.  The functional IGFBP7 promoter −418G>A polymorphism and Risk of Head and Neck Cancer 
Mutation research  2010;702(1):32-39.
Insulin-like growth factor binding protein 7 (IGFBP7) functions mostly independent of the IGF signaling pathway and acts as a tumor suppressor in multiple cancers, but roles of IGFBP7 genetic variants in cancer remains unknown. In a hospital-based study of 1,065 patients with squamous cell carcinoma of head and neck (SCCHN) and 1,112 cancer-free controls of non-Hispanic whites, we investigated associations between two putatively functional IGFBP7 promoter single nucleotide polymorphisms (SNPs) (−702G>C, rs11573014 and −418G>A, rs4075349) and SCCHN risk. A significantly lower SCCHN risk was observed in those subjects carrying −418AG (adjusted OR=0.82, 95% CI=0.67–0.99) and −418AG+AA (adjusted OR=0.82, 95% CI=0.69–0.99) genotypes than those carrying the −418GG genotype, but not for the −702G>C SNP. However, those subjects carrying two common homozygous genotypes of these two SNPs (−418GG and −702GG) had an increased risk (adjusted OR=1.21, 95% CI=1.00-0.1.46) than did those carrying variant genotypes (−418AG+AA and −702CG+CC). This increased risk was more evident in subgroups of never smokers and subjects with oral cancer. Further functional analysis showed that the IGFBP7 −418A allele had significantly higher promoter and DNA-protein binding activities than did the G allele, suggesting a tumor suppressor role of this allelic change in the SCCHN etiology. We conclude that the functional variant −418 G>C in the IGFBP7 promoter is associated with reduced risk of SCCHN, likely by enhancing the IGFBP7 promoter and DNA-protein binding activities. Larger studies are needed to validate our findings.
doi:10.1016/j.mrgentox.2010.06.012
PMCID: PMC2939148  PMID: 20599521
IGFBP7; case-control study; tumor suppressor gene; head and neck cancer; promoter polymorphism
11.  Single Nucleotide Polymorphism ADH7 A92G is associated with Risk of Squamous Cell Carcinoma of the Head and Neck 
Cancer  2010;116(12):2984-2992.
Background
We conducted a hospital-based study of 1110 SCCHN cases and 1129 controls to replicate the associations reported by a recent large European study between two potentially functional single nucleotide plymorphisms (SNPs) of the alcohol dehydrogenases genes, ADH1B R48H (rs1229984: G>A) and ADH7 A92G (rs1573496: C>G), and risk of squamous cell carcinoma of the head and neck (SCCHN).
Methods
Multivariate logistic regression was used to calculate adjusted odds ratios (OR) and 95% confidence intervals (95% CI). False-positive report probabilities were also calculated for significant findings.
Results
We found that the ADH7A92G GG and combined CG+GG genotypes were associated with a decreased risk of SCCHN (adjusted OR, 0.32; 95% CI, 0.13-0.82 for GG and adjusted OR, 0.74; 95% CI, 0.59-0.94 for CG+GG; FPRP, .098) compared with the CC genotype. This association was also evident in subgroups of older (> 57 years) subjects, males, former smokers, oral cancer, and N0 lymph node metastasis (P < .05 for all); however, such associations were not observed for the ADH1B R48H SNP.
Conclusion
Our results support the ADH7 A92G SNP as a marker for risk of SCCHN in non-Hispanic White populations.
doi:10.1002/cncr.25058
PMCID: PMC2891145  PMID: 20336794
ADH7; genetic variant; genetic susceptibility; head and neck cancer; molecular epidemiology
12.  Genetic Variants in Selected pre-mircroRNA Genes and Risk of Squamous Cell Carcinoma of the Head and Neck 
Cancer  2010;116(20):4753-4760.
BACKGROUND
Single nucleotide polymorphisms (SNPs) in microRNAs (miRNAs) may alter processing, transcription, and expression of miRNAs, and thus contribute to cancer development. We hypothesized that common polymorphisms in pre-miRNAs individually, and more likely, collectively are associated with risk of squamous cell carcinoma of the head and neck (SCCHN).
METHODS
We genotyped four common polymorphisms in pre-miRNAs (hsa-mir-146a rs2910164 G>C, hsa-mir-149 rs2292832 G>T, hsa-mir-196a2 rs11614913 C>T, and hsa-mir-499 rs3746444 A>G) in 1109 SCCHN cases and 1130 cancer-free controls in a non-Hispanic white population frequency-matched by age and sex. We used univariable and multivariable logistic regression models to calculate crude and adjusted odds ratios (OR) and 95% confidence intervals (CI).
RESULTS
Of the four SNPs studied, hsa-mir-499 AG and GG genotypes were associated with reduced risk of SCCHN (OR, 0.83; 95% CI, 0.69–0.99). When we combined the four SNPs by putative risk genotypes, we found that the number of observed risk genotypes was associated with increased risk of SCCHN in a dose-response manner: OR=1.0, 1.20 and 1.40 for 0–1, 2–3 and 4 risk genotypes (Ptrend = 0.037). Specifically, the risk was 1.23 fold (95% CI, 0.98–1.56) for subjects with 2–4 risk genotypes and 1.40 fold (95% CI, 1.02–1.92) for subjects with 4 risk genotypes, compared with subjects with 0–1 risk genotypes. This risk was more pronounced in men and patients with oropharyngeal cancer.
CONCLUSIONS
The combined risk genotypes of four common SNPs in pre-mircroRNAs were significantly associated with a moderately increased risk of SCCHN. Larger studies are needed to validate our findings.
doi:10.1002/cncr.25323
PMCID: PMC3030480  PMID: 20549817
genetic susceptibility; microRNA; head and neck cancer; polymorphism; molecular epidemiology
13.  Genetic polymorphisms in the PTPN13 gene and risk of squamous cell carcinoma of head and neck 
Carcinogenesis  2009;30(12):2053-2058.
Fas-associated phosphatase-1 is encoded by the protein tyrosine phosphatase, non-receptor type 13 (PTPN13) gene and attributes to the resistance to Fas-mediated apoptosis in several tumors, including squamous cell carcinoma of the head and neck (SCCHN). However, no epidemiological studies have investigated the roles of PTPN13 polymorphisms in SCCHN risk. In this hospital-based case–control study of 1069 SCCHN patients and 1102 non-Hispanic white cancer-free controls, we evaluated the associations between three single-nucleotide polymorphisms c.4068 T>G F1356L (rs10033029), c.4566 A>G I1522M (rs2230600) and c.6241 T>G Y2081D (rs989902) located in the coding region of PTPN13 and SCCHN risk. We found that a significantly increased SCCHN risk was associated with the c.4566 I1522M GG genotype [odds ratio (OR), 1.89; 95% confidence interval (CI), 1.27–2.79] and c.6241 Y2081D GT genotype (OR, 1.26; 95% CI, 1.03–1.53) compared with the c.4566 I1522M AA and c.6241 Y2081D TT genotypes, respectively. Further stratified analyses showed that risk associated with the c.4566 I1522M GG genotype was more profound in the subgroups of young (≤57 years), males, never smokers, current drinkers and patients with pharyngeal cancer; that risk associated with c.6241 Y2081D GT genotype persisted in subgroups of old (>57 years), males, current drinkers and patients with pharyngeal and laryngeal cancers and that risk associated with c.6241 Y2081D GG genotype was borderline in patients with laryngeal cancer. In conclusion, polymorphisms in the PTPN13 coding region may be biomarkers for susceptibility to SCCHN in USA populations.
doi:10.1093/carcin/bgp265
PMCID: PMC2792321  PMID: 19892796
14.  Secreted Interleukin-1α Induces a Metastatic Phenotype in Pancreatic Cancer by Sustaining a Constitutive Activation of Nuclear Factor-κB 
Molecular cancer research : MCR  2009;7(5):624-633.
Transcription factor nuclear factor-κB (NF-κB) is constitutively activated in most pancreatic cancer tissues and cell lines but not in normal pancreas nor in immortalized/nontumorigenic human pancreatic ductal epithelial cells. Inhibition of constitutive NF-κB activation in pancreatic cancer cell lines suppresses tumorigenesis and tumor metastasis. Recently, we identified autocrine secretion of proinflammatory cytokine interleukin (IL)-1α as the mechanism of constitutive NF-κB activation in metastatic pancreatic cancer cell lines. However, the role of IL-1α in determining the metastatic potential of pancreatic tumor remains to be further investigated. In the current study, we stably expressed IL-1α in the nonmetastatic, IL-1α–negative MiaPaCa-2 cell lines. Our results showed that the secretion of IL-1α in MiaPaCa-2 cells constitutively activated NF-κB and increased the expression of NF-κB downstream genes involved in the different steps of the metastatic cascade, such as urokinase-type plasminogen activator, vascular endothelial growth factor, and IL-8. MiaPaCa-2/IL-1α cells showed an enhanced cell invasion in vitro compared with parental MiaPaCa-2 cells and induced liver metastasis in an orthotopic mouse model. The metastatic phenotype induced by IL-1α was inhibited by the expression of phosphorylation-defective IκB (IκB S32, 36A), which blocked NF-κB activation. Consistently, silencing the expression of IL-1α by short hairpin RNA in the highly metastatic L3.6pl pancreatic cancer cells completely suppressed their metastatic spread. In summary, these findings showed that IL-1α plays key roles in pancreatic cancer metastatic behavior through the constitutive activation of NF-κB. Our findings further support the possible link between inflammation and cancer and suggest that IL-1α may be a potential therapeutic target for treating pancreatic adenocarcinoma.
doi:10.1158/1541-7786.MCR-08-0201
PMCID: PMC2856954  PMID: 19435817
15.  The VEGF -634G>C promoter polymorphism is associated with risk of gastric cancer 
BMC Gastroenterology  2009;9:77.
Background
Both TGF-β1 and VEGF play a critic role in the multiple-step process of tumorgenesis of gastric cancer. Single nucleotide polymorphisms (SNPs) of the TGFB1 and VEGF genes have been associated with risk and progression of many cancers. In this study, we investigated the association between potentially functional SNPs of these two genes and risk of gastric cancer in a US population.
Methods
The risk associated with genotypes and haplotypes of four TGFB1 SNPs and four VEGF SNPs were determined by multivariate logistic regression analysis in 171 patients with gastric cancer and 353 cancer-free controls frequency-matched by age, sex and ethnicity.
Results
Compared with the VEGF-634GG genotype, the -634CG genotype and the combined -634CG+CC genotypes were associated with a significantly elevated risk of gastric cancer (adjusted OR = 1.88, 95% CI = 1.24-2.86 and adjusted OR = 1.56, 95% CI = 1.07-2.27, respectively). However, none of other TGFB1 and VEGF SNPs was associated with risk of gastric cancer.
Conclusion
Our data suggested that the VEGF-634G>C SNP may be a marker for susceptibility to gastric cancer, and this finding needs to be validated in larger studies.
doi:10.1186/1471-230X-9-77
PMCID: PMC2771032  PMID: 19835575
16.  Polymorphisms of TGFB1 and VEGF genes and survival of patients with gastric cancer 
Background
Some TGFB1 and VEGF polymorphisms are believed to be functional. Given that these genes are involved in tumor growth and progression including angiogenesis, dissemination, and invasiveness, we hypothesized that these polymorphisms would be associated with survival in patients with gastric cancer.
Methods
We genotyped TGFB1 -509 C>T, +1869 T>C, and +915 G>C and VEGF -1498T>C, -634G>C, and +936C>T in 167 patients with gastric cancer. Using the Kaplan and Meier method, log-rank tests, and Cox proportional hazard models, we evaluated associations among TGFB1 and VEGF variants with overall, 1-year, and 2-year survival rates.
Results
Although there were no significant differences in overall survival rates among all polymorphisms tested, patients with TGFB1+915CG and CC genotypes had a poorer 2-year survival (adjusted hazard ratio (HR), 3.06; 95% confidence interval (CI), 1.09–8.62; P = 0.034) than patients with the GG genotype had. In addition, patients heterozygous for VEGF -634CG also had a poorer 1-year survival (adjusted HR, 2.08; 95% CI, 1.03–4.22; P = 0.042) than patients with the -634GG genotype.
Conclusion
Our study suggested that TGFB1+915CG/CC and VEGF -634CG genotypes may be associated with short-term survival in gastric cancer patients. However, larger studies are needed to verify these findings.
doi:10.1186/1756-9966-28-94
PMCID: PMC2717936  PMID: 19566948
17.  NF-κB and AP-1 Connection: Mechanism of NF-κB-Dependent Regulation of AP-1 Activity 
Molecular and Cellular Biology  2004;24(17):7806-7819.
Nuclear factor κB (NF-κB) and activator protein 1 (AP-1) transcription factors regulate many important biological and pathological processes. Activation of NF-κB is regulated by the inducible phosphorylation of NF-κB inhibitor IκB by IκB kinase. In contrast, Fos, a key component of AP-1, is primarily transcriptionally regulated by serum responsive factors (SRFs) and ternary complex factors (TCFs). Despite these different regulatory mechanisms, there is an intriguing possibility that NF-κB and AP-1 may modulate each other, thus expanding the scope of these two rapidly inducible transcription factors. To determine whether NF-κB activity is involved in the regulation of fos expression in response to various stimuli, we analyzed activity of AP-1 and expression of fos, fosB, fra-1, fra-2, jun, junB, and junD, as well as AP-1 downstream target gene VEGF, using MDAPanc-28 and MDAPanc-28/IκBαM pancreatic tumor cells and wild-type, IKK1−/−, and IKK2−/− murine embryonic fibroblast cells. Our results show that elk-1, a member of TCFs, is one of the NF-κB downstream target genes. Inhibition of NF-κB activity greatly decreased expression of elk-1. Consequently, the reduced level of activated Elk-1 protein by extracellular signal-regulated kinase impeded constitutive, serum-, and superoxide-inducible c-fos expression. Thus, our study revealed a distinct and essential role of NF-κB in participating in the regulation of elk-1, c-fos, and VEGF expression.
doi:10.1128/MCB.24.17.7806-7819.2004
PMCID: PMC507000  PMID: 15314185

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