bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A39: EGCG, a green tea polyphenol, can reverse methylation related silencing of genes in human colon carcinomas
Authors: Morris Jay , Moseley Vondina R. , Coleman Katie , Wargovich Michael 
Published: June 2012

Abstract
Silencing of regulatory genes through hypermethylation of CpG islands is an important mechanism in tumorigenesis. In colon cancer, RXRα, an important dimerization partner with other nuclear transcription factors, is silenced through this mechanism. Previous studies from our laboratory have shown that ApcMin/+ mice treated with the carcinogen azoxymethane (AOM) will develop colonic tumors but when treated with green tea a reduction in tumor numbers was found. We found that colon tumors had lower expression of RXR protein but expression levels were restored by treatment with green tea. We also found that the degree of promoter methylation of the RXR gene was reduced. To translate these findings to human colon cancer we treated CpG Island Methylator Phenotype sensitive and insensitive (CIMP+ & CIMP-) human colon cancer cell lines with epigallocatechin gallate (EGCG - major polyphenolic compound in green tea). We hypothesized that CIMP+ cell lines which epigenetically silence key regulatory genes would demonstrate silencing of RXRα and that EGCG would restore its expression. To test this we used the following human colon cancer cell lines: HCT116, SW48, HCT15 - CIMP+; HT29, SW480, SW620 - CIMP- and IEC-6 - normal control. We found EGCG to restore RXR activity levels in the CIMP+ lines, in a dose dependent manner (0, 50, 100 & 150 μM EGCG was tested for 48 and 72 hour durations). EGCG also reduced RXRα promoter methylation in one CpG island from a CIMP+ cell line compared to a CIMP-line. We found that EGCG produced methylation changes in several other colon cancer related genes but did not cause a decrease in global methylation. Numerous epidemiological reports have shown the benefits of green tea consumption in reducing colon cancer risk but to date no studies have shown that some of the risk reduction may be related to the epigenetic regulation of key genes by constituent tea polyphenols. Our results here show that EGCG, a common tea polyphenolic compound, can modulate the reversal of gene-silencing involved colon carcinogenesis and maybe a possible avenue for colon cancer treatment. Supported by USPHS grant CA96694 from the National Cancer Institute.
Citation Information: Cancer Prev Res 2011;4(10 Suppl):A39.
Abstract A40: Epigenetic modification of human colon cancer by the green tea polyphenol EGCG
Authors: Moseley Vondina R. , Morris Jay , Wargovich Michael J. 
Published: June 2012

Abstract
Silencing of regulatory genes through hypermethylation of CpG islands is an important mechanism in tumorigenesis of numerous cancers. We have previously shown that Retinoid X Receptor alpha (RXRα) is silenced in tumors of the colon cancer AOM-APC/min+ mouse model. Upon treatment with green tea, RXRα expression was restored and intestinal tumorigenesis was inhibited. We examined human colonic tumor microarrays by immunohistochemcial staining and found a marked decrease in RXR expression in tumor tissue compared to normal matched tissues, inversely β-Catenin levels increased. To determine how RXRα loss is reversed in human cancers by green tea, we treated HT-29 (methylation insensitive) and HCT116 (methylation sensitive) human colon cancer cell lines with different concentrations of Epigallocatechin gallate (EGCG - major polyphenolic compound in green tea). We found by western blotting nuclear protein fractions that EGCG can restore RXRα levels in HCT116 cells in a dose dependant manner. Using these same lysates, we probed for presence of the most common DNA Methyltransferases (DNMTs) and Histone Deacetylases (HDACs). We found that expression of DNMTs as well as HDACs was inhibited in a dose dependent manner following treatment with EGCG. Additionally we examined by real time PCR, the message levels of DNMTs in cells treated with EGCG to determine if they correlate with the observed downregulation in protein expression. We can conclude that the silencing of RXRα may be due in part to by repressing effects of EGCG on DNMT as well as HDAC activity. Our results here show that EGCG, a common dietary compound, can modulate the reversal of gene-silencing involved colon carcinogenesis and maybe a possible avenue for colon cancer therapy and demonstrates be one potential mechanism of cancer chemoprevention in green tea that outlines a new epigenetic pathway.
Citation Information: Cancer Prev Res 2011;4(10 Suppl):A40.
Abstract A94: ABO blood group and risk of renal cell cancer
Authors: Joh Hee-Kyung , Cho Eunyoung , Choueiri Toni K. 
Published: June 2012

Abstract
Background: The genetic determinants of sporadic renal cell cancer (RCC) are largely unknown. Previous studies have suggested associations between the ABO blood group and risk of various cancers, however, its relationship to RCC remains unclear.
Methods: We prospectively evaluated the association between the ABO blood group and risk of RCC in two large independent cohorts of women (the Nurses' Health Study) and men (the Health Professionals Follow-up Study) from 1996 to 2008. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox proportional hazards models with adjustment for other risk factors for RCC including obesity, smoking, and hypertension. All statistical tests were two-sided.
Results: During 12 years of follow-up of 77,242 women and 29,548 men, 163 cases of incident RCC were documented in women and 84 cases in men. After multivariate adjustment, non-O blood group (combined group of A, AB, and B) was associated with a 1.5-fold elevated risk of RCC (95% CI 1.09–2.09) than O blood group in women. In contrast, no significant associations were observed between the ABO blood group and risk of RCC in men. The associations between the ABO blood group and RCC were consistent across strata of known risk factors including obesity, smoking status, and history of hypertension (Pinteraction ≥ .58) in both cohorts.
Conclusion: We show for the first time that non-O blood group is significantly associated with a higher risk of RCC compared with blood group O in women. Further studies that elucidate the biological mechanisms underlying this association are warranted.
Citation Information: Cancer Prev Res 2011;4(10 Suppl):A94.
Abstract B22: Fatigue among long-term survivors of breast cancer: A prospective cohort study with longitudinal follow-up
Authors: Chen Wendy Y. , Holmes Michelle D. , Hankinson Susan E. 
Published: June 2012

Abstract
Background: Fatigue is a common side effect of cancer treatment, but the longer terms effects of cancer diagnosis and treatment on fatigue are not well quantified. Study population: Participants from the prospective Nurses' Health Study who completed the Medical Outcomes Short-Form-36 (SF36) in 1992, 1996, and 2000. Outcomes: The 5-item Fatigue subscale from the SF36. A score of ≤ 50 is considered to represent fatigue:
Results: 46,851 women without a history of cancer, 1015 women diagnosed with invasive breast cancer between 1984 and 1991, and 187 women diagnosed with in situ breast cancer between 1984 and 1991 were included in this analysis. All fatigue assessments were performed at least one year after diagnosis. Using the three time points, several fatigue trajectories were investigated including: persistently fatigued at all three time points, persistently non-fatigued at all time points, and developing fatigue over time. In age-adjusted analyses, the frequencies of the different fatigue trajectories were similar across the three groups: cancer free women, breast cancer survivors with invasive breast cancer, and survivors with in situ disease. That is, the chances of being persistently fatigued, persistently non-fatigued, or developing fatigue was similar across all three groups (p&gt;0.09). Instead, the strongest predictor of fatigue trajectories was age. The prevalence of persistent fatigue and persistent non-fatigue varied strongly with age with a U-shaped curve (p&lt;0.01). Specifically, the women aged 55–59.9 and 60–64.9 (when categorizing participants by 5 year age groups) had the lowest incidence of persistent fatigue and highest incidence of non-fatigue compared to older (65+) or younger women (&lt;55).
Conclusions: After a cancer diagnosis, the prevalence of persistent fatigue or developing fatigue is similar comparing cancer-free women compared to breast cancer survivors. Self-assessments of fatigue appear to be more strongly related to age. Age needs to be carefully considered in all fatigue analyses and would provide a useful way to target interventions to improve fatigue.
Citation Information: Cancer Prev Res 2011;4(10 Suppl):B22.
Abstract B36: Respiratory symptoms after smoking cessation among college students
Authors: Calabro Karen S. , Prokhorov Alexander V. 
Published: June 2012

Abstract
Introduction: Data about respiratory symptoms and lung function are available for middle-aged adults post-cessation. Similar evidence is lacking for those aged 18 to 24 years. This study addresses that gap. Procedures: This report is a secondary analysis of data derived from two randomized controlled smoking cessation trials among a subset of 18- to 24-year-old college students. Data from both studies were combined regardless of treatment condition. Some participants received an active intervention while controls were provided with self-help smoking materials. Self-reported respiratory symptoms were longitudinally analyzed in 273 quitters. The change in respiratory symptoms was calculated by subtracting the final scores from those at baseline.
Summary of Data: The respiratory symptoms of continued smokers were compared to the quitters at the final visit using t-tests. Significant improvements in respiratory symptoms were found among quitters for morning cough, (p =.002) daytime cough, (p =.007), and chest pain (p =.007).
Statement of Conclusions: Young individuals rarely respond to quit-smoking motivation based on long-term health consequences, such as risk of tobacco-attributable cancers. A more appropriate motivational strategy for young adults appears to be emphasizing the existing respiratory symptoms caused by smoking. Clinicians are encouraged to detect and discuss respiratory symptoms with their young tobacco-using patients as a part of smoking cessation counseling and treatment. Highlighting post-cessation reduction in these symptoms is likely to reinforce continued abstinence.
Citation Information: Cancer Prev Res 2011;4(10 Suppl):B36.
Abstract B60: Overexpression of VCAM-1 promotes tumor progression and drug resistance in breast cancer
Authors: Kuo Tzu-Lei , Hou Ming-Feng , Cheng Kuang-hung 
Published: June 2012

Abstract
VCAM-1 (CD106) is a transmembrane glycoprotein that is involved in many pathological inflammatory processes. VCAM-1 plays an important role in leukocyte adhesion, leukocyte transendothelial migration and cell activation by binding to integrin VLA-1 (α4β1). In our preliminary data, we first identified that VCAM-1 expression can be induced in many breast cancer epithelial cells by cytokine stimulation and directly correlated with breast tumor progression; however, its mechanism of action in tumor biology remains unknown. Here, we describe the establishment and use of breast cancer cell line model systems to dissect the functional roles of VCAM-1 activation in the manifestation of malignant phenotypes of human breast cancer. We show that VCAM-1 overexpression in the NMuMG breast epithelial cells increase cell adhesion and motility rates and promote chemoresistance to doxorubicin and cisplatin in vitro. Conversely, in an established metastatic breast cancer cell line, MDAMB231, we confirmed that the knockdown of endogenous VCAM-1 expression by small interfering RNA (SiRNA) reduced cell proliferation and inhibited TGFb1 or IL6 mediated cell migration. Furthermore, we also demonstrated that knockdown of endogenous VCAM-1 expression in MDAMB231 cells reduced the tumor formation in an SCID xenograft mouse model. In conclusion, our findings uncover the critical role of VCAM-1 activation in facilitating breast cancer progression by enhancing the malignant properties of breast cancer cells and suggest that targeting of VCAM-1 induced pathways is an attractive strategy for therapeutic intervention.
Citation Information: Cancer Prev Res 2011;4(10 Suppl):B60.
Abstract B67: Curcumin induces stabilization of Nrf2 protein by decreasing the activity of Cullin3-Rbx1 E3 ubiquitin ligase
Authors: Shin Jun-Wan , Surh Young-Joon 
Published: June 2012

Abstract
Curcumin, the yellow pigment of tumeric (Curcuma longa L., Zingiberaceae), is one of the most widely used spices in the East Asia. Curcumin has been shown to possess anti-inflammatory, antioxidative and chemopreventive effects. Although a growing body of evidence suggests that the chemopreventive potential of curcumin depends partly on its ability to induce cytoprotective proteins through the activation of nuclear factor erythroid-related factor-2 (Nrf2), the molecular mechanisms remain elusive. The present study was aimed to elucidate the mechanisms underlying the activation of Nrf2 and induction of cytoprotective gene expression by curcumin. Incubation of mouse epidermal (JB6) cells with curcumin resulted in the induction of heme oxygenase-1 (HO-1) and NAD(P)H oxidoreductase 1 (NQO1) at both mRNA and protein levels. Curcumin-induced expression of HO-1 and NQO1 was abrogated in cells transiently transfected with Nrf2 siRNA. Furthermore, embryo fibroblasts from Nrf2 knock-out mice were not responsive to curcumin, compared with those from wild-type animals, in terms of inducing HO-1 and NQO1 expression. While curcumin treatment increased protein expression of Nrf2, it failed to alter the steady-state level of the Nrf2 mRNA transcript, suggesting that protein stabilization might be involved in curcumin-induced Nrf2 accumulation. Treatment of JB6 cells with curcumin did stabilize Nrf2 by inhibiting ubiquitination and subsequent 26S proteasomal degradation of Nrf2. Kelch-like ECH-associated protein-1 (Keap1), a substrate adaptor of Cullin3-Rbx1 E3 ubiquitin ligase complex, has several reactive cysteine residues, and modification of these cysteine residues has been proposed as a molecular mechanism underlying oxidative and electrophilic stress-induced activation of Nrf2. The thiol-reducing agent dithiothreitol abrogated curcumin-induced accumulation of Nrf2 and expression of cytoprotective proteins. In addition, tetrahydrocurcumin, a non-electrophilic analogue of curcumin that lacks the α,β-unsaturated carbonyl group, failed to induce cytoprotective protein expression as well as Nrf2 nuclear translocation, indicative of a pivotal role of cysteine residues of Keap1 in curcumin-induced Nrf2 activation. Cells transfected with a mutant Keap1 protein in which cysteine 151 is replaced by serine exhibited reduction in curcumin-induced Nrf2 activation. Although curcumin did not cause dissociation of Cullin3-Rbx1 E3 ubiquitin ligase complex components, it increased interaction of Nrf2 with the Keap1. Thus, it is likely that curcumin inhibits the ability of the Cullin3-Rbx1 E3 ubiquitin ligase to target Nrf2 for ubiquitination by modifying Keap1 Cys 151 residue. This may change the conformation of the complex and saturates the binding capacity of Keap1 to Nrf2, facilitating nuclear translocation of Nrf2.
Citation Information: Cancer Prev Res 2011;4(10 Suppl):B67.
Abstract B69: Cellular neutral lipid content is a novel biomarker of cancer preventive activity
Authors: Uray Ivan P. , Bissonnette Reid , Brown Powel H. 
Published: June 2012

Abstract
Introduction: Commonly used biomarkers to assess the cancer preventive activity of cancer preventive agents include markers of cell proliferation or apoptosis. However, the expression of proliferation or apoptosis markers is highly variable, and measurement is often done using semi-quantitative assays. In addition, cancer preventive agents may act through mechanisms that do not depend on proliferation or apoptosis. Therefore, identification of new biomarkers indicative of the cancer preventive activity of chemopreventive agents is essential for the development of new cancer preventive drugs.
Methods: We applied high-content microscopic analysis to assess the phenotypic changes occurring in normal mammary epithelial cells (HMECs) after treatment with cancer preventive drugs by measuring cell proliferation, DNA and neutral lipid content and localization, as well as cell cycle distribution of the cells. Gene specific knock-down was achieved by transfections with siRNA duplexes. Measurement of transcript levels was performed using quantitative real-time RT-PCR.
Results: Multiparametric analysis of high-throughput image based studies have revealed that anti-proliferative activity of cancer preventive rexinoids is associated with increased formation of cytoplasmic lipid droplets.
Accumulation of cytoplasmic neutral lipids was restricted to cell types that undergo significant growth suppression by bexarotene (HMECs, SUM225, and ZR75.1), but not observed in retinoid-resistant cells (MCF10A, HCC1937, and HCC1143). Other growth suppressive drugs including the kinase inhibitor lapatinib, vitamin D, and certain natural compounds, including epicatechine monogallate, duartin, actinonin and homoisoflavonoids, were also found to increase cellular neutral lipid content in breast cells. The addition of external fatty acids, such as oleic and palmitoleic acids did not result in dose-dependent growth suppression or accumulation of neutral esterified lipid droplets. Lipid accumulation and growth suppression were associated with the up-regulation of genes involved in regulating the formation of neutral lipids, triglycerides and phospholipids, but not genes involved in de novo fatty acid synthesis. Conversely, knock-down of key proteins controlling cellular triglyceride synthesis and storage, diacylglycerol acyltransferase 1 (DGAT1) and adipophyllin (Adfp) increased cell proliferation whereas their induction was associated with growth suppression in HMECs.
Conclusion: These results suggest that increased accumulation of cellular triglycerides may be a useful biomarker to assess the preventive effect of putative cancer preventive agents. These results support the systematic testing of cellular neutral lipid levels in preclinical and clinical models testing novel chemopreventive agents.
This work was supported by the grant RO1 CA 78480 (to P.H.B.).
Citation Information: Cancer Prev Res 2011;4(10 Suppl):B69.
Abstract B70: Inhibition of nuclear bile acid receptor FXR as a target in prevention of esophageal adenocarcinoma
Authors: Guan Baoxiang , Li Hao , Yang Zhengduo , Hoque Ashraful , Xu Xiaochun 
Published: June 2012

Abstract
Incidence of esophageal adenocarcinoma is increasing in the United States and other Western countries. Frequent gastroesophageal reflux or gastroesophageal reflux disease, resulting in Barrett esophagus, may be responsible for the increase. The main function of bile acid is to facilitate the formation of micelles for promotion of the processing and absorption of dietary fat. As surfactants or detergents, bile acids are potentially toxic to the cells, so their concentrations in the small intestine are tightly regulated. However, patients with frequent gastroesophageal reflux will have reflux damage caused by acid and bile acid-containing juice in the distal esophagus, with the result that normal squamous cells around the gastroesophageal junction will change to a new cell phenotype (incomplete intestinal metaplasia), because this type of cell is more resistant to acid and bile-caused injuries; therefore, Barrett esophagus is formed. This study aimed to determine the tumor-promoting effects of bile acid on esophageal cancer cells and the underlying molecular mechanisms. The data showed that different bile acids (i.e., chenodeoxycholic acid, deoxycholic acid, and lithocholic acid) induced COX-2 but inhibited RAR-β2 expression through farnesoid X receptor (FXR) expression in esophageal cancer cell lines. FXR is a nuclear receptor for bile acids functioning as a signaling molecule in the liver and the intestines and frequent gastroesophageal reflux induces FXR expression in esophageal cells. Indeed, the ex vivo data demonstrated that FXR was highly expressed in esophageal adenocarcinoma (81%) tissues and was associated with reduced RAR-β2 expression. Knockdown of FXR expression using FXR shRNA antagonized the effects of bile acid in gene expression and suppressed tumor cell viability in vitro and in nude mouse xenografts. Moreover, guggulsterone, a FXR inhibitor, was able to reduce the viability of esophageal cancer cells in time- and dose-dependent manner in vitro. Apoptosis induced by guggulsterone was through activation of caspase 8, 9, and 3. In conclusion, suppression of FXR expression using FXR shRNA or its inhibitor guggulsterone was able to suppress tumor cell growth in vitro and in vivo and induce apoptosis in vitro. This study demonstrated that inhibition of FXR could be further evaluated as a target in prevention of esophageal adenocarcinoma.
Citation Information: Cancer Prev Res 2011;4(10 Suppl):B70.