bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tobacco Smoke Induces Polycomb-Mediated Repression of Dickkopf-1 in Lung Cancer Cells
Authors: Hussain Mustafa , Rao Mahadev , Humphries Ashley E. , Hong Julie A. , Liu Fang , Yang Maocheng , Caragacianu Diana , Schrump David S. 
Published: April 2009

Abstract
Limited information is available about epigenetic mechanisms by which cigarette smoke enhances the initiation and progression of lung cancer. To examine this issue, A549 and Calu-6 lung cancer cells were cultured in normal media with or without tobacco smoke condensate (TSC) under clinically relevant exposure conditions. Ten-day TSC exposure dramatically increased the tumorigenicity of lung cancer cells in nude mice. Microarray and quantitative reverse transcription-PCR (RT-PCR) experiments revealed that this phenomenon coincided with diminished expression of Dickkopf-1 (Dkk-1). Western blot, chromatin immunoprecipitation, methylation-specific PCR, and pyrosequencing experiments showed that repression of Dkk-1 coincided with decreased H4K16Ac, increased H3K27me3, and recruitment of SirT1, EZH2, SUZ12, and Bmi1 without DNA hypermethylation within the Dkk-1 promoter despite prolonged TSC exposures. Removal of TSC from culture media resulted in loss of promoter-associated polycomb repressor complexes and reexpression of Dkk-1. siRNA-mediated knockdown of EZH2 and SirT1 partially abrogated TSC-mediated inhibition of Dkk-1 expression. Western blot and quantitative RT-PCR array experiments showed that TSC exposure as well as knockdown of Dkk-1 activated Wnt signaling and significantly up-regulated Wnt5a in lung cancer cells. Knockdown of Dkk-1 recapitulated the dramatic protumorigenic effects of TSC exposure in Calu-6 cells. Despite the transient nature of Dkk-1 repression following TSC exposure in vitro, Dkk-1 remained silenced in tumor xenografts derived from TSC-treated Calu-6 cells. Collectively, these data provide evidence that cigarette smoke directly engages polycomb machinery to activate a signaling network implicated in maintenance of cancer stem cells. [Cancer Res 2009;69(8):3570–8]
Lineage-Specific T-Cell Responses to Cancer Mucosa Antigen Oppose Systemic Metastases without Mucosal Inflammatory Disease
Authors: Snook Adam E. , Li Peng , Stafford Benjamin J. , Faul Elizabeth J. , Huang Lan , Birbe Ruth C. , Bombonati Alessandro , Schulz Stephanie , Schnell Matthias J. , Eisenlohr Laurence C. , Waldman Scott A. 
Published: April 2009

AbstractCancer mucosa antigens are emerging as a new category of self-antigens expressed normally in immunologically privileged mucosal compartments and universally by their derivative tumors. These antigens leverage the established immunologic partitioning of systemic and mucosal compartments, limiting tolerance opposing systemic antitumor efficacy. An unresolved issue surrounding self-antigens as immunotherapeutic targets is autoimmunity following systemic immunization. In the context of cancer mucosa antigens, immune effectors to self-antigens risk amplifying mucosal inflammatory disease promoting carcinogenesis. Here, we examined the relationship between immunotherapy for systemic colon cancer metastases targeting the intestinal cancer mucosa antigen guanylyl cyclase C (GCC) and its effect on inflammatory bowel disease and carcinogenesis in mice. Immunization with GCC-expressing viral vectors opposed nascent tumor growth in mouse models of pulmonary metastasis, reflecting systemic lineage-specific tolerance characterized by CD8+, but not CD4+, T-cell or antibody responses. Responses protecting against systemic metastases spared intestinal epithelium from autoimmunity, and systemic GCC immunity did not amplify chemically induced inflammatory bowel disease. Moreover, GCC immunization failed to promote intestinal carcinogenesis induced by germ-line mutations or chronic inflammation. The established role of CD8+ T cells in antitumor efficacy, but CD4+ T cells in autoimmunity, suggests that lineage-specific responses to GCC are particularly advantageous to protect against systemic metastases without mucosal inflammation. These observations support the utility of GCC-targeted immunotherapy in patients at risk for systemic metastases, including those with inflammatory bowel disease, hereditary colorectal cancer syndromes, and sporadic colorectal cancer. [Cancer Res 2009;69(8):3537–44]
Lack of Muc1-Regulated β-Catenin Stability Results in Aberrant Expansion of CD11b+Gr1+ Myeloid-Derived Suppressor Cells from the Bone Marrow
Authors: Poh Tze Wei , Bradley Judy M. , Mukherjee Pinku , Gendler Sandra J. 
Published: April 2009

Abstract
Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of myeloid cells that inhibit T-cell activity and contribute to the immune suppression characteristic of most tumors. We discovered that bone marrow (BM) progenitor cells from the Muc1 knockout (KO) mice differentiated into CD11b+Gr1+ MDSCs in vitro under granulocyte macrophage colony-stimulating factor and interleukin-4 signaling. MUC1 is a tumor-associated mucin and its cytoplasmic tail (MUC1-CT) can regulate β-catenin to promote oncogenesis. Given the importance of β-catenin in hematopoiesis, we hypothesized that the MUC1 regulation of β-catenin is important for MDSC development. Our current study shows that the aberrant development of BM progenitors into CD11b+Gr1+ MDSCs is dependent on the down-regulation of β-catenin levels that occurs in the absence of Muc1. In light of this, KO mice showed enhanced EL4 tumor growth and were able to better tolerate allogeneic BM185 tumor growth, with an accumulation of CD11b+Gr1+ cells in the blood and tumor-draining lymph nodes. WT mice were able to similarly tolerate allogeneic tumor growth when they were injected with CD11b+Gr1+ cells from tumor-bearing KO mice, suggesting that tolerance of allogeneic tumors is dependent on MDSC-mediated immune suppression. This further delineates the ability of Muc1 to control MDSC development, which could directly affect tumorigenesis. Knowledge of the biology by which Muc1 regulates the development of myeloid progenitors into MDSCs would also be very useful in enhancing the efficacy of cancer vaccines in the face of tumor immune suppression. [Cancer Res 2009;69(8):3554–62]
Natural Killer Cell IFN-γ Levels Predict Long-term Survival with Imatinib Mesylate Therapy in Gastrointestinal Stromal Tumor–Bearing Patients
Authors: Ménard Cédric , Blay Jean-Yves , Borg Christophe , Michiels Stefan , Ghiringhelli François , Robert Caroline , Nonn Céline , Chaput Nathalie , Taïeb Julien , Delahaye Nicolas F. , Flament Caroline , Emile Jean-François , Le Cesne Axel , Zitvogel Laurence 
Published: April 2009

Abstract
Clinical outcomes of gastrointestinal stromal tumor (GIST)–bearing patients treated with imatinib mesylate (IM) are variable. Other than the site of mutation within the c-kit gene, prognostic features of GIST remain undefined. IM can exhibit off-target effects such as triggering natural killer (NK) cell activity. We addressed whether NK cell functions could predict long term survival with IM. NK cell functions were followed up in 77 GIST patients enrolled onto two phase III trials. “Immunologic responders” were defined as patients whose NK cell IFN-γ values after 2 months of IM were higher than or equal to the baseline value at entry into the trial. The prognostic effect of IFN-γ on progression-free survival was assessed by a Wald test in a Cox regression analysis using the landmark method and stratified by trial and on the c-kit mutational status. Fifty-six patients were evaluable for the NK cell IFN-γ responses at baseline and 2 months. Their median follow-up for progression-free survival was 3.7 years. Thirty-four of 56 patients were immunologic responders to IM. In the Cox regression analysis, immunologic responders possessed a hazard ratio of progression or death equal to 0.29 (95% confidence interval, 0.12–0.70; P = 0.006) compared with nonresponders. Kaplan-Meier 2-year survival estimates were 85% for immunologic responders and 50% for nonresponders. Moreover, the immunologic response added prognostic value to the c-kit mutation. The NK cell IFN-γ production after 2 months of treatment could be considered an independent predictor of long term survival in advanced GISTs treated with IM. [Cancer Res 2009;69(8):3563–9]
Inhibition of Ataxia Telangiectasia Mutated Kinase Activity Enhances TRAIL-Mediated Apoptosis in Human Melanoma Cells
Authors: Ivanov Vladimir N. , Zhou Hongning , Partridge Michael A. , Hei Tom K. 
Published: April 2009

Abstract
The aim of the present study was to elucidate the effects of ataxia telangiectasia mutated (ATM) kinase on the regulation of the extrinsic tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor 2/DR5-mediated death pathway in human melanoma cells. We revealed that total ATM protein levels were high in some human melanoma lines compared with normal cells. The basal levels of active form ATM phospho-Ser1981 were also detectable in many melanoma lines and could be further up-regulated by γ-irradiation. Pretreatment of several melanoma lines just before γ-irradiation with the inhibitor of ATM kinase KU-55933 suppressed p53 and nuclear factor-κB (NF-κB) activation but notably increased radiation-induced DR5 surface expression, down-regulated cFLIP (caspase-8 inhibitor) levels, and substantially enhanced exogenous TRAIL-induced apoptosis. Furthermore, γ-irradiation in the presence of KU-55933 rendered TRAIL-resistant HHMSX melanoma cells susceptible to TRAIL-mediated apoptosis. In addition, suppression of ATM expression by the specific short hairpin RNA also resulted in down-regulation of cFLIP levels, up-regulation of surface DR5 expression, and TRAIL-mediated apoptosis in melanoma cells. Besides p53 and NF-κB, crucial regulators of DR5 expression, transcription factor STAT3 is known to negatively regulate DR5 expression. Suppression of Ser727 and Tyr705 phosphorylation of STAT3 by KU-55933 reduced STAT3 transacting activity accompanied by elevation in DR5 expression. Dominant-negative STAT3β also efficiently up-regulated the DR5 surface expression and down-regulated cFLIP levels in melanoma cells in culture and in vivo. Taken together, our data show the existence of an ATM-dependent STAT3-mediated antiapoptotic pathway, which on suppression sensitizes human melanoma cells to TRAIL-mediated apoptosis. [Cancer Res 2009;69(8):3510–9]
IFR-9/STAT2 Functional Interaction Drives Retinoic Acid–Induced Gene G Expression Independently of STAT1
Authors: Lou Ye-Jiang , Pan Xiao-Rong , Jia Pei-Min , Li Dong , Xiao Shu , Zhang Zhang-Lin , Chen Sai-Juan , Chen Zhu , Tong Jian-Hua 
Published: April 2009

AbstractRetinoic acid–induced gene G (RIG-G), a gene originally identified in all-trans retinoic acid–treated NB4 acute promyelocytic leukemia cells, is also induced by IFNα in various hematopoietic and solid tumor cells. Our previous work showed that RIG-G possessed a potent antiproliferative activity. However, the mechanism for the transcriptional regulation of RIG-G gene remains unknown. Here, we report that signal transducer and activator of transcription (STAT) 2 together with IFN regulatory factor (IRF)-9 can effectively drive the transcription of RIG-G gene by their functional interaction through a STAT1-independent manner, even without the tyrosine phosphorylation of STAT2. The complex IRF-9/STAT2 is both necessary and sufficient for RIG-G gene expression. In addition, IRF-1 is also able to induce RIG-G gene expression through an IRF-9/STAT2–dependent or IRF-9/STAT2–independent mechanism. Moreover, the induction of RIG-G by retinoic acid in NB4 cells resulted, to some extent, from an IFNα autocrine pathway, a finding that suggests a novel mechanism for the signal cross-talk between IFNα and retinoic acid. Taken together, our results provide for the first time the evidence of the biological significance of IRF-9/STAT2 complex, and furnish an alternative pathway modulating the expression of IFN-stimulated genes, contributing to the diversity of IFN signaling to mediate their multiple biological properties in normal and tumor cells. [Cancer Res 2009;69(8):3673–80]
Genetic Mutations Associated with Cigarette Smoking in Pancreatic Cancer
Authors: Blackford Amanda , Parmigiani Giovanni , Kensler Thomas W. , Wolfgang Christopher , Jones Siân , Zhang Xiaosong , Parsons D. Willams , Lin Jimmy Cheng-Ho , Leary Rebecca J. , Eshleman James R. , Goggins Michael , Jaffee Elizabeth M. , Iacobuzio-Donahue Christine A. , Maitra Anirban , Klein Alison , Cameron John L. , Olino Kelly , Schulick Richard , Winter Jordan , Vogelstein Bert , Velculescu Victor E. , Kinzler Kenneth W. , Hruban Ralph H. 
Published: April 2009

Abstract
Cigarette smoking doubles the risk of pancreatic cancer, and smoking accounts for 20% to 25% of pancreatic cancers. The recent sequencing of the pancreatic cancer genome provides an unprecedented opportunity to identify mutational patterns associated with smoking. We previously sequenced &gt;750 million bp DNA from 23,219 transcripts in 24 adenocarcinomas of the pancreas (discovery screen). In this previous study, the 39 genes that were mutated more than once in the discovery screen were sequenced in an additional 90 adenocarcinomas of the pancreas (validation screen). Here, we compared the somatic mutations in the cancers obtained from individuals who ever smoked cigarettes (n = 64) to the somatic mutations in the cancers obtained from individuals who never smoked cigarettes (n = 50). When adjusted for age and gender, analyses of the discovery screen revealed significantly more nonsynonymous mutations in the carcinomas obtained from ever smokers (mean, 53.1 mutations per tumor; SD, 27.9) than in the carcinomas obtained from never smokers (mean, 38.5; SD, 11.1; P = 0.04). The difference between smokers and nonsmokers was not driven by mutations in known driver genes in pancreatic cancer (KRAS, TP53, CDKN2A/p16, and SMAD4), but instead was predominantly observed in genes mutated at lower frequency. No differences were observed in mutations in carcinomas from the head versus tail of the gland. Pancreatic carcinomas from cigarette smokers harbor more mutations than do carcinomas from never smokers. The types and patterns of these mutations provide insight into the mechanisms by which cigarette smoking causes pancreatic cancer. [Cancer Res 2009;69(8):3681–8]
Multiple-Type Human Papillomavirus Infection in Male Anogenital Sites: Prevalence and Associated Factors
Authors: Nielson Carrie M. , Harris Robin B. , Flores Roberto , Abrahamsen Martha , Papenfuss Mary R. , Dunne Eileen F. , Markowitz Lauri E. , Giuliano Anna R. 
Published: April 2009

Abstract
Human papillomavirus (HPV) causes cervical cancer and is strongly associated with other anogenital cancers. Multiple-type HPV infection has been associated with lengthier infection and precancerous lesions. Little is known about multiple-type HPV prevalence and associated factors in men. We examined the prevalence of and risk factors for multiple-type HPV in primarily asymptomatic men. Detection of 37 HPV types in male anogenital epithelium and semen was completed in 463 men in two U.S. cities. The proportions of men with multiple HPV of any type and with multiple oncogenic or nononcogenic types were calculated. Factors associated with multiple HPV were evaluated using multinomial logistic regression. Overall, 22.9% of men had multiple-HPV, 8.6% of men had multiple oncogenic types, and 13.4% had multiple nononcogenic types. Greater proportions of samples at the shaft, glans/corona, and scrotum had multiple HPV types (18.7%, 12.8%, and 7.3%, respectively) than did other anogenital sites (all ≤2.8%). Factors independently associated with multiple-type HPV were Hispanic ethnicity [adjusted odds ratio (AOR), 2.45; 95% confidence interval (95% CI), 1.05-5.67], concurrent detection of genital warts (AOR, 10.40; 95% CI, 1.12-96.6), smoking ≥10 cigarettes/d (AOR, 3.00; 95% CI, 1.07-8.43), greater lifetime number of female sexual partners (AOR, 13.73 for ≥21 versus 1-5; 95% CI, 5.34-35.3), and condom use less than half the time (AOR, 2.03; 95% CI, 1.07-3.84). Detection of multiple HPV types in this study of primarily asymptomatic men was common, particularly at external genital sites. Lifetime number of female sex partners, condom use, and smoking were modifiable factors associated with multiple HPV. (Cancer Epidemiol Biomarkers Prev 2009;18(4):1077–83)
A Functional Genetic Variant in microRNA-196a2 Is Associated with Increased Susceptibility of Lung Cancer in Chinese
Authors: Tian Tian , Shu Yongqian , Chen Jiaping , Hu Zhibin , Xu Lin , Jin Guangfu , Liang Jie , Liu Ping , Zhou Xiaoyi , Miao Ruifen , Ma Hongxia , Chen Yijiang , Shen Hongbing 
Published: April 2009

Abstract
microRNAs (miRNA) are a new class of non-protein-coding, small RNAs that function as tumor suppressors or oncogenes. They participate in diverse biological pathways and function as gene regulators. Recently, we conducted a survey of common single nucleotide polymorphisms (SNP) in miRNA sequences and reported that, among four SNPs (rs2910164, rs2292832, rs11614913, and rs3746444) in pre-miRNAs, rs11614913 in miR-196a2 might affect mature miR-196a expression and target mRNA-binding activity and was significantly associated with non-small cell lung cancer survival. However, it remains largely unknown whether miRNA SNPs may alter lung cancer susceptibility. In the current study, we evaluated associations between the above four SNPs in pre-miRNAs and lung cancer susceptibility in a case-control study of 1,058 incident lung cancer patients and 1,035 cancer-free controls in a Chinese population. We found that miR-196a2 rs11614913 variant homozygote CC was associated with ∼25% significantly increased risk of lung cancer compared with their wild-type homozygote TT and heterozygote TC (odds ratio, 1.25; 95% confidence interval, 1.01-1.54). However, no significant effects were observed on the association between the other three SNPs and lung cancer risk. These findings suggest that functional SNP rs11614913 in miR-196a2 could also contribute to lung cancer susceptibility. (Cancer Epidemiol Biomarkers Prev 2009;18(4):1183–7)
Risk Factors for Triple-Negative Breast Cancer in Women Under the Age of 45 Years
Authors: Dolle Jessica M. , Daling Janet R. , White Emily , Brinton Louise A. , Doody David R. , Porter Peggy L. , Malone Kathleen E. 
Published: April 2009

Abstract
Little is known about the etiologic profile of triple-negative breast cancer (negative for estrogen receptor/progesterone receptor/human epidermal growth factor), a breast cancer subtype associated with high mortality and inadequate therapeutic options. We undertook this study to assess the risk for triple-negative breast cancer among women 45 years of age and younger in relation to demographic/lifestyle factors, reproductive history, and oral contraceptive use. Study participants were ascertained in two previous population-based, case-control studies. Eligible cases included all primary invasive breast cancers among women ages 20 to 45 years in the Seattle–Puget Sound area, diagnosed between January 1983 and December 1992, for whom complete data was obtained for estrogen receptor, progesterone receptor, and human epidermal growth factor status (n = 897; including n = 187 triple-negative breast cancer cases). Controls were age matched and ascertained via random digit dialing. Oral contraceptive use ≥1 year was associated with a 2.5-fold increased risk for triple-negative breast cancer (95% confidence interval, 1.4-4.3) and no significantly increased risk for non-triple-negative breast cancer (Pheterogeneity = 0.008). Furthermore, the risk among oral contraceptive users conferred by longer oral contraceptive duration and by more recent use was significantly greater for triple-negative breast cancer than non-triple-negative breast cancer (Pheterogeneity = 0.02 and 0.01, respectively). Among women ≤40 years, the relative risk for triple-negative breast cancer associated with oral contraceptive use ≥1 year was 4.2 (95% confidence interval, 1.9-9.3), whereas there was no significantly increased risk with oral contraceptive use for non-triple-negative breast cancer among women ≤40 years, nor for triple-negative breast cancer or non-triple-negative breast cancer among women 41 to 45 years of age. In conclusion, significant heterogeneity exists for the association of oral contraceptive use and breast cancer risk between triple-negative breast cancer and non-triple-negative breast cancer among young women, lending support to a distinct etiology. (Cancer Epidemiol Biomarkers Prev 2009;18(4):1157–66)
Sex Disparities in Cancer Incidence by Period and Age
Authors: Cook Michael B. , Dawsey Sanford M. , Freedman Neal D. , Inskip Peter D. , Wichner Sara M. , Quraishi Sabah M. , Devesa Susan S. , McGlynn Katherine A. 
Published: April 2009

Abstract
Background: Cancer epidemiology articles often point out that cancer rates tend to be higher among males than females yet rarely is this theme the subject of investigation.
Methods: We used the Surveillance, Epidemiology and End Results program data to compute age-adjusted (2000 U.S. standard population) sex-specific incidence rates and male-to-female incidence rate ratios (IRR) for specific cancer sites and histologies for the period 1975 to 2004.
Results: The 10 cancers with the largest male-to-female IRR were Kaposi sarcoma (28.73), lip (7.16), larynx (5.17), mesothelioma (4.88), hypopharynx (4.13), urinary bladder (3.92), esophagus (3.49), tonsil (3.07), oropharynx (3.06), and other urinary organs (2.92). Only 5 cancers had a higher incidence in females compared with males: breast (0.01), peritoneum, omentum, and mesentery (0.18), thyroid (0.39), gallbladder (0.57), and anus, anal canal, and anorectum (0.81). Between 1975 and 2004, the largest consistent increases in male-to-female IRR were for cancers of the tonsil, oropharynx, skin excluding basal and squamous, and esophagus, whereas the largest consistent decreases in IRR were for cancers of the lip and lung and bronchus. Male-to-female IRRs varied considerably by age, the largest increases of which were for ages 40 to 59 years for tonsil cancer and hepatocellular carcinoma. The largest decreases in male-to-female IRR by age, meanwhile, were for ages 30 to 49 years for thyroid cancer, ages &gt;70 years for esophageal squamous cell carcinoma, and ages &gt;30 years for lung and bronchus cancer.
Conclusion: These observations emphasize the importance of sex in cancer etiopathogenesis and may suggest novel avenues of investigation. (Cancer Epidemiol Biomarkers Prev 2009;18(4):1174–82)