bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3816: The DNA methylation inhibitor induces telomere dysfunction and apoptosis of leukemia cells that is attenuated by telomerase over-expression
Authors: Li Bingnan , Zhang Xiaolu , Jonge Nick de , Björkholm Magnus , Xu Dawei 
Published: August 2015

Abstract
DNA methyltransferase inhibitors (DNMTIs) such as 5-azacytidine (5-AZA) have been used for the treatment of acute myeloid leukemia (AML) and other malignancies, and inhibition of global/gene-specific DNA methylation is widely accepted as a key mechanism behind their anti-tumor activity. It is currently unclear whether other mechanisms are involved in DNMTI's action. Because telomerase or telomerase reverse transcriptase (TERT) plays a key role in malignant transformation and progression through telomere elongation and other telomere lengthening-independent activities, and TERT or telomerase has been shown to confer chemo- or radio-resistance to cancer cells, we determine whether DNMTIs affect telomere function and whether TERT/telomerase interferes with their anti-cancer efficacy. We showed that 5-AZA induced DNA damage and telomere dysfunction in AML cell lines by demonstrating the presence of 53-BP1 foci and the co-localization of 53-BP1 foci with telomere signals, respectively. Telomere dysfunction was coupled with diminished TERT expression, shorter telomere and apoptosis in 5-AZA-treated cells. However, 5-AZA treatment did not lead to changes in the methylation status of subtelomere regions. Downregulation of TERT expression similarly occurred in primary leukemic cells derived from AML patients exposed to 5-AZA. TERT over-expression significantly attenuated 5-AZAmediated DNA damage, telomere dysfunction and apoptosis of AML cells. Taken together, 5-AZA mediates the down-regulation of TERT expression, and induces telomere dysfunction,which consequently exerts an anti-tumor activity. These findings may have implications in DNMTI and telomerase-based strategies for cancer therapeutics.
Citation Format: Bingnan Li, Xiaolu Zhang, Nick de Jonge, Magnus Björkholm, Dawei Xu. The DNA methylation inhibitor induces telomere dysfunction and apoptosis of leukemia cells that is attenuated by telomerase over-expression. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3816. doi:10.1158/1538-7445.AM2015-3816
Abstract 3821: Understanding the functional role of retinoic acid receptor beta2 in the development of oral cancer
Authors: Radhakrishnan Raghu , Hunter Keith 
Published: August 2015

Abstract
Background: Retinoids are the best studied chemopreventive agents in oral cancer patients, whose effects are mediated by retinoic acid receptors (RAR). The loss of RARβ2 expression early in the development of oral cancer is attributed to acquisition of cellular immortalization or abrogated senescence. Aim: To determine the functional effects of RARβ2 dysfunction (constitutive expression or loss) in precancerous oral keratinocytes. Methods: Characterization of a panel or mortal (D6, D30) and immortal precancerous oral keratinocytes (D19, D20, D34 and D38), and tert immortalized normal cells (FNB-6) for baseline RARβ2 expression and their role in senescence, differentiation, apoptosis, and methylation. Re-express RARβ2 in immortal cells by treatment with all trans retinoic acid, 5-aza-2′- deoxycytidine, administered alone and in combination and asses their effect on senescence and promoter methylation. Results: Mortal cells showed constitutive expression of RARβ2 in senescing cultures and loss of expression in immortal cells. This was reflected in tissue engineered 3D composites as well as in the corresponding biopsies, when stained with RARβ antibody. Concomitant expression of CDKN2A and CDKN1A in senescing cultures and their absence in immortals suggest that the loss of RARβ2 strongly correlate with transition from senescence to immortalization. Re-expression of RARβ2 in immortal cells by treatment with retinoic acid (RA), 5-aza-2′-deoxycytidine (Aza-C) and combination of RA + Aza-C with simultaneous upregulation of CDKN2A and CDKN1A confirm RARβ2 as tumor suppressor gene, which is silenced due to hypermethylation. Increase in the Histone Repressor A (HIRA) foci and Senescence associated β- galactosidase (SA-β gal) activity in treated cell confirmed the restoration of senescence program in an immortal cell. Promoter methylation analysis confirmed that the silencing of RARβ2 in immortal cell was due to hypermethylation. Conclusion: The role of demethylating agent in growth inhibition and apoptosis highlights the importance of RAR beta serving as an intermediate biomarker in chemoprevention. Identification of methylation status may prove useful as a selective biomarker prior to combined demethylation and retinoid treatment in oral precancerous lesions.
Citation Format: Raghu Radhakrishnan, Keith Hunter. Understanding the functional role of retinoic acid receptor beta2 in the development of oral cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3821. doi:10.1158/1538-7445.AM2015-3821
Abstract 3836: Identification of key survival-correlating microRNAs and Piwi-interacting RNAs dysregulated in head and neck squamous cell carcinoma
Authors: Ku Jonjei , Zou Angela E. , Honda Thomas K. , Zheng Hao , Saad Maarouf A. , Yu Vicky , Xuan Yinan , Singh Pranav , Rahimy Mehran , Kuo Selena Z. , Ongkeko Weg M. , Wang-Rodriguez Jessica 
Published: August 2015

Abstract
Aberrant expression of microRNAs and piwi-interacting RNAs, two distinct classes of non-coding RNA (ncRNA) and important regulators of gene expression, is known to be implicated in human diseases including cancer. The exact roles of microRNAs and piwi-interacting RNAs in the pathogenesis of head and neck squamous cell carcinoma (HNSCC), however, remain poorly understood. Utilizing next generation RNA sequencing analysis of raw data obtained from The Cancer Genome Atlas, we discovered significant dysregulation (fold change ≥ 2) in 231 microRNAs and 60 piwi-interacting RNAs between forty-three matched samples of tumor and adjacent normal tissues, including down-regulation of mirs 30e and let7-c, and up-regulation of piR34736 and mir-196a-1 in tumor tissue compared to adjacent, non-tumor tissue. Further statistical survival modeling using patient survival data and cox proportional hazard regression analysis revealed that miRs 30e, 196a-1, and let7-c, and piR34736 correlated significantly with survival in patients with HNSCC. To further investigate these microRNAs and piwi-interacting RNAs, quantitative reverse transcriptase PCR (qRT-PCR) and MTT cell proliferation assays were performed in-vitro to assess their isolated effects on cancer gene expression in established HNSCC cell lines. Endogenous expression of these ncRNA was compared between a set of three normal oral keratinocytes and five HNSCC cell lines using qRT-PCR which confirmed miR-30e and mir-let7-c down-regulation and piR34736 and mir-196a-1 up-regulation in cancer. MTT cell proliferation assays upon knock-down of miR-196a-1 and ectopically expressed mir-let7-c in HNSCC revealed significant decreases in cell proliferation compared to cells transfected with their respective negative control. Identification of key ncRNAs differentially expressed between cancer tissue and adjacent normal tissue may reveal important steps in the initiation and progression of HNSCC as they are strongly correlated with patient survival. These key microRNAs and piwi-interacting RNAs may serve as potential biomarkers and therapeutic targets for future epigenetic-based cancer therapies.
Citation Format: Jonjei Ku, Angela E. Zou, Thomas K. Honda, Hao Zheng, Maarouf A. Saad, Vicky Yu, Yinan Xuan, Pranav Singh, Mehran Rahimy, Selena Z. Kuo, Weg M. Ongkeko, Jessica Wang-Rodriguez. Identification of key survival-correlating microRNAs and Piwi-interacting RNAs dysregulated in head and neck squamous cell carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3836. doi:10.1158/1538-7445.AM2015-3836
Abstract 3845: Smarce1 facilitates survival of metastatic breast cancer cells in circulation
Authors: Sethuraman Aarti , Fan Meiyun , Brown Martin M. , Wu Zhaohui 
Published: August 2015

Abstract
Elevated BAF57/SMARCE1 protein expression has been linked to high metastatic potential of prostate cancer, while its relevance in metastatic breast cancer is not completely understood. The objective of this study is to investigate the role of SMARCE1 in regulating metastatic potential of basal-like breast tumor cells. SMARCE1 is a core subunit shared by all mammalian SWI/SNF complexes and is predicted to mediate the interaction between the SWI/SNF complex and transcriptional activators/repressors, as well as DNA binding. SWI/SNF are nucleosome modifying complexes that destabilize the histone-DNA interaction in an ATP-dependent manner to facilitate recruitment of transcription regulators to DNA. We found that SMARCE1 knockdown (SMARCE1-kd) in basal-like breast cancer cell line MDA-MB-231 reduced spontaneous lung metastasis in an orthotopic xenograft model, without affecting primary tumor growth. Through tail-vein injection of tumor cells we identified that SMARCE1-kd significantly reduced the number of metastatic foci in lungs of inoculated mice, implicating a role of SMARCE1 in promoting metastatic cell survival in later stages of metastasis occurring post-dissemination from primary tumors. In-vitro assays showed that SMARCE1-kd had no effect on cell migration and invasion, but substantially sensitized cells to anoikis. Consistently, we observed reduced activation/phosphorylation of the pro-survival proteins PTK2/FAK and MAPK/ERK and increased expression of apoptotic protein BCL2L11 in SMARCE1-kd cells compared to wild-type cells grown under suspension. We further confirmed using specific chemical inhibitors, that FAK and ERK phosphorylation are required for SMARCE1-mediated survival of tumor cells under suspension culture. Collectively, these results suggest a role for SMARCE1 in promoting metastasis by protecting cells against anoikis. The molecular mechanism underling SMARCE1-mediated regulation of FAK/ERK phosphorylation in response to loss of contact with extracellular matrix is under investigation.
Citation Format: Aarti Sethuraman, Meiyun Fan, Martin M. Brown, Zhaohui Wu. Smarce1 facilitates survival of metastatic breast cancer cells in circulation. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3845. doi:10.1158/1538-7445.AM2015-3845
Abstract 3846: DNA double-strand breaks in hypoxic but not in normoxic conditions determine different radiosensitivity of tumors
Authors: Ogi Kazuhiro , Kawata Mayumi , Nakagaki Takafumi , Takeda Kousuke , Akihiro Miyazaki , Hiroyoshi Hiratsuka 
Published: August 2015

Abstract
Purpose:
While only few biomarkers like tumor histology and stage are used in routine clinical practice to predict tumor cure probability after chemo-radiotherapy, sustained efforts are made to establish more precise predictors for individual treatment. Recently chemotherapy corresponded with radiotherapy (CCR) to oral cancer has developed treatment efficiency of killing tumor cells. However we can't distinguish the number of tumor cells that may cause recurrences after radiotherapy. Then we hypothesized that hypoxic condition may have some influence of cell death by irradiation, and we tried to demonstrate how the correlation of phosphorylated H2AX (γH2AX) was influenced by oxygenation status of the tumor regions to predict radiation treatment response.
Results: We used oral squamous cell carcinoma (OSCC) cell lines and divided them into two groups that showed hypoxic response or not. HSC-2 cells increased the expression level of HIF-1 alpha under hypoxia. No difference was observed in G1 arrest to irradiation of 6Gy in these cell lines. While the expression revel of γH2AX decreased in HSC-2, its revel didn't change under hypoxic condition in HSC-3 and SAS. From these findings, we postulate that one of the mechanism by which hypoxic cells become resistant to irradiation may involve the expression of HIF-1 alpha.
Conclusion:
The γH2AX is highly dependent on tumor cell oxygenation. Further studied are ongoing to establish the potentially important role of γH2AX under hypoxia.
Citation Format: Kazuhiro Ogi, Mayumi Kawata, Takafumi Nakagaki, Kousuke Takeda, Miyazaki Akihiro, Hiratsuka Hiroyoshi. DNA double-strand breaks in hypoxic but not in normoxic conditions determine different radiosensitivity of tumors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3846. doi:10.1158/1538-7445.AM2015-3846
Abstract 3871: Telomere length and cancer mortality and all-cause mortality
Authors: Bojesen Stig E. , Nordestgaard Børge G. , Rode Line 
Published: August 2015

Abstract
Introduction:
Short telomeres are associated with increased age and age-related diseases. We tested the hypothesis that short telomeres are associated with increased cancer mortality and all-cause mortality.
Methods:
We studied 64637 individuals recruited from 1991 and onwards from two prospective cohort studies; the Copenhagen City Heart Study and the Copenhagen General Population Study. All had telomere length measured by Q-PCR in DNA from peripheral blood and had the telomere length-associated genotypes of rs1317082 (TERC), rs7726159 (TERT), and rs2487999 (OBFC1) determined. We calculated the sum of telomere length shortening alleles from the three SNPs combined. We conducted Cox regression, and instrumental variable analyses in a mendelian randomization design, using the allele sum as a genetic instrument for telomere length.
Results:
Telomere length shortened by 17 (P&lt;10E-300) and 69 (P = 110E-104) base pairs per increase of one year of age, and one allele increase of allele sum, respectively. Of the 7607 deaths during up to 22 years of follow-up, 2420 were due to cancer. Shortening of telomeres (200 base pairs) was associated with increasing cancer mortality and all-cause mortality with hazard ratios of 1.02(95% CI;1.01-1.03) and 1.02(95% CI;1.02-1.03) in multifactorially adjusted models. In contrast, in the genetic analyses, the corresponding odds ratios were 0.86(95% CI;0.76-0.96) and 0.98(95% CI;0.91-1.05).
Conclusion:
In an observational design, short telomeres were associated with increased cancer mortality and all-cause mortality. In contrast and importantly; in a mendelian randomization design, short telomeres were associated with decreased cancer mortality, suggesting that short telomeres are likely causative in protecting against cancer mortality.
Citation Format: Stig E. Bojesen, Børge G. Nordestgaard, Line Rode. Telomere length and cancer mortality and all-cause mortality. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3871. doi:10.1158/1538-7445.AM2015-3871
Abstract 388: EGR1 is a mediator of TWEAK-Fn14 pathway induced prostate cancer bone metastasis
Authors: Ameri Amir H. , Yin JuanJuan Ivy , Jansen Keith , Wang Simeng , Snyder Jessica , Hynes Paul , Kelly Kathleen 
Published: August 2015

Abstract
Patients with advanced or castration-resistant prostate cancer have a high probability of developing bone metastasis. However, the molecular mechanisms driving bone metastasis in prostate cancer remain poorly understood. We have previously demonstrated that Fn14 expression is increased significantly in metastatic lesions from prostate cancer patients. Fn14 is a member of the TNF receptor family, and our in vivo study using DU145/RasB1 cells indicated that the TWEAK-Fn14 pathway promotes prostate cancer bone metastasis via the canonical NFκB pathway. However, the downstream targets of the TWEAK-Fn14 pathway have yet to be characterized in prostate cancer cells. To elucidate the precise mechanism underlying Fn14-promoted metastasis, we analyzed the gene expression profile of highly metastatic DU145/RasB1 and low metastatic DU145/RasB1 Fn14depleted (Fn14KD) cells. Fn14 depletion significantly altered expression of 147 genes, including ECM components, cell adhesives, and cytoskeletal regulators. In addition, DU145/RasB1 and DU145/RasB1 Fn14KD cells responded differently to TWEAK treatment. We found increased expression of early growth response 1, (EGR1), in the TWEAK-treated DU145/RasB1 cells relative to DU145/RasB1 Fn14KD cells. To determine if EGR1 plays a role in prostate cancer metastasis, we depleted EGR1 expression with two shRNAs in highly metastatic DU145/RasB1 cells. Our results show that both EGR1 shRNAs significantly inhibited bone metastasis in vivo. We also found that EGR1 expression was decreased when the NFκB pathways were inhibited by an IκB super repressor in DU145/RasB1 cells. Interestingly, both Fn14 depletion and EGR1 depletion increased TFPI2 expression and inhibited adhesion to fibrin. Fibrin has been shown to facilitate metastatic spread by assisting platelet adhesion to circulating tumor cells. These results suggest one scenario whereby activation of Fn14 signaling may promote prostate cancer bone metastasis through enhancing tumor-platelet interaction via an EGR1-dependent mechanism.
Citation Format: Amir H. Ameri, JuanJuan Ivy Yin, Keith Jansen, Simeng Wang, Jessica Snyder, Paul Hynes, Kathleen Kelly. EGR1 is a mediator of TWEAK-Fn14 pathway induced prostate cancer bone metastasis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 388. doi:10.1158/1538-7445.AM2015-388
Abstract 3883: Clonal evolution of a lethal prostate cancer: Integrated whole genome analysis case study
Authors: Kallio Heini M.L. , Annala Matti , Kivinummi Kati , Högnäs Gunilla , Gundem Gunes , Wedge David C. , Van Loo Peter , Heyn Holger , Emmert-Buck Michael R. , Isaacs William B. , Esteller Manel , McDermott Ultan , Nykter Matti , Visakorpi Tapio , Bova G. Steven 
Published: August 2015

Abstract
Prostate cancer (PC) is prevalent in both indolent and lethal forms. Although many PC patients diagnosed today have organ-confined disease curable by prostatectomy or radiation therapy, 20-30% of PCs will relapse to lethal disease within 5-years of treatment. Relatively little attention has been paid to distinguishing the molecular characteristics of proven lethal metastatic PC from non-lethal cancers. A better understanding of the origins and evolution of lethal cancers should allow screening and treatment to be better tailored to the needs of each patient. To this end, we performed an integrative molecular profiling of a lethal PC from one patient (A21). High-coverage whole genome sequence, transcriptome sequence, and methylation analysis was performed on 9 anatomically separate metastases obtained by autopsy, and targeted sequencing was performed in multiple cancerous and noncancerous foci within the radical prostatectomy specimen removed 5 years prior to death. Molecular results were analyzed in relation to detailed clinical data. Integrated whole genome sequence analysis revealed convergent evolution of AR gene amplification events, and inception of p.L702H mutation in the AR present only in liver metastases. In addition, the analysis showed parallel increases in AR regulated transcripts in the liver metastases, suggesting a dominant effect by the mutation. Mutation of PI3/PI4 kinase member PIK3CG was found in all metastases but in no primary tumor foci studied. The study demonstrated the power of an integrated approach to interrogate clonal evolution of cancer suggesting that such studies are valuable on the individual level and could lead the way towards personalized treatment. In the individual studied, cessation of corticosteroid treatment and/or therapeutic manipulation of PI3K/AKT/mTOR activity theoretically could have provided a personalized benefit. These findings suggest that similar integrated analysis in large cohorts of patients with metastatic cancer could accelerate progress in establishing effective personalized cancer medicine.
Citation Format: Heini M.L. Kallio, Matti Annala, Kati Kivinummi, Gunilla Högnäs, Gunes Gundem, David C. Wedge, Peter Van Loo, Holger Heyn, Michael R. Emmert-Buck, William B. Isaacs, Manel Esteller, Ultan McDermott, Matti Nykter, Tapio Visakorpi, G. Steven Bova. Clonal evolution of a lethal prostate cancer: Integrated whole genome analysis case study. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3883. doi:10.1158/1538-7445.AM2015-3883
Abstract 3903: Differential transcript expression in nasopharyngeal carcinoma by cDNA microarray analysis
Authors: Yip Timothy T.C. , Kwong Dora L.W. , Ngan Roger K.C. , Lim Cadmon K.P. , Cheng Wai-Wai , Ma Victor W.S. , Law Stephen C.K. , Tse Loretta 
Published: August 2015

Abstract
By cDNA microarray, gene expression profiling was carried out in 360 paired tumor & normal biopsies from 60 nasopharyngeal cancer (NPC) patients at 3 time points, namely, at diagnosis of NPC, on treatment with an anti-inflammatory drug, Celecoxib (Celec) and on radiotherapy (RT). We found 1 cluster of 82 transcripts with statistically significant difference in expression between tumor & normal tissues at diagnosis, a second cluster of 214 tumor versus normal transcripts on Celec treatment and finally a third cluster of 202 tumor versus normal transcripts on RT. Differential expression of selected tumor associated transcripts was confirmed by RT-PCR. These include 8 tumor up-regulated transcripts with 3 encoding for immunological/inflammatory molecules, IL8, CXCL9 & CXCL10, 1 matrix metallopeptidase, MMP12, which breaks down extracellular matrix and thus is associated with cancer metastasis, 1 osteonectin protein which is involved in cell shape changes and thus related to cancer invasion, SPARC, 1 bone morphogenic protein with a role in tissue differentiation, GREM1, 1 GTPase-activating protein for phorbol ester receptor, CHN1 and a sorting nexin family member with a role in intracellular trafficking, SNX10. Genes which were prominently down-regulated in tumor were a variety of polymorphic xenobiotic detoxification enzyme genes or genes with antioxidant function (e.g. GSTA1, GSTA2, GSTA3, CYP4B1, ALDH1A1, ADHFE1, MAOB, NQO1 & OAT). Many genes were also down-regulated by RT in tumor tissues and one notable example was TOP2A which encodes topoisomerase 2A involving in chromosome condensation & chromatid separation during DNA replication, CLDN1 which has tight junction adhesion function, ANLN which is required for cytokinesis, and STMN1 which can regulate microtubule filament. These genes had good potential in applying for clinical applications in diagnosis or treatment of NPC in the future. Further exploration of the clinical applications of these genes is underway.
Citation Format: Timothy T.C. Yip, Dora L.W. Kwong, Roger K.C. Ngan, Cadmon K.P. Lim, Wai-Wai Cheng, Victor W.S. Ma, Stephen C.K. Law, Loretta Tse. Differential transcript expression in nasopharyngeal carcinoma by cDNA microarray analysis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3903. doi:10.1158/1538-7445.AM2015-3903