bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3014: Identification of the NDP kinase critical for DNA repair
Authors: Tsao Ning , Deng Yu-Jyun , Chang Zee-Fen , Zhang Wei 
Published: August 2015

Abstract
Introduction and Purpose:
Cellular supply of deoxynucleoside triphosphates (dNTPs) is crucial for DNA replication and repair. It is known that ribonucleotide reductase (RNR), a rate-limiting enzyme for dNTP synthesis, is required for DNA repair. The catalytic function of RNR produces dNDPs. There are eight isoforms of NDP kinase that catalyzes the subsequent step for dNTP formation in human cells. In this study, we aim to identify the isoform of NDP kinase required for DNA repair.
Preliminary results:
By RNA interference experiments, we identified NME3, one isoform of the nucleoside diphosphate kinases, critical for DNA repair. It has been shown that RNR forms a complex with Tip60, a histone acetyltransferase, by which RNR is recruited to DNA damage sites for repair. In this study, we found that NME3 directly interacts with Tip60. The effect of knockdown of NME3 on DNA repair was rescued by re-expression of wild-type but not the mutant type defective in Tip60 interaction. Overexpression of NME3 was able to facilitate DNA repair, which was intervened by disrupting the interaction of NME3 with Tip60. Moreover, exogenous addition of deoxynucleosides facilitates NME3-mediated DNA repair.
Conclusion:
Among 8 isoforms of NDP kinase, NME3 is identified to be critical for DNA repair, indicating its potential as a target for developing chemosensitization agent.
Citation Format: Ning Tsao, Yu-Jyun Deng, Zee-Fen Chang, Wei Zhang. Identification of the NDP kinase critical for DNA repair. [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 3014. doi:10.1158/1538-7445.AM2015-3014
Abstract 3015: BCL10 is a novel DNA damage response factor whose expression inversely correlates with the clinical outcome of breast invasive ductal carcinoma
Authors: Zhu Min , Zhao Hongchang , Xu Xingzhi 
Published: August 2015

Abstract
Timely and properly cellular response to DNA damage is essential for maintenance of genome stability and integrity. B-cell lymphoma/leukemia 10 (BCL10) facilitates ubiquitination of NEMO in the cytosol, activating NFκB signaling. Translocation and/or point mutations of BCL10 associate with mucosa-associated lymphoid tissue lymphomas and other malignancies. We recently found that BCL10 in nucleus is enriched onto the DNA damage sites in an ATM- and RNF8-dependent manner, and ATM-dependent phosphorylation and RNF8-dependent ubiquitination of BCL10 confers UBC13 to RNF8/RNF168 to regulate ubiquitination-mediated DSB signaling and repair. In this report, we further found that inhibition of BCL10 expression compromised RNF168 dimerization and RNF168-dependent histone H2A ubiquitination. Immunohistochemistry staining analysis revealed that BCL10 expression status inversely correlates with prognosis in 339 cases of breast invasive ductal carcinoma with a median follow up of 60 months (range, 3-127 months). Taken together, our results demonstrated that BCL10 is a novel DDR factor with a potential role as a biomarker in breast cancer therapy.
Note: This abstract was not presented at the meeting.
Citation Format: Min Zhu, Hongchang Zhao, Xingzhi Xu. BCL10 is a novel DNA damage response factor whose expression inversely correlates with the clinical outcome of breast invasive ductal 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 3015. doi:10.1158/1538-7445.AM2015-3015
Abstract 3017: Ribonucleotide reductase promotes uracil-mediated genome instability in tumor progression
Authors: Chen Chih-Wei , Tsao Ning , Yen Yun , Lehman Christine E. , Wang Yuh-Hwa , Chen Chian-Feng , Wu Tse-Hsiang , Tien Sui-Chih , Lee Ming-Hsiang , Chang Zee-Fen 
Published: August 2015

Abstract
The elevation of RRM2A subunit of ribonucleotide reductase (RNR) has been shown oncogenic and associated with human cancers. However, the molecular mechanism of RRM2A in cancer promotion is unclear. In this study, we investigated whether RNR-mediated dUTP formation is involved in promoting genome instability. Since dUTP is degraded by dUTPase, we analyzed the expression of RRM2A and dUTPase in clinical samples from colorectal and breast cancer patients. The results revealed that high RRM2A and low dUTPase in tumors are correlated with poorer survival. In cancer cell lines that express high level of RRM2A and dUTPase, knockdown of dUTPase increases genome instability. Conversely, overexpression of dUTPase reduces genome stress in cancer cells expressing high RRM2A and low dUTPase. In non-tumorigenic cells, overexpression of RRM2A increases replication stress and genome instability accompanied by higher levels of 53BP1 foci and increased breaks at AT-rich fragile sites bound by 53BP1. Thymidine supplement in growth medium or co-expression of dUTPase was able to reduce RRM2A-mediated replication stress and 53BP1 foci. We further provide evidence that RRM2A promotes replication stress and error prone-translesion synthesis dependent on uracil DNA glycosylase. These results suggest that up-regulation of RRM2A in tumor cells increases uracil-mediated replication stress to promote genome instability. Therefore, high RRM2A/low dUTPase context confers tumor genome evolution advantage, correlating with poorer prognosis.
Citation Format: Chih-Wei Chen, Ning Tsao, Yun Yen, Christine E. Lehman, Yuh-Hwa Wang, Chian-Feng Chen, Tse-Hsiang Wu, Sui-Chih Tien, Ming-Hsiang Lee, Zee-Fen Chang. Ribonucleotide reductase promotes uracil-mediated genome instability in tumor progression. [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 3017. doi:10.1158/1538-7445.AM2015-3017
Abstract 3024: Lack of CK1δ increases DNA damage and genomic instability due to defects in DNA repair and mitotic checkpoints
Authors: Greer Yoshimi E. , Gao Bo , Yang Yingzi , Lipkowitz Stanley , Rubin Jeff S. 
Published: August 2015

Abstract
Casein kinase 1 delta (CK1δ) is a conserved serine/threonine protein kinase that regulates diverse cellular processes including vesicle trafficking and circadian rhythm. We previously reported that CK1δ is a mediator of Wnt-3a-dependent neurite outgrowth (Greer and Rubin, JCB, 2011) and ciliogenesis (Greer et al. MBoC, 2014). Mice that lack Csnk1d exhibit a perinatal lethal phenotype and typically weigh 30-50% less than their wild type littermates, however, the exact causes of death and small size are unknown. We hypothesized that the absence of CK1δ contributes to cellular stresses that adversely affect cell survival. Mouse embryonic fibroblasts (MEFs) were collected from mice homozygous for a Csnk1d floxed allele, and MEFCsnk1d null cells were generated by infection with adenovirus (Ad) expressing Cre. As control, MEFCtl. cells were produced by infection with Ad-GFP. In addition, MEFCtl cells were treated with CK1δ siRNA reagents to transiently suppress endogenous expression. Cells were analyzed by confocal microscopy, western blotting and flow cytometry. At early passage (P2), many MEFCsnk1d null cells had detached from the culture dish, raising the possibility of cell death. Subsequent MTS assay confirmed a significantly lower cell viability of MEFCsnk1d null cells compared to MEFCtl cells. MEFCsnk1d null cells (P3) exhibited a larger sub-Go fraction (64%) than MEFCtl cells (34%) in flow cytometric analysis. γ-H2AX staining and comet assay confirmed significant DNA damage in MEFCsnk1d null cells. MEFCsnk1d null cells exhibited micronuclei, a characteristic of genomic instability. Similarly, abrogation of CK1δ expression in MEFCtl cells induced micronuclei formation in response to DNA damage triggered by doxorubicin, suggesting that the absence of CK1δ increases susceptibility to genotoxic exposure. Chk1, a kinase with a major role in DNA damage response, and its downstream substrate, Cdc2/CDK1 kinase, were inhibited in MEFCsnk1d null cells as well as in MEFCtl cells transfected with CK1δ siRNA, suggesting that CK1δ is required for the G2/M mitotic checkpoint. Hydroxyurea-induced Chk1 activation was also impaired in cells lacking CK1δ, and re-expression of CK1δ rescued the phenotype. Together, the data indicate that CK1δ is required for efficient repair of DNA damage and the proper functioning of mitotic checkpoints. The mechanism(s) responsible for these activities are currently under investigation.
Citation Format: Yoshimi E. Greer, Bo Gao, Yingzi Yang, Stanley Lipkowitz, Jeff S. Rubin. Lack of CK1δ increases DNA damage and genomic instability due to defects in DNA repair and mitotic checkpoints. [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 3024. doi:10.1158/1538-7445.AM2015-3024
Abstract 3032: Genomic deregulation and therapeutic role of the cell-cycle kinase TLK2 in more aggressive breast cancers
Authors: KIM Jin-Ah , Tan Ying , Wang Xian , Cao Xixi , Veeraraghavan Jamunarani , Liang Yulong , Edwards Dean P. , Pan Xuewen , Li Kaiyi , Schiff Rachel , Wang Xiaosong 
Published: August 2015

Abstract
More aggressive breast cancers often coincide with enhanced chromosomal instability (CIN), which poses a great challenge to clinical management. By integrative analysis of genomic data, we observed the amplification of tousled-like kinase 2 (TLK2), a cell cycle serine-threonine kinase, in approximately 9% of breast cancer, which is more frequent in the luminal B and late-stage breast tumors. The resulting TLK2 upregulation correlates with the level of CIN in breast tumors, and predicts worse outcome regardless of endocrine therapy. Further studies suggest that TLK2 overexpression leads to a G2/M checkpoint defect, delayed DNA repair, and enhanced invasiveness. TLK2 silencing selectively inhibits the growth of TLK2-high breast cancer cells, and induces apoptosis. This response is retained in the breast cancer cells with acquired endocrine resistance. TLK2 inhibition in a preclinical tumor model significantly improved progression-free survival. Together, targeting TLK2 presents an attractive therapeutic strategy on TLK2-amplified breast cancers.
Citation Format: Jin-Ah KIM, Ying Tan, Xian Wang, Xixi Cao, Jamunarani Veeraraghavan, Yulong Liang, Dean P. Edwards, Xuewen Pan, Kaiyi Li, Rachel Schiff, Xiaosong Wang. Genomic deregulation and therapeutic role of the cell-cycle kinase TLK2 in more aggressive breast cancers. [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 3032. doi:10.1158/1538-7445.AM2015-3032
Abstract 3043: Discovery of a novel mitochondrial protein complex containing pro-apoptotic Noxa in leukemia
Authors: Gaynes Jeffrey S. , Hanse Eric A. , Kelekar Ameeta 
Published: August 2015

Abstract
Apoptosis evasion and altered nutrient metabolism are recognized as major contributors to cancer development. However, the degree to which apoptosis and metabolism are integrated in malignant cells remains poorly understood. Previously our group observed alterations in mitochondrial function mediated by expression of the pro-apoptotic member of the Bcl-2 family Noxa. Here, we report the presence of a large 650 kilodalton multi-protein complex specific to the mitochondria of Jurkat leukemia cells that contains Noxa. We also detect a similar mitochondrial protein complex in cells expressing Noxa with a mutated BH3 domain, suggestive of an apoptosis-independent metabolic function for this Bcl-2 family member. Lastly, we present here the successful isolation of this complex aimed at identifying other complex components via mass spectrometry. This unique strategy included purifying the complex by gel-filtration chromatography, and then resolving the complex into an acrylamide gel by either size or charge, followed by separating the individual complex components by size. Future studies are geared towards identifying the other components of the complex, looking for presence of this complex in other cancers, and understanding how this complex may function in maintaining mitochondrial homeostasis in cancer. In summary, the data presented here strongly suggests a non-canonical function for Noxa in regulating mitochondrial function independent of apoptosis in leukemia, and possibly other malignancies.
Note: This abstract was not presented at the meeting.
Citation Format: Jeffrey S. Gaynes, Eric A. Hanse, Ameeta Kelekar. Discovery of a novel mitochondrial protein complex containing pro-apoptotic Noxa in leukemia. [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 3043. doi:10.1158/1538-7445.AM2015-3043
Abstract 3058: Oxidative phosphorylation-dependent regulation of cancer cell apoptosis in response to anticancer agents
Authors: Kumar Sandeep , Yadav Neelu , Marlowe Tim , Chaudhary Ajay , Wang Jianmin , O'Malley Jordan , Boland Patrick , Jayanthi Srinivas , Kumar Thallapuranam Krishnaswamy Suresh , Yadava Nagendra , Chandra Dhyan 
Published: August 2015

Abstract
Although cancer cells develop resistance to multiple types of anticancer agents, whether they adopt similar or differential mechanisms to evade cell death in response to a broad spectrum of cancer therapeutics is not fully defined. We show differential sensitivity, caspase activation, and cytokines/chemokines release in response to multiple anticancer agents. We demonstrated that DNA-damaging agents (etoposide and doxorubicin), ER stressor (thapsigargin), and histone deacetylase inhibitor (apicidin) target oxidative phosphorylation (OXPHOS) for apoptosis induction, whereas other anticancer agents including staurosporine, taxol, and sorafenib induced apoptosis in OXPHOS-independent manner. DNA-damaging agents induced mitochondrial biogenesis accompanied by increased production of cellular and mitochondrial ROS. Mitochondrial biogenesis upregulated both mitochondrial protein-folding machinery and unfolded protein response. Induction of mitochondrial biogenesis occurred in a caspase activation-independent mechanism but was reduced by autophagy inhibition and p53-deficiency. Abrogation of complex-I blocked DNA damage-induced caspase activation, whereas inhibition of complex II or gross complexes did not modulate the caspase activity. Interestingly, DNA damaging agent doxorubicin showed strong binding to mitochondria, which was disrupted upon OXPHOS complex I-deficiency but not by OXPHOS complex II-deficiency. Thapsigargin-induced caspase activation was reduced upon abrogation of complex-I or gross-complexes whereas a reverse trend was observed with apicidin. Together, our findings define the specific targets of apoptosis induction in response to a broad range of anticancer therapeutics, which provide a new strategy for differential mitochondrial targeting for cancer therapy.
Citation Format: Sandeep Kumar, Neelu Yadav, Tim Marlowe, Ajay Chaudhary, Jianmin Wang, Jordan O'Malley, Patrick Boland, Srinivas Jayanthi, Thallapuranam Krishnaswamy Suresh Kumar, Nagendra Yadava, Dhyan Chandra. Oxidative phosphorylation-dependent regulation of cancer cell apoptosis in response to anticancer agents. [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 3058. doi:10.1158/1538-7445.AM2015-3058
Abstract 3068: Integrative tcga analyses identify key microRNAs involved in chemoresistance
Authors: Shen Fangrong , Vasudha Sehgal , Wu Sherry , Ehsan A Ehsanipour , Robert C Olson , Cristina Ivan , Keith A Baggerly , Prahlad Ram , Anil K Sood 
Published: August 2015

Abstract
Objective. High-grade serous ovarian cancer (HGSOC) is the most common and lethal type of ovarian carcinoma. Our study aims to identify key microRNAs (miRs) that are responsible for promoting chemoresistance in HGSOC. Methods. We developed fast and robust computational algorithm to identify miRs that are significantly associated with improved or worsened survival in HGSOC patients. We subsequently used this algorithm to mine The Cancer Genome Atlas (TCGA) ovarian cancer database to identify miRs that are up-regulated in tumors from patients whose cancer had progressed within 6 months of diagnosis (chemoresistant group) compared to tumors from patients who had no disease progression for more than 2 years (chemosensitive group). We also constructed miRNA-mRNA functional networks for the key miRs identified. The biological roles of selected miRs were subsequently examined in multiple chemoresistant (SKOV3-TR, HeyA8-MDR, and A2780-CP20) ovarian cancer cell lines. Results. From our integrative analyses, we identified several miRs being highly up-regulated or down-regulated in chemoresistant HGSOC (p&lt;0.05, top 10%). To examine the functional roles of these miRs, we transfected miR mimics and anti-miR constructs into taxane or platinum resistant cell lines. We showed that anti-miR-1271 significantly enhanced the sensitivity of taxane-resistant cancer cells (SKOV3-TR and HeyA8-MDR) to paclitaxel and docetaxel treatments. In contrast, transfecting anti-miR-1271 did not alter the sensitivity of A2780-CP20 cells to cisplatin treatment. Conclusion. These data provide the first integrated and functional approach for overcoming chemoresistance using miRs.
Citation Format: Fangrong Shen, Sehgal Vasudha, Sherry Wu, Ehsanipour, Ehsan A, Olson Robert C, Ivan, Cristina, Baggerly, Keith A, Ram, Prahlad, Sood, Anil K. Integrative tcga analyses identify key microRNAs involved in chemoresistance. [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 3068. doi:10.1158/1538-7445.AM2015-3068
Abstract 3069: The role of miR-30c-2* in clinical outcome and drug resistance in HPV-infected non-small cell lung cancer
Authors: Cheng Ya-Wen , Lin Hsiao-Ching 
Published: August 2015

Abstract
Lung cancer is leading cause of cancer death in Taiwanese women who are mostly to be life-time never smokers. Majority of drugs and combinations are used to treat with smoking lung cancer patients, not for nonsmokers. However, the 5-year survival rate in lung cancer patients remains ∼15% during the past three decades. Therefore, dissolving tumor recurrence and drug resistance is urgent needed for improving outcome in lung cancer, especially in nonsmokers. Mir-30c-2* has been considered to be tumor suppressor gene in various cancers. MiR-30c-2* levels were associated with in gemcitabine sensitivity of lung cancer cells. Down-regulation of miR-30c promotes tumor invasion via an increased in MTA1 expression. Our previous reports have indicated that HPV16/18 infection may be involved in Taiwanese lung tumorigenesis. Preliminary data showed that miR-30C-2* levels were elevated 45-fold in E6-knockdown TL-1 cells as compared with parental cells with non-specific RNAi tranfection. More interestingly, MTA-1 expression was negatively correlated with miR-30C-2* in lung tumors from lung cancer patients. Expression levels of MTA-1 were positive correlated with tumor stage and nodal metastasis in tumor tissues of lung cancer patients. Our cell model studies also found that miR-30C-2* suppressed by E6 could contribute to tumor metastasis and drug resistance via an increased in MTA-1 expression. These results were showed that miR-30C-2* levels in patients’ tumor tissues could be useful to predict outcome and therapeutic response and to select useful therapy drugs for lung cancer patients, especially in patients with HPV-infection.
Citation Format: Ya-Wen Cheng, Hsiao-Ching Lin. The role of miR-30c-2* in clinical outcome and drug resistance in HPV-infected non-small cell lung 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 3069. doi:10.1158/1538-7445.AM2015-3069
Abstract 3078: Epigenetic regulation of miR-138 confers cancer stem cell characteristics of renal cell carcinoma
Authors: Yun Eun-Jin , Zhou Jiancheng , Lin Chun-Jung , Hernandez Elizabeth , Santoyo John , Hsieh Jer-Tsong 
Published: August 2015

Abstract
Chemotherapy is the standard care for metastatic disease, in renal cell carcinoma (RCC), the outcome of chemotherapy only prolongs short survival of patients. The reason for the resistance of RCC to chemotherapy is not fully understood, although it has been speculated that overabundance of ATP-binding cassette (ABC)/p-glycoprotein transporter system in RCC might be the reason to repel various chemotherapeutic agents away from the cancer cell. Meanwhile, cancer stem cells (CSC) theory has also focused a significant attention in recent years as a potential explanation for drug resistance and metastasis of RCC. In this study, we demonstrate that drug resistant RCC cells exhibit CSC phenotypes and miR-138 that is significantly downregulated in RCC acted critical role in suppressing CSC phenotype by targeting ABC transporter ABCA13 and oncogenic histone methyltransferase EZH2. Importantly, miR-138 levels were significantly enhanced by treatment of DNA hypomethylating agent (i.e., 5-aza) or histone deactylases inhibitor (i.e., TSA). Epigenetic silencing of tumor-suppressive micro-RNAs has been shown a key oncogenic mechanism for the activation of oncogenes in tumors. Indeed, depletion of miR-138 promoted CSC phenotype followed by enhanced expressions of ABCA13 and EZH2. Furthermore, a novel tumor suppressor DAB2IP can inhibit DNA methyltransferase 1 (DNMT1) activity, which results in miR-138 expression. Taken together, this study identifies the new role of miR-138 in RCC-CSC and unveils a unique regulation of tumor suppressor protein in DNMT1. Overall study provides not only a new biomarker of RCC-CSC and but also potential therapeutic strategy of targeting drug resistant RCC.
Citation Format: Eun-Jin Yun, Jiancheng Zhou, Chun-Jung Lin, Elizabeth Hernandez, John Santoyo, Jer-Tsong Hsieh. Epigenetic regulation of miR-138 confers cancer stem cell characteristics of renal 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 3078. doi:10.1158/1538-7445.AM2015-3078