bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3456: Distinct control of PERIOD2 degradation and circadian rhythms by the oncoprotein MDM2
Authors: Zou Xianlin , Liu Jingjing , Gotoh Tetsuya , Brown Anne M. , Jiang Liang , Wisdom Esther L. , Kim Jae Kyoung , Finkielstein Carla V. 
Published: August 2019

Abstract
The circadian clock relies on post-translational modifications to set the timing for degradation of core regulatory components and, thus, sets clock progression. Ubiquitin-modifying enzymes targeting clock components for degradation are known to mostly recognize phosphorylated substrates. A case in point is the circadian factor PERIOD 2 (PER2) whose phospho-specific turnover involves its recognition by β-transducin repeat containing proteins (β-TrCPs). Yet, the existence of this unique mode of regulation of PER2’s stability falls short of explaining persistent oscillatory phenotypes reported in biological systems lacking functional elements of the phospho-dependent PER2 degradation machinery.
In this study, we challenge the phosphorylation-centric view that PER2 degradation enhances circadian rhythm robustness by i) identifying the PER2:MDM2 endogenous complex, ii) establishing PER2 as a previously uncharacterized substrate for MDM2, iii) revealing an alternative phosphorylation-independent mechanism for PER2 ubiquitin-mediated degradation, iv) pinpointing residues for ubiquitin modification, and v) establishing the importance of MDM2-mediated PER2 turnover for defining the circadian period length. Our results not only expand MDM2’s suite of specific substrates beyond the cell cycle to include circadian components but also uncover novel regulatory players that likely impact our view of how other mechanisms crosstalk and modulate the clock itself.
Citation Format: Xianlin Zou, Jingjing Liu, Tetsuya Gotoh, Anne M. Brown, Liang Jiang, Esther L. Wisdom, Jae Kyoung Kim, Carla V. Finkielstein. Distinct control of PERIOD2 degradation and circadian rhythms by the oncoprotein MDM2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3456.
Abstract 346: E2F8 induces proliferation and invasion through the epithelial-mesenchymal transition and notch signaling pathways in ovarian cancer
Authors: Eoh Kyung Jin , Lee Jong Woo , Kim Young Tae , Koo Peter Jaseok 
Published: August 2019

Abstract
Purpose: Recent research has investigated the role of E2F8 in cancer progression. However, whether the progression of ovarian cancer involves E2F8 remains to be elucidated. In this study, the bio-functional consequences of E2F8 knockdown in vitro and in vivo were explored. Experimental
Design: E2F8 expression was compared between ovarian cancer and non-cancer tissues, and the association between E2F8 expression and progression-free survival in ovarian cancer patients was analyzed. To demonstrate the function of E2F8 in cell proliferation, migration, and invasion, RNA interference was employed to suppress E2F8 expression in ovarian cancer cell lines. Finally, the effect of E2F8-knockdown was investigated in an ovarian cancer xenograft mouse model.
Results: Ovarian cancer tissue exhibited significantly higher E2F8 expression than normal ovarian tissue. Clinical data confirmed that E2F8 was a significant predictor of progression-free survival, and ovarian cancer patients with high E2F8 expression exhibited poorer prognosis than patients with low E2F8 expression. In vitro experiments using E2F8-knockdown ovarian cancer cell lines showed that E2F8 knockdown inhibited cell proliferation, migration, and tumor invasion. Additionally, E2F8 was a potent inducer and modulator of the expression of epithelial-mesenchymal transition (EMT) and Notch signaling pathway-related markers. We confirmed the function of E2F8 in vivo, demonstrating that E2F8-knockdown was significantly correlated with reduced tumor size and weight.
Conclusions: In conclusion, our study suggests that E2F8 is highly correlated with ovarian cancer progression; hence, E2F8 may be a prognostic marker and therapeutic target for ovarian malignancy.
Note: This abstract was not presented at the meeting.
Citation Format: Kyung Jin Eoh, Jong Woo Lee, Young Tae Kim, Peter Jaseok Koo. E2F8 induces proliferation and invasion through the epithelial-mesenchymal transition and notch signaling pathways in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 346.
Abstract 3465: FANCD2 depletion suppresses tumor growth in esophageal squamous cell carcinoma
Authors: Lei Chan , Yu Zhuoyou , Ning Lvwen , Ko Mun-Yee , Wang Lidong , Lung Maria Li 
Published: August 2019

Abstract
Introduction: Esophageal squamous cell carcinoma (ESCC) has a remarkably high incidence in Northern China. Our next-generation sequencing analysis on familial ESCC samples suggests that members of the Fanconi Anemia (FA) pathway play important roles in ESCC development. Fanconi anemia complementation group D2 (FANCD2) as a key player of FA pathway has multiple cellular functions. It is well-known for its role in DNA damage repair through the FA pathway. Patients with germline FANCD2 mutations are prone to tumor formation. Identifying roles of FANCD2 in ESCC development may enhance our foundation for future development of specific treatment regimens for this deadly disease.
Methods and Results: To study the function of FANCD2 in ESCC, we applied the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) technique to inhibit FANCD2 protein expression by functional knock-out (fKO). As expected, we observed increased DNA damage in FANCD2 fKO cells as shown by Comet assay, consistent with the classic role of FANCD2 in genome integrity. We also observed that the DNA damage by irradiation takes longer to be repaired in FANCD2 fKO cells, indicating that FANCD2 enhances irradiation-induced DNA damage repair but is not necessary. Similarly, cells with FANCD2 fKO are more sensitive to irradiation, as indicated by cell cycle arrest at S/G2 phase.
Surprisingly, without inducing any DNA damage, FANCD2 fKO cells also show cell cycle arrest at S/G2 phase. The MTT cell proliferation assay also show that FANCD2 fKO reduces proliferation and colony-forming ability. Consistent with the in vitro data, FANCD2 fKO cells also form smaller tumors in vivo by the nude mouse tumorigenicity assay.
Conclusion: These results indicate that FANCD2 plays important roles in ESCC development and suggest a pro-oncogenic feature of wildtype FANCD2 in ESCC. Further investigation is ongoing to examine the functional role and molecular mechanisms of the oncogenic FANCD2, ultimately aiming at improving ESCC disease management.
Acknowledgement: We acknowledge the grant support from the Hong Kong Research Grants Council Collaborative Research Fund (C7031.15G) and the Asian Fund for Cancer Research to M.L.L.
Citation Format: Chan Lei, Zhuoyou Yu, Lvwen Ning, Mun-Yee Ko, Lidong Wang, Maria Li Lung. FANCD2 depletion suppresses tumor growth in esophageal squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3465.
Abstract 3497: SAMHD1 is a Novel Biomarker and Therapeutic Target for Radiation Therapy and PARP Inhibition in Breast Cancer
Authors: Thompson Elizabeth 
Published: August 2019

Abstract
SAMHD1 is a Novel Biomarker and Therapeutic Target for Radiation Therapy and PARP Inhibition in Breast Cancer
Ashley Schlafstein, Waaqo Daddacha, David S. Yu
Background/Introduction:
Patients with breast cancer are often treated by ionizing radiation (IR) and PARP inhibitors; however, the effectiveness of these treatments is often limited by lack of response and/or resistance. Sterile alpha motif and HD domain-containing protein 1 (SAMHD1) is a deoxyribonucleotide triphosphate (dNTP) triphosphohydrolase with a well-established role in HIV-1 restriction by depleting dNTPs required for reverse transcription and replication. SAMHD1 is also dysregulated in breast and other cancers and in autoimmune disease. In addition to its well-established dNTPase activity, our lab has defined a novel role for SAMHD1 in DNA end resection to facilitate DNA double strand break (DSB) repair by homologous recombination (HR). Because of its role in DNA DSB repair and its link to breast cancer, we hypothesized that SAMHD1 could be used as a novel biomarker and target for breast cancer therapy.
Methods:
We queried the TCGA database for patients with breast cancer who were treated with or without IR to determine if there was an association of SAMHD1 expression level with clinical outcome. We also determined if targeting SAMHD1 for proteasomal degradation with novel virus like particles (VLPs) containing Vpx, a viral accessory protein, can sensitize breast cancer cells and tumors to DNA damaging agents.
Results:
In patients with breast cancer treated with IR, low SAMHD1 expression was associated with a statistically significant improvement in overall survival, while for those not treated with IR, no significant difference in association of SAMHD1 expression with outcome was observed. Breast cancer cells and tumors treated with VLPs containing Vpx were hypersensitive to IR and PARP inhibitor.
Conclusion:
Our results identify SAMHD1 as a novel biomarker for stratifying breast cancer patients for treatment with IR. In addition, targeting SAMHD1 with VLPs containing Vpx may be a novel therapeutic strategy for sensitizing breast cancer to IR, PARP inhibitors, and other agents that induce DNA DSBs.
Citation Format: Elizabeth Thompson. SAMHD1 is a Novel Biomarker and Therapeutic Target for Radiation Therapy and PARP Inhibition in Breast Cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3497.
Abstract 3500: Highly potent and selective ATM kinase inhibitor M4076: A clinical candidate drug with strong anti-tumor activity in combination therapies
Authors: Fuchss Thomas , Graedler Ulrich , Schiemann Kai , Kuhn Daniel , Kubas Holger , Dahmen Heike , Zimmermann Astrid , Zenke Frank , Blaukat Andree 
Published: August 2019

Abstract
M4076 is an ATP-competitive inhibitor of the Ataxia telangiectasia mutated (ATM) kinase (IC50 &lt; 1 nM), which targets tumor cell survival and growth by inhibiting double-strand break (DSB) repair as well as checkpoint control. DSB repair is crucial for survival of malignant tumor cells, especially under treatment with DNA damaging chemo- and radiotherapy. As such, the rationale of pharmacological inhibition of ATM is to increase and maintain the extent of unrepaired DNA damage generated by radio-, chemotherapy, and targeted therapies to drive tumor cells into cell death. We have developed an orally administered, sub-nanomolar potent & selective kinase inhibitor of ATM, M4076, for cancer therapy in combination with DNA damaging modalities. Here, we present its structure-activity relationship, its chemical structure (first-time disclosure) & physicochemical profile as well as its preclinical characterization using biochemical, cellular & human tumor xenograft models. M4076 sensitizes tumor cell lines to radiation therapy in vitro and strongly enhances the anti-tumor activity of ionizing radiation in vivo. These effects are due to the inhibition of ATM kinase activity as demonstrated by the inhibition of radiotherapy induced ATM autophosphorylation and CHK2 phosphorylation in xenograft lysates.
Citation Format: Thomas Fuchss, Ulrich Graedler, Kai Schiemann, Daniel Kuhn, Holger Kubas, Heike Dahmen, Astrid Zimmermann, Frank Zenke, Andree Blaukat. Highly potent and selective ATM kinase inhibitor M4076: A clinical candidate drug with strong anti-tumor activity in combination therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3500.
Abstract 351: A targeted nanocomplex of the IKBKE siRNA inhibits invasiveness and growth of triple negative breast cancer cells
Authors: Zhao Zhen , Li Yuanke , Cheng Kun 
Published: August 2019

Abstract
IκB kinase ϵ (IKBKE, or known as IKKϵ), an important mediator in the activation of NF-κB pathway, was recently identified as an oncogene in breast cancer and overexpressed in approximately 30% of breast carcinomas. It is also highly expressed in TNBC cells, which is correlated with angiogenesis process, high metastasis in NF-κB pathway of TNBC. We found that silencing IKBKE in TNBC cells using siRNA significantly inhibits the proliferation, migration and invasion of TNBC cells by specific silenced 71% of IKBKE in vitro. In vivo study indicated that IKBKE siRNA can inhibit TNBC tumor growth after peritumoral injection at a IKBKE siRNA dose of 0.3 mg/kg. We next developed a CD44-targeting, cholesterol-peptide based nanocomplex to co-deliver the IKBKE siRNA and cabazitaxel to TNBC cells. The nanocomplex showed the synergistic effect of the IKBKE siRNA and cabazitaxel on inhibiting the growth of TNBC tumors in vivo. Modification of the nanocomplex with CD44 further improved tumor uptake and anti-tumor efficacy of the nanocomplex. Our results suggest that IKBKE siRNA is a promising anti-tumor agent for TNBC therapy, and co-delivery of IKBKE siRNA and cabazitaxel using a CD44-targeting nanocomplex is a potential strategy for TNBC treatment. Moreover, this multifunctional delivery system provides a platform for other combination therapy including an siRNA and a chemotherapy drug.
Citation Format: Zhen Zhao, Yuanke Li, Kun Cheng. A targeted nanocomplex of the IKBKE siRNA inhibits invasiveness and growth of triple negative breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 351.
Abstract 3518: SPARC related signaling genes in non-small cell lung cancer by RNA-sequencing transcriptome analysis
Authors: Lakka Sajani S. , Ahir Bhavesh K. 
Published: August 2019

Abstract
Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, accounting for about 80 % cases of lung cancer and is the leading cause of cancer-related death in the United States and worldwide. SPARC (secreted protein acidic and rich in cysteine), a multicellular non-structural glycoprotein is known to be involved in the regulation of cell adhesion, cell proliferation as well as in tumorigenesis and metastasis in various cancers including NSCLC. SPARC contributes to matrix remodeling and turnover and is involved in modulating the tumor microenvironment. Previous studies have suggested that SPARC can be used as a prognostic factor for NSCLC and represents a highly promising therapeutic modality. In this study we used high-throughput RNA-sequencing transcriptome profiling analysis to delineate pathways involved in SPARC signaling. We assessed differentially expressed genes, novel genes, biological processes and biological signaling pathways in SPARC expressed NSCLC cell line. We identified a total of 3,280 upregulated and 1,608 downregulated differentially expressed genes with known functions in SPARC expressed NSCLC cells. KEGG enrichment analysis indicated that the differentially expressed genes were involved in cellular metabolic processes, regulation of biological processes or biological signaling pathways like cell cycle, spliceosome, apoptosis and WNT signaling pathway. The RNA-seq analysis further revealed that genes involved in apoptosis were significantly altered after SPARC modulation to NSCLC cells. Co-transfection experiments using SPARC shRNA indicated that SPARC modulation induced apoptosis via regulating PI3K/AKT signaling pathway. In summary, this study uncovers SPARC dependent regulatory mechanisms in NSCLC.
Note: This abstract was not presented at the meeting.
Citation Format: Sajani S. Lakka, Bhavesh K. Ahir. SPARC related signaling genes in non-small cell lung cancer by RNA-sequencing transcriptome analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3518.
Abstract 355: A novel anti-HER2 antibody that displays superior synergetic effects in Trastuzumab mediated HER2-overexpressing tumor arrest
Authors: Huang Haomin , zhang xuesai , Chen jianhe , Zhao Le , Li qingrou , zhu zhenping 
Published: August 2019

Abstract
The majority of patients with metastatic breast cancer on Trastuzumab, an anti-HER2 monoclonal antibody, generally develop resistance to the drug within a year after initiation of the treatment. Therefore, there is an unmet need for a novel agent to treat HER2 overexpressing breast cancers. Here we described a novel anti-HER2 humanized monoclonal antibody, 19H6-hu, which binds to HER2 ECD with high affinity and could inhibit the proliferation of multiple HER2-overexpressing cancer cell lines as a single agent, though, to a lesser degree when compared to Trastuzumab alone. Interestingly, when in combination with Trastuzumab, 19H6-hu exhibited much stronger potency in inhibition of BT474, N87 and SKBR3 cell growth relative to that of Perjeta in combination with Trastuzumab as well as in suppression of tumor growth in vivo when compared to Trastuzumab alone. Alanine scanning demonstrated that the antibody binds to an alpha-helix located within the domain III and in proximity to the domain IV of HER2 ECD, which is different from the known binding sites of Trastuzumab and Perjeta. Western blotting further confirmed that 19H6-hu in combination with Trastuzumab is more efficacious in blocking phosphorylation of ERK and phosphorylation of HER2 at Y1248 when compared to Trastuzumab in combination with Perjeta or applied alone. Thereby, our results highlight the functional variability of HER2 domains and provide a new insight into the design of HER2-targeting agents.
Citation Format: Haomin Huang, xuesai zhang, jianhe Chen, Le Zhao, qingrou Li, zhenping zhu. A novel anti-HER2 antibody that displays superior synergetic effects in Trastuzumab mediated HER2-overexpressing tumor arrest [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 355.
Abstract 3551: Dysregulation in microprocessor processing of a primary miRNA, mir-21, leads to downregulation of a tumor suppressor, GHR, progressing hepatocellular carcinoma
Authors: Park Seokju , Yang Hee Doo , Seo Jwawon , Nam Seokwoo , Nam Jin-Wu 
Published: August 2019

Abstract
Improper miRNA biogenesis produces the 5’ variants of miRNA with a shifted seed region (also called isomiRs). Although the presence of stably abundant isomiRs were repeatedly reported, it is still unclear whether the generation of isomiRs results either from the mistake of microprocessor or from the regulation by other intrinsic or extrinsic factors, and whether the isomiRs participate in critical cellular processes, particularly in cancer progress. Here, we performed both high-throughput RNA sequencing (RNA-seq) and small RNA sequencing (sRNA-seq) from 75 hepatocellular carcinoma (HCC) and normal samples (fresh frozen) of Korean HCC cohort. Combined analysis with other publicly available sequencing data, showed that although the expression signatures of isomiRs largely follow those of canonical ones, the relative abundance of some isomiRs are dynamically changed over cancer progression, forming new isomiR-target interactions. Particularly, the biogenesis of highly abundant miR-21 is dysregulated by interaction with HNRNPC to primary mir-21 during cancer progress, producing relatively more isomiR-21-5p in HCC. Introducing isomiR-21-5p mimic or antagomir against isomiR-21-5p, and the dysregulation of HNRNPC expression perturbed the relative abundance of isomiR-21-5p, leading to dysregulation of miRNA targeting on a tumor suppressor gene, GHR, and affecting cancer progress. Our study not only describes that isomiR-21-5p is an independent prognostic marker and a potential therapeutic target of HCC but also presents that the production of isomiRs is tightly regulated by other extrinsic factors in cells.
Citation Format: Seokju Park, Hee Doo Yang, Jwawon Seo, Seokwoo Nam, Jin-Wu Nam. Dysregulation in microprocessor processing of a primary miRNA, mir-21, leads to downregulation of a tumor suppressor, GHR, progressing hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3551.
Abstract 3565: Role of novel microRNA 4287 at a frequently deleted chromosome 8p region in prostate cancer
Authors: Bhagirath Divya , Yang Thao , Tabatabai Laura , Majid Shahana , Yamamura Soichiro , Dahiya Rajvir , Tanaka Yuichiro , Saini Sharanjot 
Published: August 2019

Abstract
Deletion of chromosome (chr)8p21-22 region that has been traditionally associated with the loss of homeodomain protein, NKX3.1 and with tumor initiation, is frequently observed in prostate cancer (PCa). More significantly, loss of this region is associated with aggressiveness and poor prognosis of PCa, thereby emphasizing a key role of this region in advanced prostate cancer. In a paradigm shifting hypothesis, we proposed that this frequently deleted locus is associated with a cluster of miRNA genes - miR-3622a/b and miR-383- that are lost in PCa and play an important mechanistic role in PCa progression and metastasis by regulating Epithelial-mesenchymal-transition (EMT) and stemness. Extending our hypothesis, in this study we evaluated the role of miR-4287, a miRNA gene located within this region in PCa. We profiled the expression of miR-4287 in laser capture microdissected (LCM) PCa tissues and matched adjacent normal regions by real time PCR. miR-4287 expression was down regulated in ~79% of tissue samples. High miR-4287 expression was observed in 20% of cases. Analyses of miR-4287 expression in prostate cell lines showed that its expression is specifically attenuated in PCa cell lines compared to normal or immortalized prostate epithelial cells. Further, we evaluated the functional role of miR-4287 in prostate cancer by overexpressing miR-4287 precursor in PCa cell lines PC3 and LNCaP. miR-4287 overexpression in PCa cell lines led to decreased cellular viabilities as compared to control cells. Moreover, PCa cell lines overexpressing miR-4287 showed an increase in apoptosis and G0/G1 arrest. Further, we found that miR-4287 inhibits epithelial to mesenchymal transition (EMT) in PCa as its overexpression in PCa cell lines led to increased E-cadherin and decreased vimentin expression concomitant with morphological changes consistent with mesenchymal to epithelial transition (MET). We identified SRC, SFPR4 and CD44 as potential miR-4287 targets. Taken together, our data suggests that miR-4287 plays a significant role as tumor suppressor in PCa pathogenesis.
Citation Format: Divya Bhagirath, Thao Yang, Laura Tabatabai, Shahana Majid, Soichiro Yamamura, Rajvir Dahiya, Yuichiro Tanaka, Sharanjot Saini. Role of novel microRNA 4287 at a frequently deleted chromosome 8p region in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3565.