bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5401: Dysregulated microRNAs in aflatoxin-induced hepatocellular carcinoma: Serum miR-182 as a potential predictive biomarker
Authors: Livingstone Merricka C. , Johnson Natalie M. , Roebuck Bill D. , Kensler Thomas W. , Groopman John D. 
Published: August 2018

Abstract
Hepatocellular carcinoma (HCC) continues to be a major cause of cancer death globally, with aflatoxin B1 (AFB1) as a prevalent risk factor in low- and middle-income countries. MicroRNAs have been shown to be differentially expressed in HCC and may serve as predictive biomarkers. In this study, we analyzed tumor and non-tumor tissue from rats dosed with AFB1 (200 µg/kg BW) for 28 consecutive days that received vehicle only or AFB1 plus the chemopreventive agent CDDO-Im (30 µmol), and control animals (Johnson et al., CaPR, 2014). Total RNA was isolated from tumor or non-tumor tissue at the time of sacrifice and sequenced. MicroRNA transcriptomic analysis revealed 17 miRNAs significantly upregulated (&gt; 5 fold) in tumors compared to non-tumor tissue. The top ten dysregulated miRNAs determined by fold change and biological significance were selected for further investigation: rno-miR- 205, 200b-3p, 182, 429, 31a-5p, 10b-5p, 141-3p, 132-3p, 802-5p. Validation of sequencing results by quantitative PCR (qPCR) confirmed the upregulation of the majority of candidate miRNAs in tumors and rno-miR-224-5p as the most dysregulated miRNA (over 400 fold). We also examined the levels of these candidates in terminal sera of the same animals by qPCR. Circulating miRs-224-5p, 182, and 122-5p were increased (&gt; 1.5 fold) in animals diagnosed with HCC compared to untreated animals and those previously dosed with AFB1 plus CDDO-Im. Analysis of tracking of serum miR-182 by generalized estimating equations (GEE) revealed significantly increased levels (5 fold; CI: 2.17- 2.50) in animals that developed HCC. This sustained increase in serum miR-182 is seen months before any tumors or other symptoms are present, and highlights this miRNA as a potential predictive biomarker in AFB1-induced HCC. Supported by T32ES007141-31A1 and CA197222.
Citation Format: Merricka C. Livingstone, Natalie M. Johnson, Bill D. Roebuck, Thomas W. Kensler, John D. Groopman. Dysregulated microRNAs in aflatoxin-induced hepatocellular carcinoma: Serum miR-182 as a potential predictive biomarker [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5401.
Abstract 5408: Elevated level of serum miR-1290 is correlated with high-grade serous ovarian epithelial ovarian cancer and might be a potential biomarker
Authors: Kobayashi Masaki , Kenjiro Sawada , Akihiko Yoshimura , Mayuko Miyamoto , Erika Nakatsuka , Michiko Kodama , Kae Hashimoto , Seiji Mabuchi , Tadashi Kimura 
Published: August 2018

Abstract
Objective: There is a critical need for improved diagnostic markers to detect ovarian high grade serous ovarian cancer (HGSOC). MicroRNAs (miRNAs) stably exist in circulating blood, reflecting tissue or organ conditions and present in circulating microvesicles such as exosomes. Recent studies have confirmed the potential use of miRNAs profiling as a novel non-invasive biomarker for diagnosis of HGSOCs. The aim of this study is to identify which miRNAs are highly produced from HGSOCs and analyze whether serum miRNA can discriminate patients with HGSOC from healthy controls. Methods: Secreted exosomes from ovarian cancer cell lines were collected and exosomal miRNAs extracted. miRNA microarray was performed and several elevated miRNAs specific to HGSOCs were picked up. Among these, we focused on miR-1290. Serum from 71 pre-operative, 46 post-operative ovarian cancer patients and 13 healthy controls were gathered and its expression levels were detected by quantitative Real Time PCR. Results: In HGSOC patients, miR-1290 emerged overexpressed compared to healthy controls (3.52-fold). ROC analysis showed that at the cut-off of 1.61(healthy controls ; 1), the sensitivity and specificity were 63 % and 85 % respectively for detecting HGSOC (AUC = 0.71). The AUC of CA125 + miR-1290 combination was 1.00. Its expression singnificantly decreased after operation(5.87 → 1.17 ; P &lt; 0.01). In advanced stage HGSOC patients, moreover, it expressed marginally higher than early stage ones(4.23 VS 1.58 ; P = 0.23). Conclusions: Serum miR-1290 can be a potential diagnostic biomarker for HGSOC.
Citation Format: Masaki Kobayashi, Sawada Kenjiro, Yoshimura Akihiko, Miyamoto Mayuko, Nakatsuka Erika, Kodama Michiko, Hashimoto Kae, Mabuchi Seiji, Kimura Tadashi. Elevated level of serum miR-1290 is correlated with high-grade serous ovarian epithelial ovarian cancer and might be a potential biomarker [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5408.
Abstract 542: A disintergrin and metalloprotease (ADAM) 15 promotes non-small cell lung cancer (NSCLC) proliferation through cytosolic domain, not extra-cytosolic metalloprotease activity
Authors: Hou Hsin-Han 
Published: August 2018

Abstract
Emerging evidence indicates that proteins of a disintergrin and metalloprotease (ADAM) family contribute to cancer progression and metastasis. ADAM15 is up-regulated in multiple cancers and the enzymatic activities of its extracellular metalloprotrease domain promote cancer proliferation and migration by mediating the ErbB signaling pathway. In lung cancer, the enzymatic activity of ADAM15 extracellular domain is reported to be independent of ErbB signaling, indicating an alternative mechanism in promoting lung cancer progression. However, the role of ADAM15 in non-small cell lung cancer (NSCLC) and its correlation to patient prognosis is not well understood. This study demonstrated the longest ADAM15 isoforms, isoform 6 (i6), which contained the most cytoplasmic Src homology 3 (SH3) binding motifs, was significantly up-regulated in progressive NSCLC cell. Comparison of i6 and isoform 1 (i1) revealed that the cytoplasmic domain was essential for NSCLC cell proliferation and aggressiveness. ADAM15 i6, but not i1, mediated the activation the activation of the Src homolog 2 domain containing (Shc) through physical interaction with growth factor receptor-bound protein 2 (Grb2). ADAM15 i6 overexpression promoted NSCLC cell growth in a xenograft mouse model, while ADAM15 or Grb2 knockdown resulted in tumor shrinkage. ADAM15 was overexpressed in primary NSCLC tissues compared to adjacent normal tissues. Patients with ADAM15 i6 high-expressing lung tumors had shorter survival times. Thus, a novel mechanism of the ADAM15 cytoplasmic domain is identified in NSCLC tumor progression. This may help shed light on the molecular mechanisms of ADAM proteins and facilitate development of novel therapy for NSCLC.
Citation Format: Hsin-Han Hou. A disintergrin and metalloprotease (ADAM) 15 promotes non-small cell lung cancer (NSCLC) proliferation through cytosolic domain, not extra-cytosolic metalloprotease activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 542.
Abstract 5431: BRD4 regulates cellular senescence in gastric cancer cells via E2F/miR-106b/p21 axis
Authors: Dong Xingchen 
Published: August 2018

Abstract
Small molecules targeting bromodomains of BET proteins possess strong anti-tumor activities and have emerged as potential therapeutics for cancer. However, the underlying mechanisms for the anti-proliferative activity of these inhibitors are still not fully characterized. In this study, we demonstrated that BET inhibitor JQ1 suppressed the proliferation and invasiveness of gastric cancer cells by inducing cellular senescence. Depletion of BRD4, which was overexpressed in gastric cancer tissues, but not other BET proteins recapitulated JQ1-induced cellular senescence with increased cellular SA-β-Gal activity and elevated p21 levels. In addition, we showed that the levels of p21 were regulated at the post-transcriptional level by BRD4-dependent expression of miR-106b-5p, which targets the 3'-UTR of p21 mRNA. Overexpression of miR-106b-5p prevented JQ1-induced p21 expression and BRD4 inhibition-associated cellular senescence, whereas miR-106b-5p inhibitor up-regulated p21 and induced cellular senescence. Finally, we demonstrated that inhibition of E2F suppressed the binding of BRD4 to the promoter of miR-106b-5p and inhibited its transcription, leading to the increased p21 levels and cellular senescence in gastric cancer cells. Our results reveal a novel mechanism by which BRD4 regulates cancer cell proliferation by modulating the cellular senescence through E2F/miR-106b-5p/p21 axis and provide new insights into using BET inhibitors as potential anti-cancer drugs.
Citation Format: Xingchen Dong. BRD4 regulates cellular senescence in gastric cancer cells via E2F/miR-106b/p21 axis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5431.
Abstract 5432: Cancer-induced hypercalcemia promotes breast cancer progression via AP-1 transcription factor mediated upregulation of malignancy-associated genes
Authors: Beasley Heather K. , Widatalla Sarrah E. , Williams Stephen D. , Whalen Diva S. , Korolkova Olga Y. , Sakwe Amos M. 
Published: August 2018

Abstract
Cancer-induced hypercalcemia (CIH), is common in breast cancer patients with metastatic disease and in up to 30% of cases with solid tumors without evidence of metastasis. However, its role in the development of large and aggressive breast tumors remain poorly understood. In this study, we show that prolong exposure of triple negative breast cancer (TNBC) cells to high Ca2+ is accompanied by reduced sensitivity of the calcium sensing receptor to high Ca2+, increased growth and tumor cell motility. Gene expression profiling of TNBC cells cultured at high Ca2+ (5.0 mM) revealed that in addition to early response genes (FOS/FOSB), high extracellular Ca2+ also modulated the expression of MAGEC2/CT10 and PAI-2 and other malignancy associated genes (MAGs). To determine whether the expression of MAGs is regulated by FOS/FOSB we show that down regulation of FOSB strongly inhibited the high Ca2+-induced expression of MAGEC2 and that FOSB, as a component of the AP-1 transcription factor bound to the MAGEC2 promoter at high Ca2+. We also show that down regulation of MAGEC2 or FOSB affected the migration and proliferation of TNBC cells at high Ca2+. These data suggest that high Ca2+-induced expression of malignancy promoting genes such as MAGEC2/CT10 underlie the successful tumor cell survival, growth and/or motility in calcium-rich microenvironments and presumably, during the hypercalcemia prone late stages of the disease. This research is supported by NIH/NIGMS 5SC2 CA170244 and 1SC1 CA211030, NIH/NCI 2U54CA 163069-07
Citation Format: Heather K. Beasley, Sarrah E. Widatalla, Stephen D. Williams, Diva S. Whalen, Olga Y. Korolkova, Amos M. Sakwe. Cancer-induced hypercalcemia promotes breast cancer progression via AP-1 transcription factor mediated upregulation of malignancy-associated genes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5432.
Abstract 5434: Screen for immune-related transcriptional targets of the Hippo pathway in human breast cancer cells
Authors: Rensburg Helena J. Janse van , Azad Taha , Ling Min , Hao Yawei , Minassian Lori M. , Snetsinger Brooke , Khanal Prem , Rauh Michael J. , Graham Charles H. , Yang Xiaolong 
Published: August 2018

Abstract
The Hippo signaling pathway has recently emerged as a cellular network that is dysregulated in cancer. In breast cancer cells, aberrant activation of the Hippo transducers (and transcriptional co-activators) TAZ and YAP leads to altered expression of their downstream gene targets and endows cells with multiple “hallmarks of cancer”. While several transcriptional targets of TAZ and YAP underlying their pro-tumorigenic activity have been described (e.g. CTGF, CYR61), gene targets of TAZ and YAP that modulate immune cell behavior in the tumor microenvironment are poorly understood. We have performed a comprehensive screen for immune-related transcriptional targets of TAZ and YAP in human breast cells. We have identified many candidate genes that are potentially regulated by TAZ and YAP including the immune checkpoint molecules PD-L1 and PD-L2, the lymphocyte regulator S1PR1 and the inflammasome component NLRP3. We have further validated PD-L1 as a bona fide transcriptional target of TAZ and YAP. These findings reveal new functions for the Hippo pathway in modifying immune responses and implicate TAZ and YAP in cancer immune evasion.
Citation Format: Helena J. Janse van Rensburg, Taha Azad, Min Ling, Yawei Hao, Lori M. Minassian, Brooke Snetsinger, Prem Khanal, Michael J. Rauh, Charles H. Graham, Xiaolong Yang. Screen for immune-related transcriptional targets of the Hippo pathway in human breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5434.
Abstract 5453: Novel pan-PI3K inhibitor WX008 demonstrates significant antitumor efficacy in three xenograft tumor models
Authors: Yu Tao , Kong Lingwei , Wang Yong , Jiang Peipei , Rong Zhe min , Wang Chang jun , Huang Jing jie , Yao Dan , Qin Yu xin , Wu Cheng de , Chen Shu hui , Tian Xin , Liu Fei , Dong Ping , Chen Zhi Lin 
Published: August 2018

Abstract
Background: PI3K/Akt signaling pathway plays a key role in a series of cellular functions related to cell growth, proliferation, survival and differentiation. Dysregulation of the PI3K pathway is implicated in many human cancers. Thus we intended to discover novel pan-PI3K inhibitors to treat various solid tumors, such as colorectal cancer, gastric carcinoma, lung carcinoma and breast cancer, etc.
Methods: We explored SAR based on a PI3K/mTOR dual inhibitor series to selectively improve the PI3K activity over that of mTOR. PI3Kα/mTOR enzymatic activity assays, MCF-7 cellular (p-AktS473) activity assay and mouse in vivo pharmacokinetic analyses were used to direct compound optimization. Compounds with superior in vitro activity and in vivo pharmacokinetic properties were then tested for in vivo antitumor efficacy in patient derived xenograft (PDX) tumor models.
Results: WX008 was identified as a potent PI3K inhibitor with PI3Kα/mTOR IC50 of 0.07 nM/233 nM (selectivity 3328×) and superior MCF-7 cellular (p-AktS473) activity (IC50 of 5.91 nM). For its excellent pharmacokinetic properties WX008 was evaluated for in vivo antitumor efficacy. As results, WX008 displayed equivalent efficacy at much lower dose than BKM-120 in several PDX tumor models (Table 1).
Table 1 In vivo efficacy of BKM-120 and WX008
Cmpd_IDBKM-120WX008CO-04-0032 PDX72% TGI @30 mpk86% TGI @8 mpkST-02-0013 PDX50% TGI @8 mpk 77% TGI @15 mpk53% TGI @4 mpk 90% TGI @8 mpkLU-01-0010 PDX74% TGI @30 mpk74% TGI @8 mpk Conclusions: WX008 is a novel potent pan-PI3K inhibitor with high selectivity over mTOR and inhibits tumor growth in several PDX tumor models. Citation Format: Tao Yu, Lingwei Kong, Yong Wang, Peipei Jiang, Zhe min Rong, Chang jun Wang, Jing jie Huang, Dan Yao, Yu xin Qin, Cheng de Wu, Shu hui Chen, Xin Tian, Fei Liu, Ping Dong, Zhi Lin Chen. Novel pan-PI3K inhibitor WX008 demonstrates significant antitumor efficacy in three xenograft tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5453.
Abstract 5458: Antiproliferative activity of a novel 8-hydroxyquinoline ruthenium II complex against human breast cancer cell lines
Authors: Khalifa Amr M. , Sultan Ahmed S. 
Published: August 2018

Abstract
Ruthenium (Ru) complexes are recognized as the most perspective chemotherapeutic agents available, because of their low general toxicity and variety of modes of action. Ru(II)-based complexes show a higher tendency for ligand exchange reactions and therefore interact with target molecules more rapidly and there cytotoxicity often correlates with the DNA binding ability. The present study was aimed to test the anti-tumor effect of a new formulated ruthenium (II) complex Bis(quinolin-8-olato)bis(triphenylphosphine)ruthenium(II) complex (Ru(quin)2) that was prepared by reaction of the precursor RuCl2(PPh3)3 with Quinolin-8-ol on two human breast cancer cell lines, estrogen receptor-positive (ER+), T-47D, and MDA-MB-231, triple negative breast cancer cell line that display different phenotypic and differentiation patterns ranging from poor to high differentiation.
The two tested breast cancer cells showed a significant growth inhibition after 24 h of treatment, but the response of T47D cells to treatment was much higher than that of MDA-MB231 cells. In contrast, the near-normal mammary cell lines, MCF-10A, showed no response to Ru(quin)2 at higher doses. In tested cells, Ru(quin)2 significantly inhibited cells proliferation after 24 h treatment as evaluated by MTT assay, cell morphology alteration, and clonogenic assay. In addition, treated cells showed significant morphological and biochemical signs of apoptosis induction through releasing of histone protein, caspase-3 activation, and G2/M phase cell cycle arrest in a dose-dependent manner compared to control.
In T47D cells, Ru(quin)2 significantly downregulated protein expression of STAT3, and S6 kinase1 (S6K1) and significantly upregulated LC3B expression protein, a hallmark of autophagosomes formation, after 24 h of treatment as detected by western blot analysis and immunocytochemistry.
Furthermore, in established xenograft tumor model of MDA-MB231 cells in nude mice, the growth of MDA-MB231 tumors that treated with Ru(quin)2 was inhibited by 46.88% compared to the mock group (t=2.821, P&lt;0.05) after three weeks of treatment. Besides, there was no cytotoxicity on both liver and kidney function tests. Collectively, our observations support the anticancer role of the novel Ru(II)- macrocyclic complex that might be through apoptosis and autophagy induction in human breast cancer cell lines.
Citation Format: Amr M. Khalifa, Ahmed S. Sultan. Antiproliferative activity of a novel 8-hydroxyquinoline ruthenium II complex against human breast cancer cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5458.
Abstract 5468: Neratinib significantly inhibits responses to androgen in human prostate cancer cells
Authors: Dart Dafydd A. , Lalani Alshad S. , Avogadri-Connors Francesca , Bryce Richard , Jiang Wen G. 
Published: August 2018

Abstract
Background: Prostate cancer (PCa) is the most commonly diagnosed male cancer in the Western world. Tumor growth is initially androgen dependent - and driven by the androgen receptor (AR). The mainstays of prostate cancer treatment are androgen ablation and antiandrogen treatment, which block AR signalling. However, PCa often relapses to an androgen- independent disease. Androgens can transactivate genes directly via the AR-mediated transcription factor and indirectly via less well understood signal transduction pathways. These signal transduction pathways become increasingly relevant as prostate cancer cells progress to anti-androgen resistance, with HER2 being associated with higher relapse rates. Neratinib is an orally available tyrosine kinase inhibitor that irreversibly binds and inhibits EGFR, HER2 and HER4 receptor tyrosine kinases. This study aimed to examine the effect of neratinib on androgen signalling and on the expression of androgen-regulated genes in prostate cancer cells.
Methods: Changes in protein phosphorylation after androgen treatment of hormonally starved prostate cancer cells (LNCaP) was assessed using protein microarrays (Kinexus, Canada). Changes in gene expression after neratinib or androgen treatment were ascertained using AmpliSseq® technology or standard qPCR, and analysed via IPA Ingenuity software.
Results: Androgen treatment of hormonally starved prostate cancer cells (LNCaP) caused phosphorylation of several members of the signal transduction cascade including HER2 and Src within 2 hours, indicating a role for HER2 in rapid androgen signalling. Additionally, from over 1000 genes upregulated by androgen treatment (&gt;2fold within 2 hours), 87% showed downregulation with neratinib treatment. Ingenuity pathway analysis indicated that STAT3, ETS-family and NF-κB transcription factors may be responsible for the rapid androgen-induced gene upregulation observed, and that these pathways were inhibited by neratinib treatment. Q-Quantitative PCR analysis of PSA expression in LNCaP cells stimulated with androgen in the presence of increasing concentrations of neratinib resulted in a dose-dependent inhibition of androgen activity.
Conclusions: These results show that neratinib is able to inhibit the responses of prostate cancer cells to androgens, and that a strong potential signaling cross-talk exists between the androgen receptor and the certain signal transduction pathways - pathways known to be involved in the progression of androgen-independent prostate cancer.
Citation Format: Dafydd A. Dart, Alshad S. Lalani, Francesca Avogadri-Connors, Richard Bryce, Wen G. Jiang. Neratinib significantly inhibits responses to androgen in human prostate cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5468.