2^nd International Conference on Cancer Genetics and Epigenetics November 12-13, 2018 | Radisson Hotel Narita | Tokyo, Japan

WEN-REN WU is a PhD student in the Institute of Biomedical Sciences at National Sun Yat-sen University. He is a molecular biologist. His research focus on cancer biology. He has published more than 15 papers in journals.

Purpose: Urinary bladder urothelial carcinoma (UBUC) is a common malignant disease in developed countries. Cell cycle dysregulation resulting in uncontrolled cell proliferation has been associated with UBUC development. This study aimed to explore the roles of TMCO1 in UBUCs. Experimental Design: Data mining, branched DNA assay, immunohistochemistry, xenograft, cell culture, quantitative RT-PCR, immunoblotting, stable and transient transfection, lentivirus production and stable knockdown, cell cycle, cell viability and proliferation, soft agar, wound healing, transwell migration and invasion, co-immunoprecipitation, immunocytochemistry, AKT serine/threonine kinase (AKT) activity assays and site-directed mutagenesis were used to study TMCO1 involvement in vivo and in vitro. Results: Data mining identified that the TMCO1 transcript was downregulated during the progression of UBUCs. In distinct UBUC-derived cell lines, changes in TMCO1 levels altered the cell-cycle distribution, cell viability, cell proliferation, colony formation and modulated the AKT pathway. TMCO1 recruited the PH domain and leucine rich repeat protein phosphatase 2 (PHLPP2) to dephosphorylate pAKT1(serine 473) (S473). Mutagenesis at S60 of the TMCO1 protein released TMCO1-induced cell cycle arrest and restored the AKT pathway in BFTC905 cells. Stable TMCO1 (wild-type) overexpression suppressed, while T33A and S60A mutants recovered, tumor size in xenograft mice. Conclusions: Clinical associations, xenograft mice and in vitro indications provide solid evidence that the TMCO1 gene is a novel tumor suppressor in UBUCs. TMCO1 dysregulates cell cycle progression via suppression of the AKT pathway, and S60 of the TMCO1 protein is crucial for its tumor suppressor roles.

Dr. Shin received his PhD in 1989 at the University of Tokyo, and worked as a postdoc fellow and a research associate at NCI, USA. He was nominated as a chief of National Research Lab and a PM of National Cancer-Aging Research Program, and served as a Chair for Korean Assoaiciation of Genrontology and now serves as a professor and director of Aging-Cancer Center of Dankook Univ. He provided first evidence that p53 can induce senescence in human tumor and suggested a novel cancer therapy to induce senescence in human tumors.

We previously reported the anti-apoptosis functions of a novel anti-apoptotic E3 ubiquitin ligase, AREL1, which ubiquitinates and promotes the proteasome-dependent degradation of cytosolic forms of IAP antagonists. In the present study, we identified AREL1 as an oncogene that targets PHD2. Elevated expression of AREL1 was detected in 65% of randomly selected human lung and colon cancer cell lines and also found in 42% of 424 human tumor tissues. Furthermore, AREL1-trangenic mice enhanced chemical-induced carcinogenesis as compared to wild-type ones. The oncogenic function of AREL1 led us to screen AREL1 target proteins involving in oncogenesis. PHD2, which regulates angiogenesis and tumor development, was identified as an AREL1-interacting protein from a yeast two-hybrid screen. PHD2 was down-regulated by AREL1. This down-regulation was blocked by either a potent proteasome inhibitor, MG132 or expression of an E3 activity-deficient mutant form of AREL1, AREL1-A790A. Taken together with that ubiquitination of endogenous PHD2 was enhanced by AREL1, these results indicate that AREL1 ubiquitinates and promotes a proteasome-dependent degradation of PHD2. Tumor angiogenesis of xenograft of AREL1-expressing cells was enhanced in association with down-regulation of PHD2 and up-regulation of HIF-1. Furthermore, endothelial cell tube formation assay revealed enhanced release of pro-angiogenic factors from AREL1-expressing cells. Therefore, these results suggest that elevated expression of AREL1 contributes to tumorigenesis through targeting PHD2 as well as IAP antagonists, thus blocking apoptosis and enhancing angiogenesis.

Seugneun Lee is pursuing her Masters in Pharmacy from Duksung Women’s University of Pharmacy. She has received her Bachelor’s degree in Chemistry at Duksung Women’s University, Seoul, South Korea in 2016.

Tumor-Associated Macrophages (TAMs) are major components of tumor microenvironment that promote invasion and metastasis of cancer cells. In this study, we investigated the eff ect of TAMs on phenotypic conversion of non-neoplastic MCF10A human breast epithelial cells using an indirect co-culture system. Co-culture with TAMs induced epithelial-tomesenchymal transition, invasive phenotype, and MMP-9 up-regulation in MCF10A cells. Comparative proteomic analysis revealed that Endoplasmic Reticulum Oxidoreductase (ERO)1-α was increased in MCF10A cells co-cultured with TAMs compared to that in mono-cultured cells. ERO1-α was crucial for TAMs induced invasive phenotype and MMP-9 upregulation involving transcription factors c-Fos and c-Jun. Cytokine array analysis showed that levels of interleukin (IL)-6, C-X-C motif ligand (CXCL)1, C-C motif ligand (CCL)2, Growth-Regulated Protein (GRO), IL-8 and granulocyte-macrophage colonystimulating factor (GM-CSF) were increased in conditioned media of co-cultured cells. Among these cytokines increased in conditioned media of co-cultured cells, CCL2 was secreted from TAMs, leading to induction of ERO1-α, MMP-9 up-regulation and invasiveness in MCF10A cells. Our fi ndings elucidated a molecular mechanism underlying the aggressive phenotypic change of non-neoplastic breast cells by co-culture with TAMs, providing useful information for prevention or treatment of recurrent breast cancer.

Gordon Moffat has his experience if Life Sciences with an Honors in Biology with training in Radiology. His passion for science and interest in microbiology lead him to pursue and obtain a Doctor of Medicine. Currently he is working at the State University of New York Brooklyn Health Sciences Center in Internal Medicine and the forthcoming Medicine Chief Resident. His professional interests include: Medical Oncology, Hospice and Palliative Medicine, and Geriatric Medicine. He is currently working on research projects at Memorial Sloan Kettering Cancer Center in Manhattan, New York that are expected to be published. He is also a candidate for the Alpha Omega Alpha Honor Medical Society Postgraduate Fellowship Award.

Purpose: Identifying mutations in breast cancer genes (BRCA1, BRCA2, PABL2) has important clinical implications on a woman's lifetime susceptibility to breast cancer development. Nearly 10% of immigrants to the United States come from the Caribbean and few studies exist that examine breast cancer gene mutations in African-Caribbean women with existing breast cancer. The purpose is to specifically describe breast cancer epidemiology statistics and review prevalence of BRCA mutations in this cohort. Methods: Epidemiologic data on select Caribbean countries and USA was abstracted from GLOBOCAN 2012, a database of estimated global cancer statistics produced by the International Agency for Research on Cancer and World Health Organization. A Literature Search was also conducted through PubMed database using following terms: Caribbean , (familial breast cancer), (hereditary breast cancer), and (BRCA breast cancer) that was subsequently narrowed to epidemiologic relevance resulting in five citations. Conclusions: The GLOBOCAN 2012 data provides an estimate of breast cancer incidence and mortality in Caribbean women. This study summarizes the known prevalence of BRCA1/2 and PALB2 breast cancer gene mutations in select Caribbean cohorts. This is critical as part of a formal genetic risk assessment and counseling of patients with breast cancer, particularly in areas that serve a Caribbean population. Further research and understanding the contributions of inherited gene mutations will guide the optimal health policy in breast cancer screening and risk management.

Jiranan Chotitumnavee achieved her Doctor of Pharmacy degree from the Faculty of Pharmaceutical Science, Khon Kaen University, Thailand in 2016. In that time, she had an opportunity to be a research internship at National Synchrotron Radiation Research Center in Hsinchu, Taiwan for three months operating a project at IR beamline end-station. After graduation, she worked as a teacher assistant at Mahidol University, Thailand. Then, she got a scholarship to be a research student, and currently, she is the first-year PhD student in the graduate school of medical science, Kyoto Prefectural University of Medicine.

Histone lysine demethylases (KDMs) play an essential role in the demethylation process of histone lysine residues by the oxidative mechanism. Two families of histone lysine demethylases have been identified based on their structure and catalytic reaction, which are flavin-dependent lysine demethylases and Jumonji C-containing (JmjC) lysine demethylases. The JmjC lysine demethylases are Fe(II)/α-ketoglutarate (αKG)-dependent oxygenases. KDM5A, an isoform of the JmjC lysine demethylases was chosen as a target KDM in this work. KDM5A plays a pivotal role in removing the di-and tri-methylation mark of lysine 4 on histone 3 (H3K4). KDM5A is overexpressed in several human cancer cells including lung, gastric, breast, and liver cancers. KDM5A has been reported to be involved in tumor formation, metastasis and advance of drug resistance in human cancers, suggesting KDM5A as a potential target for cancer treatment. In this study, we designed αKG analogues as JmjC lysine demethylase inhibitors since αKG acts as a crucial cofactor of these enzymes. The inhibitory activity of the αKG analogues was evaluated by an AlphaScreen KDM5A enzymatic assay, and western blotting analysis was performed to examine the methylation level change of H3K4 in A549 lung cancer cell lines. The results of the enzymatic assay and western blotting analysis showed that an αKG analogue inhibited KDM5A activity significantly and its ester prodrug enhanced the methylation of H3K4 in a dose-dependent manner in A549 lung cancer cell lines. Thus, the αKG analogue is a promising lead for KDM5A inhibitors.

Chiao Yun Lin has completed her PhD at the age of 29 years from Chang Gung University and postdoctoral studies from Gynecologic Cancer Research Center, Linkou Chang Gung Memorial hospital, Taiwan. She is assistant Professor of Gynecologic Cancer Research Center, Chang Gung hospital in Taiwan. She has published 25 papers in reputed journals.

Oncogenic PIK3CA mutations are common in endometrial cancers, and the PI3K/AKT/mTOR pathway is targetable by drugs. We sought to investigate whether the combination of an mTOR inhibitor, everolimus (RAD001), and an AKT inhibitor, terameprocol (M4N), exerts better antiproliferative effects in endometrial cancer. The molecular mechanisms underlying their pharmacological action were also examined. The combination of RAD001 and M4N exerted in vitro synergistic effects on cell viability, apoptosis, and expression of IGFBP2 in endometrial cancer cells. The Sp1 site on the IGFBP2 promoter was required for RAD001- and M4N-induced downregulation. IGFBP2 protein expression was higher in endometrial cancer than in the normal endometrium (P < 0.001). Furthermore, elevated IGFBP2 histoscores were significantly associated with a lower overall survival (P= 0.021). In conclusion, our in vitro results demonstrate that RAD001 and M4N exert synergistic antiproliferative effects against endometrial cancer cells, which appeared to be mediated by the inhibition of IGFBP2, a key anti-apoptotic regulator. Further clinical studies of this drug combination in patients with endometrial cancer may be warranted, especially in the presence of PIK3CA and IGFBP2 aberrations.

Fadwa M Al-Sharif has completed her PhD from the Medical School of Manchester. She was the Director of Medical Technology Department. She has published more than 25 papers in reputed journals. She has been involved in different committee in the faculty such as, Academic Affairs Committee, PhD Program Committee and Academic Accreditation Committee.

Introduction: Currently, the global prevalence of asthma and obesity is progressively rising. However, obesity is linked with systemic inflammation and altered immune system parameters. There is limited studies investigated the immuno-competence among asthmatic obese patients. Objective: This study is designed to detect the association between immune system response, inflammatory cytokines and body mass index among asthmatic Saudi patients. Subjects & Method: One hundred (100) asthmatic obese Saudi patients of both sexes; their age mean was 42.63±9.15 year and their Body Mass Index (BMI) mean was 32.42±2.96 Kg/m2 known as group A, in addition to 100 non-obese asthmatic, who were gender, age and BMI matched with study group, were enrolled in the study. Result: There was higher levels of high-sensitivity C-Reactive Protein (hsCRP), Interleukin-6 (IL-6), Tumor Necrotic Factoralpha (TNF-α), serum IgE, white blood cells count, total leukocytes count, neutrophils count, monocytes, lymphocytes count, T-lymphocytes (CD3) count and B lymphocytes (CD19) count among obese asthmatics (group A) than lean asthmatic (group B), in addition to a strong association between these parameters and body mass index in both groups. Conclusion: There is a strong association between inflammatory cytokines, immune system response and BMI among obese asthmatic patients; therefore future studies are essential to explore impact of life style modification intervention on immune system and systemic inflammation modulation.

Saba Haq is currently a PhD candidate in Hanyang University, South Korea. She is pursuing her PhD in the fi eld of deubiquitylating enzymes and their role in protein regulation. She has published articles on the intra DUB regulation as well as potential role of DUBs in regulation of various core stem cell factors.

RNA-binding protein LIN28A is oft en highly expressed in human malignant tumors and is involved in tumor metastasis and poor prognosis. Knowledge about post-translational regulatory mechanisms governing LIN28A protein stability and function is scarce. Here we investigated the role of ubiquitination and deubiquitination on LIN28A protein stability and report that LIN28A protein undergoes ubiquitination. Ubiquitin-specifi c protease 28 (USP28), a deubiquitinating enzyme, interacts with and stabilizes LIN28A protein to extend its half-life. USP28, through its deubiquitinating activity, antagonizes LIN28A protein turnover by reversing its proteasomal degradation. Our study describes the consequential impacts of USP28-mediated stabilization of LIN28A protein on enhancing cancer cell viability, proliferation and migration. Additionally, USP28 augments the LIN28A-mediated tumor progression. Overall, our data suggest that a synergistic, combinatorial approach of targeting LIN28A with USP28 would contribute to eff ective cancer therapeutics.