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MicroRNAs in cancer
S28
Abstracts / Toxicology Letters 196S (2010) S1–S36
S22-2 The role of miRNAs in PPARalpha induced hepatocellular carcinomas Y.M. Shah 1 , F.J. González 2 1
National Cancer Institute, Laboratory of Metabolism, Bethesda, MD, USA, 2 University of Michigan, Molecular & Integrative Physiology, Ann Arbor, MI, USA Studies in the last decade have demonstrated the importance of microRNAs (miRNA) in the regulation of metabolism, embryogenesis, development and oncogenesis. However, there is relatively little data of how miRNA expression is regulated. The present study demonstrates that the liganded transcription factor PPARalpha is major regulator of miRNA expression in the liver. PPARalpha, a highly enriched transcription factor in hepatocytes, is the molecular target for fibrate hypolipidemic drugs including fenofibrate (TriCor), gemfibrozil (Gemcor, Lopid), and clofibrate (Atromid-S) that are widely prescribed to lower plasma triglycerides levels. PPARalpha also regulates hepatocellular proliferation and long-term treatment of rats and mice with PPARalpha agonist induce hepatocellular carcinomas. The mechanism by which PPARalpha regulate cellular proliferation is undefined. Using genome-wide miRNA profiling the present study found several miRNAs critical in tumorigenesis to be deregulated following PPARa agonist treatment. In particular let-7C a potential tumor suppressor was down-regulated following agonist treatment. To directly investigate the role of PPARalpha in regulation of let-7C, WT and PPARalpha-null mice were treated with a PPARalpha agonist for 4-h and 2-weeks. Northern blot analysis demonstrated a suppression of let-7C miRNA following 4-h agonist treatment and 2-week sustained treatment, whereas no decrease was observed in the PPARalpha-null mice. Let-7C was shown to target c-myc via direct interaction with the 3 untranslated region of c-myc and degradation of the mRNA. Interestingly, the increase in c-myc lead to increase in the oncogenenic miRNA cluster mir-17-92, and these events did not occur in the PPARalpha-null mice. Overexpression of let-7C decreased c-myc and mir-17, and suppressed the growth of Hepa-1 cells. These observations revealed a novel let-7C signaling cascade critical for PPAR-alpha agonist-induced liver tumorigenesis and clearly demonstrate PPARalpha as a bona fide regulator of hepatic miRNA expression. doi:10.1016/j.toxlet.2010.03.127
S22-3 MicroRNAs in cancer A.H. Lund BRIC, University of Copenhagen, Denmark MicroRNAs have emerged as important regulators of many pathways central to normal development and disease. We study microRNA biology and pathobiology using several strategies including: (i) experimental identification and verification of mRNA targets, (ii) knockout mouse models, (iii) expression profiling of human cancers and cellular cancer models, and (iv) highthroughput functional screenings using libraries of pre-miRs, AntimiRs and siRNAs. Our recent advances in mapping miRNAs onto cancer-relevant pathways will be discussed. doi:10.1016/j.toxlet.2010.03.128
S23 Education and Chemical Safety in Developing Countries S23-1 Education in toxicology and chemical safety in developing countries S. Barros School of Pharmaceutical Sciences, University of São Paulo, Brazil The use of chemicals including drugs, pesticides and chemicals substances in general is increasing in developing countries as a consequence of the industrialization, the improve in medical care and increase in areas planted for crop production. This increased should be followed by well-trained toxicologists to deal with the problems that accompany this increase in the use of chemicals to promote human and environment health and safety, the main objective of Modern Toxicology. Although many developing countries have well structured graduate programs in toxicology related basic sciences as biochemistry, pharmacology, analytical chemistry, physiology, not enough graduate programs in Toxicology exist. Besides that, toxicology is not taught as a course at most of undergraduate curricula with consequent lack of interest of the students to follow a career in toxicology. Also, Toxicology is not recognized as a profession in many developing countries, and recognition and certification of Toxicologists could provide an incentive to attract students to the field. To achieve this goal, there is an increasing need in promote graduate programs in the different areas of Toxicology (Clinical, Occupational, Environmental, Risk Assessment, Regulatory, etc.). International programs between developing countries and also between developed and developing countries could in a short period of time achieve the objective of training toxicologists in developing countries around the world. doi:10.1016/j.toxlet.2010.03.130
S23-2 Reality and needs of toxicology research and education in developing countries M.F. Cavieres Faculty of Pharmacy, University of Valparaíso, United States With the exception of the United States, Canada, Japan and some European countries, toxicology is, in most countries, an underdeveloped discipline. Results of literature search in commonly used databases reflect this situation. For instance, a basic search in ISI Web of knowledge® , using toxicology as a key word, results in 13,975 entries, of which over 50% corresponds to publications authored by USA scientists. European Japanese, Canadian and Australian authors account for 44%, while Latinamerican, Asian and African authors contribute to only 6% of publications. This situation maybe due to a series of factors and lack of financial support for research is undoubtedly a major cause. Thus, poor research leads to minimum development of the field, which in turn leads to lack of interest to develop toxicology programs in universities. The creation of working networks between countries with different realities allows the exchange of knowledge and ideas that may lead to collaboration schemes. In this context, the recently created Iberoamerican Network for Toxicology and Chemical Safety (RITSQ), promotes such exchange allowing toxicologists from Spain, Portugal and Latinamerica, to come together for the enhancement of toxicology. As a first step, we have surveyed 96
Abstracts / Toxicology Letters 196S (2010) S1–S36
S22-2 The role of miRNAs in PPARalpha induced hepatocellular carcinomas Y.M. Shah 1 , F.J. González 2 1
National Cancer Institute, Laboratory of Metabolism, Bethesda, MD, USA, 2 University of Michigan, Molecular & Integrative Physiology, Ann Arbor, MI, USA Studies in the last decade have demonstrated the importance of microRNAs (miRNA) in the regulation of metabolism, embryogenesis, development and oncogenesis. However, there is relatively little data of how miRNA expression is regulated. The present study demonstrates that the liganded transcription factor PPARalpha is major regulator of miRNA expression in the liver. PPARalpha, a highly enriched transcription factor in hepatocytes, is the molecular target for fibrate hypolipidemic drugs including fenofibrate (TriCor), gemfibrozil (Gemcor, Lopid), and clofibrate (Atromid-S) that are widely prescribed to lower plasma triglycerides levels. PPARalpha also regulates hepatocellular proliferation and long-term treatment of rats and mice with PPARalpha agonist induce hepatocellular carcinomas. The mechanism by which PPARalpha regulate cellular proliferation is undefined. Using genome-wide miRNA profiling the present study found several miRNAs critical in tumorigenesis to be deregulated following PPARa agonist treatment. In particular let-7C a potential tumor suppressor was down-regulated following agonist treatment. To directly investigate the role of PPARalpha in regulation of let-7C, WT and PPARalpha-null mice were treated with a PPARalpha agonist for 4-h and 2-weeks. Northern blot analysis demonstrated a suppression of let-7C miRNA following 4-h agonist treatment and 2-week sustained treatment, whereas no decrease was observed in the PPARalpha-null mice. Let-7C was shown to target c-myc via direct interaction with the 3 untranslated region of c-myc and degradation of the mRNA. Interestingly, the increase in c-myc lead to increase in the oncogenenic miRNA cluster mir-17-92, and these events did not occur in the PPARalpha-null mice. Overexpression of let-7C decreased c-myc and mir-17, and suppressed the growth of Hepa-1 cells. These observations revealed a novel let-7C signaling cascade critical for PPAR-alpha agonist-induced liver tumorigenesis and clearly demonstrate PPARalpha as a bona fide regulator of hepatic miRNA expression. doi:10.1016/j.toxlet.2010.03.127
S22-3 MicroRNAs in cancer A.H. Lund BRIC, University of Copenhagen, Denmark MicroRNAs have emerged as important regulators of many pathways central to normal development and disease. We study microRNA biology and pathobiology using several strategies including: (i) experimental identification and verification of mRNA targets, (ii) knockout mouse models, (iii) expression profiling of human cancers and cellular cancer models, and (iv) highthroughput functional screenings using libraries of pre-miRs, AntimiRs and siRNAs. Our recent advances in mapping miRNAs onto cancer-relevant pathways will be discussed. doi:10.1016/j.toxlet.2010.03.128
S23 Education and Chemical Safety in Developing Countries S23-1 Education in toxicology and chemical safety in developing countries S. Barros School of Pharmaceutical Sciences, University of São Paulo, Brazil The use of chemicals including drugs, pesticides and chemicals substances in general is increasing in developing countries as a consequence of the industrialization, the improve in medical care and increase in areas planted for crop production. This increased should be followed by well-trained toxicologists to deal with the problems that accompany this increase in the use of chemicals to promote human and environment health and safety, the main objective of Modern Toxicology. Although many developing countries have well structured graduate programs in toxicology related basic sciences as biochemistry, pharmacology, analytical chemistry, physiology, not enough graduate programs in Toxicology exist. Besides that, toxicology is not taught as a course at most of undergraduate curricula with consequent lack of interest of the students to follow a career in toxicology. Also, Toxicology is not recognized as a profession in many developing countries, and recognition and certification of Toxicologists could provide an incentive to attract students to the field. To achieve this goal, there is an increasing need in promote graduate programs in the different areas of Toxicology (Clinical, Occupational, Environmental, Risk Assessment, Regulatory, etc.). International programs between developing countries and also between developed and developing countries could in a short period of time achieve the objective of training toxicologists in developing countries around the world. doi:10.1016/j.toxlet.2010.03.130
S23-2 Reality and needs of toxicology research and education in developing countries M.F. Cavieres Faculty of Pharmacy, University of Valparaíso, United States With the exception of the United States, Canada, Japan and some European countries, toxicology is, in most countries, an underdeveloped discipline. Results of literature search in commonly used databases reflect this situation. For instance, a basic search in ISI Web of knowledge® , using toxicology as a key word, results in 13,975 entries, of which over 50% corresponds to publications authored by USA scientists. European Japanese, Canadian and Australian authors account for 44%, while Latinamerican, Asian and African authors contribute to only 6% of publications. This situation maybe due to a series of factors and lack of financial support for research is undoubtedly a major cause. Thus, poor research leads to minimum development of the field, which in turn leads to lack of interest to develop toxicology programs in universities. The creation of working networks between countries with different realities allows the exchange of knowledge and ideas that may lead to collaboration schemes. In this context, the recently created Iberoamerican Network for Toxicology and Chemical Safety (RITSQ), promotes such exchange allowing toxicologists from Spain, Portugal and Latinamerica, to come together for the enhancement of toxicology. As a first step, we have surveyed 96