北京大学基础医学院

院长论坛

报告题目：Inflammation and Cancer: Interweaving MicroRNA, Innate Immune and p53 Networks

报 告 人：Curtis C Harris, M.D.,

                     Chief ,Laboratory of Human Carcinogenesis

                     National Cancer Institute, NIH,  US

时    间： 2011年3月24日 （星期四）下午3:00

地    点：医学部逸夫教学楼409

主 持 人：尹玉新 教授

报告人简介：

Dr. Curtis Harris is a physician-scientist with a wide range of scientific interests and accomplishments spanning molecular genetics of human cancer to molecular epidemiology of human cancer. His scientific contributions to the fields of molecular carcinogenesis, molecular epidemiology of human cancer, and clinical cancer research have placed him at the international forefront. His research on environmental carcinogenesis, cancer risk factors and molecular genetics of human cancer, p53 and microRNA pathways in cancer prognosis and therapy has significantly impacted the field of cancer risk assessment and our understanding of human cancer.

Dr. Harris has received numerous honors throughout his distinguished career, including the Alton Ochsner Award relating Smoking and Health (American College of Physicians), Deichmann Award (International Union of Toxicology), Charles Heidelberger Award (International Society of Gastroenterological Carcinogenesis) and the Distinguished Service Medal (the highest honor of the U.S. Public Health Service), NCI Outstanding Mentor Award, an honorary Ph.D. from Nippon Medical School, and the American Association of Cancer Research (AACR)-Princess Takamatsu Award. He has published more than 500 journal articles, 100 book chapters, 10 books, and holds more than 25 patents in the field of advanced biotechnology that are owned by the U.S. Government. He also serves as Editor-in-Chief for the journal Carcinogenesis and has held or currently holds elected offices in scholarly societies and non-profit foundations including the AACR, the International Society of Differentiation, the Keystone Symposia on Molecular and Cellular Biology, and the Aspen Cancer Conference.

Dr. Harris is the Chief of the Laboratory of Human Carcinogenesis and Chief of its Molecular Genetics and Carcinogenesis Section at the National Cancer Institute. He also is Clinical Professor of Medicine and Oncology at Georgetown University School of Medicine.

本期论坛简介：

Inflammation and Cancer: Interweaving microRNA, Free Radical, Innate Immune and p53 Networks

  Kaori Fujita1, Izumi Horikawa1, Aaron Schetter1, Yiqiang Zhao1, Suet Y. Leung2, Yang Ke3, and Curtis C. Harris1

1Laboratory of Human Carcinogenesis, CCR, NCI, Bethesda, MD 20892, USA; 2The University of Hong Kong, Queen Mary Hospital, Hong Kong; 3Peking University, Beijing, China

Infection and chronic inflammation contribute to the etiology and pathogenesis of about 1 in 4 of all cancer cases. Mediators of the inflammatory response, e.g., cytokines, free radicals, prostaglandins, non-coding RNAs, and growth factors, can induce genetic and epigenetic changes including point mutations in tumor suppressor genes, DNA methylation and post-translation modifications, causing alterations in critical pathways responsible for maintaining the normal cellular homeostasis and leading to the development and progression of cancer. IL-6 and IL-8 cooperate with microRNA in the induction of cellular senescence in benign tumors and as autocrine growth factors in carcinoma.

Cellular senescence is also a tumor suppressor mechanism of p53. We are studying the molecular mechanisms of cellular senescence in normal and malignant human cells and the role of the telomeric multiprotein complex, shelterin, that includes TRF2 and POT1. Our ongoing studies have revealed that p53 and its endogenous isoforms regulate both specific microRNAs and TRF2 expression as mechanisms of replicative senescence. In addition, POT1 isoforms are functionally diverse in both maintaining telomeric integrity and preventing p53-dependent senescence induced by telomeric shortening. A switch in the expression patterns of p53 isoforms Δ133Np53 and p53beta can cause cellular senescence in vitro and is also associated with the transition of benign to malignant human colon tumors in vivo. A positive feedback between p53 and TRF2 during telomere-damage signaling and cellular senescence has been discovered.

Expression of microRNAs and inflammatory genes are biomarkers of cancer risk, diagnosis, prognosis, and therapeutic outcome. We are especially interested in the interaction of the innate immune pathway with environmental tobacco smoking in lung cancer risk and the interaction of inflammatory cytokines, p53 isoforms, and microRNAs as prognostic classifiers of early stage lung, esophageal, and colon cancer and their functional role in the development of micrometastases.