Mutations in foregut SOX2^+ cells induce efficient proliferation via CXCR2 pathway  

作　　者：Tomoaki Hishida Eric Vazquez-Ferrer Yuriko Hishida-Nozaki Ignacio Sancho-Martinez Yuta Takahashi Fumiyuki Hatanaka Jun Wu Alejandro Ocampo Pradeep Reddy Min-Zu Wu Laurie Gerken Reuben J. Shaw Concepcion Rodriguez Esteban Christopher Benner Hiroshi Nakagawa Pedro Guillen Garcia Estrella Nunez Delicado Antoni Castells Josep M. Campistol Guang-Hui Liu Juan Carlos Izpisua Belmonte 

机构地区：[1]Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA [10]Advaneed Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing 100053, China [11]National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China [12]University of the Chinese Academy of Sciences, Beijing 100049, China [13]Insitute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China [14]Beijing Institute for Brain Disorder, Beijing 100069, China [2]Universidad Catolica, San Antonio de Murcia, Campus de los Jeronimos 135, Guadalupe 30107, Spain [3]Molecular and Cell Biology Laboratory, Dulbecco Center for Cancer Research, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA [4]Howard Hughes Medical Institute, Dulbecco Center for Cancer Research, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA [5]Integrative Genomics Core, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA [6]Division of Gastroenterology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA [7]Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA [8]Department of Traumatology and Research Unit, Clinica CEMTRO, Av. Ventisquero de la Condesa, 42, Madrid 28035, Spain [9]Gastroenterology Department, Hospital Clinic, University of Barcelona, IDIBAPS, CIBEREHD, Barcelona 08036, Spain

出　　处：《Protein & Cell》2019年第7期485-495,共11页蛋白质与细胞（英文版）

基　　金：National Key Research and Development Program of China (2015CB964800);the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA16010100);the National Natural Science Foundation of China (81625009, 81330008, 91749202, 81861168034);Program of Beijing Municipal Science and Technology Commission (Z151100003915072);Advanced Innovation Center for Human Brain Protection (117212, 3500-1192012);Beijing Municipal Commissio n of Health and Family Planning PXM2018_026283_000002);Work in the laboratory of J.C.I.B was supported by a Cancer Center Support Grant, the G. Harold and Leila Y, Mathers Charitable Foundation, The Leona M. and Harry B. Helmsley Charitable Trust (2012-PG-MED002);The Moxie Foundation, Fundacion Dr. Pedro Guillen and Universidad Catdlica San Antonio de Murcia (UCAM). T.H. was supported by a Pioneer Fund Postdoctoral Scholar Award, Nomis Fellowship;Uehara Memorial Foundation research fellowship.

摘　　要：Identification of the precise molecular pathways involved in oncogene-induced transformation may help us gain a better understanding of tumor initiation and promotion. Here, we demonstrate that SOX2^+ foregut epithelial cells are prone to oncogenic transformation upon mutagenic insults, such as Kras^G12D and p53 deletion. GFP-based lineage-tracing experiments indicate that SOX2^+ cells are the cells-of-origin of esophagus and stomach hyperplasia. Our observations indicate distinct roles for oncogenic KRAS mutation and P53 deletion. p53 homozygous deletion is required for the acquisition of an invasive potential, and Kras^G12D expression, but not p53 deletion, suffices for tumor formation. Global gene expression analysis reveals secreting factors upregulated in the hyperplasia induced by oncogenic KRAS and highlights a crucial role for the CXCR2 pathway in driving hyperplasia. Collectively, the array of genetic models presented here demonstrate that stratified epithelial cells are susceptible to oncogenic insults, which may lead to a better understanding of tumor initiation and aid in the design of new cancer therapeutics.

关 键 词：SOX2 tumor CXCR2 stratified EPITHELIA 

分 类 号：Q[生物学]