Genomic and functional characterizations of phosphodiesterase subtype 4D in human cancers

Lin D.-C.; Xu L.; Ding L.-W.Sharma A.Liu L.-Z.Yang H.Tan P.Vadgama J.Karlan B.Y.Lester J.Urban N.Schummer M.Doan N.Said J.W.Sun H.Walsh M.Thomas C.J.Patel P.Yin D.Chan D.Phillip Koeffler H.

首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Genomic and functional characterizations of phosphodiesterase subtype 4D in human cancers

【24h】

Genomic and functional characterizations of phosphodiesterase subtype 4D in human cancers

机译：Genomic and functional characterizations of phosphodiesterase subtype 4D in human cancers

获取原文

获取原文并翻译 | 示例

掌桥外文数据库（机构版） >>

开具论文收录证明 >>

文献代查 >>

页面导航

摘要
著录项
相关主题

摘要

Discovery of cancer genes through interrogation of genomic dosage is one of the major approaches in cancer research. In this study, we report that phosphodiesterase subtype 4D(PDE4D) gene was homozygously deleted in 198 cases of 5,569 primary solid tumors (3.56), with most being internal microdeletions. Unexpectedly, the microdeletions did not result in loss of their gene products. Screening PDE4D expression in 11 different types of primary tumor samples (n = 165) with immunohistochemistry staining revealed that its protein levels were up-regulated compared with corresponding nontransformed tissues. Importantly, depletion of endogenous PDE4D with three independent shRNAs caused apoptosis and growth inhibition in multiple types of cancer cells, including breast, lung, ovary, endometrium, gastric, and melanoma, which could be rescued by reexpression of PDE4D. We further showed that antitumor events triggered by PDE4D suppression were lineage-dependently associated with Bcl-2 interacting mediator of cell death (BIM) induction and microphthalmia-associated transcription factor (MITF) downregulation. Furthermore, ectopic expression of the PDE4D short isoform, PDE4D2, enhanced the proliferation of cancer cells both in vitro and in vivo. Moreover, treatmentofcancer cells withaunique specific PDE4D inhibitor, 26B, triggered massive cell death and growth retardation. Notably, these antineoplastic effects induced by either shRNAs or small molecule occurred preferentially in cancer cells but not in nonmalignant epithelial cells. These results suggest that although targeted by genomic homozygous microdeletions, PDE4D functions as a tumor-promoting factor and represents a unique targetable enzyme of cancer cells.

著录项

来源
《Proceedings of the National Academy of Sciences of the United States of America》 |2013年第15期|6109-6114|共6页
作者
Lin D.-C.; Xu L.; Ding L.-W.Sharma A.Liu L.-Z.Yang H.Tan P.Vadgama J.Karlan B.Y.Lester J.Urban N.Schummer M.Doan N.Said J.W.Sun H.Walsh M.Thomas C.J.Patel P.Yin D.Chan D.Phillip Koeffler H.;
展开▼
作者单位

Women's Cancer Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States;

Fred Hutchinson Cancer Research Center, Seattle, WA 98109, United States;

Santa Monica University of California-Los Angeles, Medical Center, Los Angeles, CA 90404, United StatesNational Institutes of Health (NIH), Chemical Genomics Center, National Center for Advancing Translational Sciences, NIH, Bethesda, MD 20892, United StatesNational University Cancer Institute, National University Hospital, Singapore 117599, SingaporeBasic Science Program, SAIC-Frederick, Inc., Chemical Biology Laboratory, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, United StatesKey Laboratory of Malignant Tumor Gene Regulation and Target Therapy, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, ChinaDivision of Hematology/Oncology, Cedars-Sinai Medical Center, University of California, Los Angeles, CA 90048, United StatesCancer Science Institute of Singapore, National University of Singapore, Singapore 117599, SingaporeCharles R. Drew University of Medicine and Science, Los Angeles, CA 90059, United States;

展开▼
收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种英语
中图分类自然科学总论;
关键词

Genomic and functional characterizations of phosphodiesterase subtype 4D in human cancers

摘要

著录项

相关主题

期刊订阅