Deciphering the genomic and lncRNA landscapes of aerobic glycolysis identifies potential therapeutic targets in pancreatic cancer.
作者： Li-Li Zhu , Zheng Wu , Rong-Kun Li , Xin Xing , Yong-Sheng Jiang
DOI: 10.7150/IJBS.49243
关键词: Warburg effect 、 Gene silencing 、 Pancreatic cancer 、 Biology 、 Anaerobic glycolysis 、 Cancer cell 、 Cancer research 、 KRAS 、 Phenotype 、 Glycolysis
摘要: Aerobic glycolysis, also known as the Warburg effect, is emerged a hallmark of most cancer cells. Increased aerobic glycolysis closely associated with tumor aggressiveness and predicts poor prognosis. Pancreatic ductal adenocarcinoma (PDAC) characterized by prominent genomic aberrations increased glycolytic phenotype. However, detailed molecular events implicated in PDAC are not well understood. In this study, we performed comprehensive characterization using multidimensional ''omic'' data from The Cancer Genome Atlas (TCGA). Detailed analysis 89 informative tumors identified substantial copy number variations (MYC, GATA6, FGFR1, IDO1, SMAD4) mutations (KRAS, SMAD4, RNF43) related to glycolysis. Moreover, integrated transcriptional profiles revealed many differentially expressed long non-coding RNAs involved Loss-of-function studies showed that LINC01559 UNC5B-AS1 knockdown significantly inhibited capacity cells reduced glucose uptake, lactate production, extracellular acidification rate. genetic silencing suppressed growth resulted alterations several signaling pathways, such TNF pathway, IL-17 misregulation cancer. Notably, high expression predicted patient prognosis correlated maximum standard uptakevalue (SUVmax) patients who received preoperative 18F-FDG PET/CT. Taken together, our results decipher glycolysis-associated variations, mutations, lncRNA landscapes PDAC. These findings improve knowledge mechanism may have practical implications for precision therapy.
sci-hub.st 参考文章(33)
Lola Rahib, Benjamin D. Smith, Rhonda Aizenberg, Allison B. Rosenzweig, Julie M. Fleshman, Lynn M. Matrisian, Projecting Cancer Incidence and Deaths to 2030: The Unexpected Burden of Thyroid, Liver, and Pancreas Cancers in the United States Cancer Research. ,vol. 74, pp. 2913- 2921 ,(2014) , 10.1158/0008-5472.CAN-14-0155
Nicola Waddell, Marina Pajic, Ann-Marie Patch, David K Chang, Karin S Kassahn, Peter Bailey, Amber L Johns, David Miller, Katia Nones, Kelly Quek, Michael CJ Quinn, Alan J Robertson, Muhammad ZH Fadlullah, Tim JC Bruxner, Angelika N Christ, Ivon Harliwong, Senel Idrisoglu, Suzanne Manning, Craig Nourse, Ehsan Nourbakhsh, Shivangi Wani, Peter J Wilson, Emma Markham, Nicole Cloonan, Matthew J Anderson, J Lynn Fink, Oliver Holmes, Stephen H Kazakoff, Conrad Leonard, Felicity Newell, Barsha Poudel, Sarah Song, Darrin Taylor, Nick Waddell, Scott Wood, Qinying Xu, Jianmin Wu, Mark Pinese, Mark J Cowley, Hong C Lee, Marc D Jones, Adnan M Nagrial, Jeremy Humphris, Lorraine A Chantrill, Venessa Chin, Angela M Steinmann, Amanda Mawson, Emily S Humphrey, Emily K Colvin, Angela Chou, Christopher J Scarlett, Andreia V Pinho, Marc Giry-Laterriere, Ilse Rooman, Jaswinder S Samra, James G Kench, Jessica A Pettitt, Neil D Merrett, Christopher Toon, Krishna Epari, Nam Q Nguyen, Andrew Barbour, Nikolajs Zeps, Nigel B Jamieson, Janet S Graham, Simone P Niclou, Rolf Bjerkvig, Robert Grützmann, Daniela Aust, Ralph H Hruban, Anirban Maitra, Christine A Iacobuzio-Donahue, Christopher L Wolfgang, Richard A Morgan, Rita T Lawlor, Vincenzo Corbo, Claudio Bassi, Massimo Falconi, Giuseppe Zamboni, Giampaolo Tortora, Margaret A Tempero, Royal North Shore Hospital Samra Jaswinder S. 39 Gill Anthony J. 39 Pavlakis Nick 39 Guminski Alex 39 Toon Christopher 39, Bankstown Hospital Asghari Ray 40 Merrett Neil D. 40 Pavey Darren 40 Das Amitabha 40, Liverpool Hospital Cosman Peter H. 41 Ismail Kasim 41 O’Connnor Chelsie 41, Westmead Hospital Lam Duncan McLeod Vincent W. 42 42 Pleass Henry C. 42 Richardson Arthur 42 James Virginia 42, Royal Prince Alfred Hospital Kench James G. 43 Cooper Caroline L. 43 Joseph David 43 Sandroussi Charbel 43 Crawford Michael 43 Gallagher James 43, Fremantle Hospital Texler Michael 44 Forest Cindy 44 Laycock Andrew 44 Epari Krishna P. 44 Ballal Mo 44 Fletcher David R. 44 Mukhedkar Sanjay 44, Sir Charles Gairdner Hospital Spry Nigel A. 45 DeBoer Bastiaan 45 Chai Ming 45, St John of God Healthcare Zeps Nikolajs 46 Beilin Maria 46 Feeney Kynan 46, Royal Adelaide Hospital Nguyen Nan Q. 47 Ruszkiewicz Andrew R. 47 Worthley Chris 47 Tan Chuan P. 47 Debrencini Tamara 47, Flinders Medical Centre Chen John 48 Brooke-Smith Mark E. 48 Papangelis Virginia 48, Greenslopes Private Hospital Tang Henry 49 Barbour Andrew P. 49, Envoi Pathology Clouston Andrew D. 50 Martin Patrick 50, Princess Alexandria Hospital O’Rourke Thomas J. 51 Chiang Amy 51 Fawcett Jonathan W. 51 Slater Kellee 51 Yeung Shinn 51 Hatzifotis Michael 51 Hodgkinson Peter 51, Austin Hospital Christophi Christopher 52 Nikfarjam Mehrdad 52 Mountain Angela 52, Victorian Cancer Biobank, Johns Hopkins Medical Institutes Eshleman James R. 54 Hruban Ralph H. 54 Maitra Anirban 54 Iacobuzio-Donahue Christine A. 54 Schulick Richard D. 54 Wolfgang Christopher L. 54 Morgan Richard A 54 Hodgin Mary 54, ARC-Net Centre for Applied Research on Cancer Scarpa Aldo 55 Lawlor Rita T. 55 Beghelli Stefania 55 Corbo Vincenzo 55 Scardoni Maria 55 Bassi Claudio 55, University of California, San Francisco Tempero Margaret A. 56, University of Glasgow Biankin Andrew V. 36 37 57 Grimmond Sean M. 37 38 Chang David K. 36 37 57 Musgrove Elizabeth A. 37 Jones Marc D. 36 37 Nourse Craig 37 38 Jamieson Nigel B. 37 57 Graham Janet S. 37 57, Greater Glasgow & Clyde National Health Service Biankin Andrew V. 36 37 57 Chang David K. 36 37 57 Jamieson Nigel B. 37 57 Graham Janet S. 37 57 Oien Karen 37 57 Hair Jane 57, None, Whole genomes redefine the mutational landscape of pancreatic cancer. Nature. ,vol. 518, pp. 495- 501 ,(2015) , 10.1038/NATURE14169
Chi V. Dang, MYC on the Path to Cancer Cell. ,vol. 149, pp. 22- 35 ,(2012) , 10.1016/J.CELL.2012.03.003
Rob A. Cairns, Isaac S. Harris, Tak W. Mak, Regulation of cancer cell metabolism Nature Reviews Cancer. ,vol. 11, pp. 85- 95 ,(2011) , 10.1038/NRC2981
Haoqiang Ying, Alec C. Kimmelman, Costas A. Lyssiotis, Sujun Hua, Gerald C. Chu, Eliot Fletcher-Sananikone, Jason W. Locasale, Jaekyoung Son, Hailei Zhang, Jonathan L. Coloff, Haiyan Yan, Wei Wang, Shujuan Chen, Andrea Viale, Hongwu Zheng, Ji-hye Paik, Carol Lim, Alexander R. Guimaraes, Eric S. Martin, Jeffery Chang, Aram F. Hezel, Samuel R. Perry, Jian Hu, Boyi Gan, Yonghong Xiao, John M. Asara, Ralph Weissleder, Y. Alan Wang, Lynda Chin, Lewis C. Cantley, Ronald A. DePinho, Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism Cell. ,vol. 149, pp. 656- 670 ,(2012) , 10.1016/J.CELL.2012.01.058
M. G. Vander Heiden, L. C. Cantley, C. B. Thompson, Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation Science. ,vol. 324, pp. 1029- 1033 ,(2009) , 10.1126/SCIENCE.1160809
X.-g. Mao, X.-y. Xue, L. Wang, X. Zhang, M. Yan, Y.-y. Tu, W. Lin, X.-f. Jiang, H.-g. Ren, W. Zhang, S.-j. Song, CDH5 is specifically activated in glioblastoma stemlike cells and contributes to vasculogenic mimicry induced by hypoxia. Neuro-oncology. ,vol. 15, pp. 865- 879 ,(2013) , 10.1093/NEUONC/NOT029
Douglas Hanahan, Robert A. Weinberg, Hallmarks of cancer: the next generation. Cell. ,vol. 144, pp. 646- 674 ,(2011) , 10.1016/J.CELL.2011.02.013
Yvonne Tay, John Rinn, Pier Paolo Pandolfi, The multilayered complexity of ceRNA crosstalk and competition Nature. ,vol. 505, pp. 344- 352 ,(2014) , 10.1038/NATURE12986
Panagiotis Papageorgis, Kuanghung Cheng, Sait Ozturk, Yi Gong, Arthur W. Lambert, Hamid M. Abdolmaleky, Jin-Rong Zhou, Sam Thiagalingam, Smad4 Inactivation Promotes Malignancy and Drug Resistance of Colon Cancer Cancer Research. ,vol. 71, pp. 998- 1008 ,(2011) , 10.1158/0008-5472.CAN-09-3269