The RNA binding protein FXR1 is a new driver in the 3q26-29 amplicon and predicts poor prognosis in human cancers

被引:81
作者
Qian, Jun [1 ]
Hassanein, Mohamed [1 ]
Hoeksema, Megan D. [1 ]
Harris, Bradford K. [1 ]
Zou, Yong [1 ]
Chen, Heidi [2 ]
Lu, Pengcheng [2 ]
Eisenberg, Rosana [3 ]
Wang, Jing [4 ]
Espinosa, Allan [5 ]
Ji, Xiangming [1 ]
Harris, Fredrick T. [1 ,6 ]
Rahman, S. M. Jamshedur [1 ]
Massion, Pierre P. [1 ,7 ]
机构
[1] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Div Allergy Pulm & Crit Care Med,Dept Med,Thorac, Nashville, TN 37232 USA
[2] Vanderbilt Univ, Sch Med, Ctr Quantitat Sci, Dept Biostat, Nashville, TN 37232 USA
[3] Vanderbilt Univ, Dept Pathol Microbiol & Immunol, Nashville, TN 37232 USA
[4] Vanderbilt Univ, Sch Med, Dept Biomed Informat, Nashville, TN 37203 USA
[5] Vanderbilt Univ, Sch Med, Dept Med, Div Hematol Oncol, Nashville, TN 37232 USA
[6] Meharry Med Coll, Dept Biochem & Canc Biol, Nashville, TN 37208 USA
[7] Tennessee Valley Healthcare Syst, Vet Affairs, Nashville, TN 37212 USA
关键词
3q amplification; FXR1; RNA binding protein; non-small cell lung cancer; SQUAMOUS-CELL CARCINOMA; KINASE-C-IOTA; LUNG-CANCER; GENE-EXPRESSION; AMPLIFICATION; ONCOGENE; COMPLEX; OVEREXPRESSION; ACTIVATION; EVOLUTION;
D O I
10.1073/pnas.1421975112
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Aberrant expression of RNA-binding proteins has profound implications for cellular physiology and the pathogenesis of human diseases such as cancer. We previously identified the Fragile X-Related 1 gene (FXR1) as one amplified candidate driver gene at 3q26-29 in lung squamous cell carcinoma (SCC). FXR1 is an autosomal paralog of Fragile X mental retardation 1 and has not been directly linked to human cancers. Here we demonstrate that FXR1 is a key regulator of tumor progression and its overexpression is critical for nonsmall cell lung cancer (NSCLC) cell growth in vitro and in vivo. We identified the mechanisms by which FXR1 executes its regulatory function by forming a novel complex with two other oncogenes, protein kinase C, iota and epithelial cell transforming 2, located in the same amplicon via distinct binding mechanisms. FXR1 expression is a candidate biomarker predictive of poor survival in multiple solid tumors including NSCLCs. Because FXR1 is overexpressed and associated with poor clinical outcomes in multiple cancers, these results have implications for other solid malignancies.
引用
收藏
页码:3469 / 3474
页数:6
相关论文
共 32 条
  • [1] FMRP targets distinct mRNA sequence elements to regulate protein expression
    Ascano, Manuel, Jr.
    Mukherjee, Neelanjan
    Bandaru, Pradeep
    Miller, Jason B.
    Nusbaum, Jeffrey D.
    Corcoran, David L.
    Langlois, Christine
    Munschauer, Mathias
    Dewell, Scott
    Hafner, Markus
    Williams, Zev
    Ohler, Uwe
    Tuschl, Thomas
    [J]. NATURE, 2012, 492 (7429) : 382 - +
  • [2] The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity
    Barretina, Jordi
    Caponigro, Giordano
    Stransky, Nicolas
    Venkatesan, Kavitha
    Margolin, Adam A.
    Kim, Sungjoon
    Wilson, Christopher J.
    Lehar, Joseph
    Kryukov, Gregory V.
    Sonkin, Dmitriy
    Reddy, Anupama
    Liu, Manway
    Murray, Lauren
    Berger, Michael F.
    Monahan, John E.
    Morais, Paula
    Meltzer, Jodi
    Korejwa, Adam
    Jane-Valbuena, Judit
    Mapa, Felipa A.
    Thibault, Joseph
    Bric-Furlong, Eva
    Raman, Pichai
    Shipway, Aaron
    Engels, Ingo H.
    Cheng, Jill
    Yu, Guoying K.
    Yu, Jianjun
    Aspesi, Peter, Jr.
    de Silva, Melanie
    Jagtap, Kalpana
    Jones, Michael D.
    Wang, Li
    Hatton, Charles
    Palescandolo, Emanuele
    Gupta, Supriya
    Mahan, Scott
    Sougnez, Carrie
    Onofrio, Robert C.
    Liefeld, Ted
    MacConaill, Laura
    Winckler, Wendy
    Reich, Michael
    Li, Nanxin
    Mesirov, Jill P.
    Gabriel, Stacey B.
    Getz, Gad
    Ardlie, Kristin
    Chan, Vivien
    Myer, Vic E.
    [J]. NATURE, 2012, 483 (7391) : 603 - 607
  • [3] SOX2 is an amplified lineage-survival oncogene in lung and esophageal squamous cell carcinomas
    Bass, Adam J.
    Watanabe, Hideo
    Mermel, Craig H.
    Yu, Soyoung
    Perner, Sven
    Verhaak, Roel G.
    Kim, So Young
    Wardwell, Leslie
    Tamayo, Pablo
    Gat-Viks, Irit
    Ramos, Alex H.
    Woo, Michele S.
    Weir, Barbara A.
    Getz, Gad
    Beroukhim, Rameen
    O'Kelly, Michael
    Dutt, Amit
    Rozenblatt-Rosen, Orit
    Dziunycz, Piotr
    Komisarof, Justin
    Chirieac, Lucian R.
    LaFargue, Christopher J.
    Scheble, Veit
    Wilbertz, Theresia
    Ma, Changqing
    Rao, Shilpa
    Nakagawa, Hiroshi
    Stairs, Douglas B.
    Lin, Lin
    Giordano, Thomas J.
    Wagner, Patrick
    Minna, John D.
    Gazdar, Adi F.
    Zhu, Chang Qi
    Brose, Marcia S.
    Cecconello, Ivan
    Ribeiro, Ulysses, Jr.
    Marie, Suely K.
    Dahl, Olav
    Shivdasani, Ramesh A.
    Tsao, Ming-Sound
    Rubin, Mark A.
    Wong, Kwok K.
    Regev, Aviv
    Hahn, William C.
    Beer, David G.
    Rustgi, Anil K.
    Meyerson, Matthew
    [J]. NATURE GENETICS, 2009, 41 (11) : 1238 - U105
  • [4] Frequent overexpression of the genes FXR1, CLAPM1 and E1F4G located on amplicon 3q26-27 in squamous cell carcinoma of the lung
    Comtesse, Nicole
    Keller, Andreas
    Diesinger, Isabel
    Bauer, Christine
    Kayser, Klaus
    Huwer, Hanno
    Lenhof, Hans-Peter
    Meese, Eckart
    [J]. INTERNATIONAL JOURNAL OF CANCER, 2007, 120 (12) : 2538 - 2544
  • [5] Protein kinase Cι:: Human oncogene, prognostic marker and therapeutic target
    Fields, Alan P.
    Regala, Roderick P.
    [J]. PHARMACOLOGICAL RESEARCH, 2007, 55 (06) : 487 - 497
  • [6] The guanine nucleotide exchange factor (GEF) Ect2 is an oncogene in human cancer
    Fields, Alan P.
    Justilien, Verline
    [J]. ADVANCES IN ENZYME REGULATION, VOL 50, 2010, 50 : 190 - 200
  • [7] Systematic Interrogation of 3q26 Identifies TLOC1 and SKIL as Cancer Drivers
    Hagerstrand, Daniel
    Tong, Alexander
    Schumacher, Steven E.
    Ilic, Nina
    Shen, Rhine R.
    Cheung, Hiu Wing
    Vazquez, Francisca
    Shrestha, Yashaswi
    Kim, So Young
    Giacomelli, Andrew O.
    Rosenbluh, Joseph
    Schinzel, Anna C.
    Spardy, Nicole A.
    Barbie, David A.
    Mermel, Craig H.
    Weir, Barbara A.
    Garraway, Levi A.
    Tamayo, Pablo
    Mesirov, Jill P.
    Beroukhim, Rameen
    Hahn, William C.
    [J]. CANCER DISCOVERY, 2013, 3 (09) : 1044 - 1057
  • [8] Ect2 links the PKCι-Par6α complex to Rac1 activation and cellular transformation
    Justilien, V.
    Fields, A. P.
    [J]. ONCOGENE, 2009, 28 (41) : 3597 - 3607
  • [9] The PRKCI and SOX2 Oncogenes Are Coamplified and Cooperate to Activate Hedgehog Signaling in Lung Squamous Cell Carcinoma
    Justilien, Verline
    Walsh, Michael P.
    Ali, Syed A.
    Thompson, E. Aubrey
    Murray, Nicole R.
    Fields, Alan P.
    [J]. CANCER CELL, 2014, 25 (02) : 139 - 151
  • [10] Oncogenic Activity of Ect2 Is Regulated through Protein Kinase Cι-mediated Phosphorylation
    Justilien, Verline
    Jameison, Lee
    Der, Channing J.
    Rossman, Kent L.
    Fields, Alan P.
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2011, 286 (10) : 8149 - 8157