The RNA binding protein FXR1 is a new driver in the 3q26-29 amplicon and predicts poor prognosis in human cancers.
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.
Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Thoracic Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232;
Jun
J
Qian
Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Thoracic Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232;
Mohamed
M
Hassanein
Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Thoracic Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232;
Megan D
MD
Hoeksema
Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Thoracic Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232;
Bradford K
BK
Harris
Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Thoracic Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232;
Yong
Y
Zou
Department of Biostatistics, Center for Quantitative Sciences, Vanderbilt University School of Medicine, Nashville, TN 37232;
Heidi
H
Chen
Department of Biostatistics, Center for Quantitative Sciences, Vanderbilt University School of Medicine, Nashville, TN 37232;
Pengcheng
P
Lu
Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, TN 37232;
Rosana
R
Eisenberg
Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, TN 37203;
Jing
J
Wang
Division of Hematology/Oncology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232;
Allan
A
Espinosa
Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Thoracic Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232;
Xiangming
X
Ji
Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Thoracic Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232; Department of Biochemistry and Cancer Biology, Meharry Medical College, Nashville, TN 37208; and.
Fredrick T
FT
Harris
Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Thoracic Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232;
S M Jamshedur
SM
Rahman
Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Thoracic Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232; Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN 37212 pierre.massion@vanderbilt.edu.
Pierre P
PP
Massion
D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics*; D056915:DNA Copy Number Variations / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D011379:Prognosis; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D016019:Survival Analysis; D016896:Treatment Outcome; D000099293:Protein Kinase C-lambda
D007527:Isoenzymes; D011493:Protein Kinase C; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D000099293:Protein Kinase C-lambda; C489850:ECT2 protein, human; C096916:FXR1 protein, human
3q amplification; FXR1; RNA binding protein; non-small cell lung cancer