title: miR-141 is a key regulator of renal cell carcinoma proliferation and metastasis by controlling EphA2 expression.
abstract: OBJECTIVE
  Although microRNAs (miRNA) have been revealed as crucial modulators of tumorigenesis, our understanding of their roles in renal cell carcinoma (RCC) is limited. Here we sought to identify human miRNAs that act as key regulators of renal carcinogenesis.
  
  
  METHODS
  We performed microarray-based miRNA profiling of clear cell RCC (ccRCC) and adjacent normal tissues and then explored the roles of miR-141 both in vitro and in vivo, which was the most significantly downregulated in ccRCC tissues.
  
  
  RESULTS
  A total of 74 miRNAs were dysregulated in ccRCC compared with normal tissues. miR-141 was remarkably downregulated in 92.6% (63/68) ccRCC tissues and would serve as a promising biomarker for discriminating ccRCC from normal tissues with an area under the receiver operating characteristics curve of 0.93. Overexpression of miR-141 robustly impaired ccRCC cell migratory and invasive properties and suppressed cell proliferation by arresting cells at G0-G1 phase in vitro and in human RCC orthotopic xenografts. Significantly, the antitumor activities of miR-141 were mediated by its reversal regulation of erythropoietin-producing hepatocellular (Eph) A2 (EphA2), which then relayed a signaling transduction cascade to attenuate the functions of focal adhesion kinase (FAK), AKT, and MMP2/9. In addition, a specific and inverse correlation between miR-141 and EphA2 expression was obtained in human ccRCC samples. Finally, miR-141 could be secreted from the ccRCC donor cells, and be taken up and function moderately in the ccRCC recipient cells.
  
  
  CONCLUSIONS
  miR-141 serves as a potential biomarker for discriminating ccRCC from normal tissues and a crucial suppressor of ccRCC cell proliferation and metastasis by modulating the EphA2/p-FAK/p-AKT/MMPs signaling cascade.
authors.affiliation: Authors' Affiliations: Department of Urology, Union Hospital; Department of Pathogen Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Cancer Biology Program, Hematology-Oncology Division, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts; and Department of Neurology, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Georgia Regents University, Augusta, Georgia.
authors.forename: Xuanyu
authors.initials: X
authors.lastname: Chen
authors.affiliation: Authors' Affiliations: Department of Urology, Union Hospital; Department of Pathogen Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Cancer Biology Program, Hematology-Oncology Division, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts; and Department of Neurology, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Georgia Regents University, Augusta, Georgia.
authors.forename: Xuegang
authors.initials: X
authors.lastname: Wang
authors.affiliation: Authors' Affiliations: Department of Urology, Union Hospital; Department of Pathogen Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Cancer Biology Program, Hematology-Oncology Division, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts; and Department of Neurology, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Georgia Regents University, Augusta, Georgia.
authors.forename: Anming
authors.initials: A
authors.lastname: Ruan
authors.affiliation: Authors' Affiliations: Department of Urology, Union Hospital; Department of Pathogen Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Cancer Biology Program, Hematology-Oncology Division, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts; and Department of Neurology, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Georgia Regents University, Augusta, Georgia.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Han
authors.affiliation: Authors' Affiliations: Department of Urology, Union Hospital; Department of Pathogen Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Cancer Biology Program, Hematology-Oncology Division, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts; and Department of Neurology, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Georgia Regents University, Augusta, Georgia.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Authors' Affiliations: Department of Urology, Union Hospital; Department of Pathogen Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Cancer Biology Program, Hematology-Oncology Division, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts; and Department of Neurology, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Georgia Regents University, Augusta, Georgia.
authors.forename: Xing
authors.initials: X
authors.lastname: Lu
authors.affiliation: Authors' Affiliations: Department of Urology, Union Hospital; Department of Pathogen Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Cancer Biology Program, Hematology-Oncology Division, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts; and Department of Neurology, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Georgia Regents University, Augusta, Georgia.
authors.forename: Pei
authors.initials: P
authors.lastname: Xiao
authors.affiliation: Authors' Affiliations: Department of Urology, Union Hospital; Department of Pathogen Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Cancer Biology Program, Hematology-Oncology Division, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts; and Department of Neurology, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Georgia Regents University, Augusta, Georgia.
authors.forename: Hangchuan
authors.initials: H
authors.lastname: Shi
authors.affiliation: Authors' Affiliations: Department of Urology, Union Hospital; Department of Pathogen Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Cancer Biology Program, Hematology-Oncology Division, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts; and Department of Neurology, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Georgia Regents University, Augusta, Georgia.
authors.forename: Rong
authors.initials: R
authors.lastname: Wang
authors.affiliation: Authors' Affiliations: Department of Urology, Union Hospital; Department of Pathogen Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Cancer Biology Program, Hematology-Oncology Division, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts; and Department of Neurology, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Georgia Regents University, Augusta, Georgia.
authors.forename: Li
authors.initials: L
authors.lastname: Chen
authors.affiliation: Authors' Affiliations: Department of Urology, Union Hospital; Department of Pathogen Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Cancer Biology Program, Hematology-Oncology Division, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts; and Department of Neurology, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Georgia Regents University, Augusta, Georgia.
authors.forename: Shaoyong
authors.initials: S
authors.lastname: Chen
authors.affiliation: Authors' Affiliations: Department of Urology, Union Hospital; Department of Pathogen Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Cancer Biology Program, Hematology-Oncology Division, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts; and Department of Neurology, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Georgia Regents University, Augusta, Georgia.
authors.forename: Quansheng
authors.initials: Q
authors.lastname: Du
authors.affiliation: Authors' Affiliations: Department of Urology, Union Hospital; Department of Pathogen Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Cancer Biology Program, Hematology-Oncology Division, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts; and Department of Neurology, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Georgia Regents University, Augusta, Georgia xiaoping.zhang2008@gmail.com macy.yang88@gmail.com.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Yang
authors.affiliation: Authors' Affiliations: Department of Urology, Union Hospital; Department of Pathogen Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Cancer Biology Program, Hematology-Oncology Division, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts; and Department of Neurology, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Georgia Regents University, Augusta, Georgia xiaoping.zhang2008@gmail.com macy.yang88@gmail.com.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Zhang
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000328:Adult; D000368:Aged; D000818:Animals; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D009362:Neoplasm Metastasis; D020411:Oligonucleotide Array Sequence Analysis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D036104:Receptor, EphA2 / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014183:Transplantation, Heterologous
chemical_list: D020413:3' Untranslated Regions; C533895:MIRN141 microRNA, human; D035683:MicroRNAs; D036104:Receptor, EphA2; D051416:Focal Adhesion Protein-Tyrosine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020782:Matrix Metalloproteinases