title: Role of MYC-regulated long noncoding RNAs in cell cycle regulation and tumorigenesis.
abstract: BACKGROUND
  The functions of long noncoding RNAs (lncRNAs) have been identified in several cancers, but the roles of lncRNAs in colorectal cancer (CRC) are less well understood. The transcription factor MYC is known to regulate lncRNAs and has been implicated in cancer cell proliferation and tumorigenesis.
  
  
  METHODS
  CRC cells and tissues were profiled to identify lncRNAs differentially expressed in CRC, from which we further selected MYC-regulated lncRNAs. We used luciferase promoter assay, ChIP, RNA pull-down assay, deletion mapping assay, LC-MS/MS and RNA immunoprecipitation to determine the mechanisms of MYC regulation of lncRNAs. Moreover, soft agar assay and in vivo xenograft experiments (four athymic nude mice per group) provided evidence of MYC-regulated lncRNAs in cancer cell transformation and tumorigenesis. The Kaplan-Meier method was used for survival analyses. All statistical tests were two-sided.
  
  
  RESULTS
  We identified lncRNAs differentially expressed in CRC (P < .05, greater than two-fold) and verified four lncRNAs upregulated and two downregulated in CRC cells and tissues. We further identified MYC-regulated lncRNAs, named MYCLos. The MYC-regulated MYCLos may function in cell proliferation and cell cycle by regulating MYC target genes such as CDKN1A (p21) and CDKN2B (p15), suggesting new regulatory mechanisms of MYC-repressed target genes through lncRNAs. RNA binding proteins including HuR and hnRNPK are involved in the function of MYCLos by interacting with MYCLo-1 and MYCLo-2, respectively. Knockdown experiments also showed that MYCLo-2, differentially expressed not only in CRC but also in prostate cancer, has a role in cancer transformation and tumorigenesis.
  
  
  CONCLUSIONS
  Our results provide novel regulatory mechanisms in MYC function through lncRNAs and new potential lncRNA targets of CRC.
authors: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX (TK); Department of Molecular Virology, Immunology and Medical Genetics (TK, YJJ, RC, ET, HA, CMC), Department of Neurological Surgery (SHK), and Department of Anesthesiology (ET), Wexner Medical Center, The Ohio State University, OH; School of Biological Sciences, Seoul National University and National Creative Research Initiative Center for Symbiosystem, Seoul, Republic of Korea (JHL); State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China (YP); School of Life Sciences and Biotechnology, Korea University, Republic of Korea (SHK).
authors: Taewan
authors: T
authors: Kim
authors: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX (TK); Department of Molecular Virology, Immunology and Medical Genetics (TK, YJJ, RC, ET, HA, CMC), Department of Neurological Surgery (SHK), and Department of Anesthesiology (ET), Wexner Medical Center, The Ohio State University, OH; School of Biological Sciences, Seoul National University and National Creative Research Initiative Center for Symbiosystem, Seoul, Republic of Korea (JHL); State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China (YP); School of Life Sciences and Biotechnology, Korea University, Republic of Korea (SHK).
authors: Young-Jun
authors: YJ
authors: Jeon
authors: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX (TK); Department of Molecular Virology, Immunology and Medical Genetics (TK, YJJ, RC, ET, HA, CMC), Department of Neurological Surgery (SHK), and Department of Anesthesiology (ET), Wexner Medical Center, The Ohio State University, OH; School of Biological Sciences, Seoul National University and National Creative Research Initiative Center for Symbiosystem, Seoul, Republic of Korea (JHL); State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China (YP); School of Life Sciences and Biotechnology, Korea University, Republic of Korea (SHK).
authors: Ri
authors: R
authors: Cui
authors: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX (TK); Department of Molecular Virology, Immunology and Medical Genetics (TK, YJJ, RC, ET, HA, CMC), Department of Neurological Surgery (SHK), and Department of Anesthesiology (ET), Wexner Medical Center, The Ohio State University, OH; School of Biological Sciences, Seoul National University and National Creative Research Initiative Center for Symbiosystem, Seoul, Republic of Korea (JHL); State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China (YP); School of Life Sciences and Biotechnology, Korea University, Republic of Korea (SHK).
authors: Ji-Hoon
authors: JH
authors: Lee
authors: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX (TK); Department of Molecular Virology, Immunology and Medical Genetics (TK, YJJ, RC, ET, HA, CMC), Department of Neurological Surgery (SHK), and Department of Anesthesiology (ET), Wexner Medical Center, The Ohio State University, OH; School of Biological Sciences, Seoul National University and National Creative Research Initiative Center for Symbiosystem, Seoul, Republic of Korea (JHL); State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China (YP); School of Life Sciences and Biotechnology, Korea University, Republic of Korea (SHK).
authors: Yong
authors: Y
authors: Peng
authors: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX (TK); Department of Molecular Virology, Immunology and Medical Genetics (TK, YJJ, RC, ET, HA, CMC), Department of Neurological Surgery (SHK), and Department of Anesthesiology (ET), Wexner Medical Center, The Ohio State University, OH; School of Biological Sciences, Seoul National University and National Creative Research Initiative Center for Symbiosystem, Seoul, Republic of Korea (JHL); State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China (YP); School of Life Sciences and Biotechnology, Korea University, Republic of Korea (SHK).
authors: Sung-Hak
authors: SH
authors: Kim
authors: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX (TK); Department of Molecular Virology, Immunology and Medical Genetics (TK, YJJ, RC, ET, HA, CMC), Department of Neurological Surgery (SHK), and Department of Anesthesiology (ET), Wexner Medical Center, The Ohio State University, OH; School of Biological Sciences, Seoul National University and National Creative Research Initiative Center for Symbiosystem, Seoul, Republic of Korea (JHL); State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China (YP); School of Life Sciences and Biotechnology, Korea University, Republic of Korea (SHK).
authors: Esmerina
authors: E
authors: Tili
authors: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX (TK); Department of Molecular Virology, Immunology and Medical Genetics (TK, YJJ, RC, ET, HA, CMC), Department of Neurological Surgery (SHK), and Department of Anesthesiology (ET), Wexner Medical Center, The Ohio State University, OH; School of Biological Sciences, Seoul National University and National Creative Research Initiative Center for Symbiosystem, Seoul, Republic of Korea (JHL); State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China (YP); School of Life Sciences and Biotechnology, Korea University, Republic of Korea (SHK).
authors: Hansjuerg
authors: H
authors: Alder
authors: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX (TK); Department of Molecular Virology, Immunology and Medical Genetics (TK, YJJ, RC, ET, HA, CMC), Department of Neurological Surgery (SHK), and Department of Anesthesiology (ET), Wexner Medical Center, The Ohio State University, OH; School of Biological Sciences, Seoul National University and National Creative Research Initiative Center for Symbiosystem, Seoul, Republic of Korea (JHL); State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China (YP); School of Life Sciences and Biotechnology, Korea University, Republic of Korea (SHK). carlo.croce@osumc.edu.
authors: Carlo M
authors: CM
authors: Croce
mesh_terms: D000818:Animals; D063646:Carcinogenesis; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D051959:ELAV Proteins / Q000378:metabolism; D005434:Flow Cytometry; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic; D034641:Heterogeneous-Nuclear Ribonucleoprotein K; D064593:Heterografts; D006801:Humans; D047468:Immunoprecipitation; D053208:Kaplan-Meier Estimate; D051379:Mice; D008819:Mice, Nude; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000378:metabolism*; D062085:RNA, Long Noncoding / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D012261:Ribonucleoproteins / Q000378:metabolism
chemical_list: C493956:CDKN1A protein, human; C493966:CDKN2B protein, human; D018797:Cell Cycle Proteins; D050762:Cyclin-Dependent Kinase Inhibitor p15; D050759:Cyclin-Dependent Kinase Inhibitor p21; D051959:ELAV Proteins; D034641:Heterogeneous-Nuclear Ribonucleoprotein K; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D062085:RNA, Long Noncoding; D012261:Ribonucleoproteins; C072074:HNRNPK protein, human