title: Long noncoding RNA HULC modulates the phosphorylation of YB-1 through serving as a scaffold of extracellular signal-regulated kinase and YB-1 to enhance hepatocarcinogenesis.
abstract: Dysregulated expression of long noncoding RNAs has been reported in many types of cancers, indicating that it may play a critical role in tumorigenesis. The long noncoding RNA highly up-regulated in liver cancer (HULC) was first characterized in hepatocellular carcinoma. However, the detailed mechanisms of HULC remain unclear. Here, we demonstrate a novel mechanism by which long noncoding RNA plays oncogenic roles through modulating the phosphorylation status of its interaction protein. First, we validated the markedly increased expression levels of HULC in hepatocellular carcinoma tissues compared to their adjacent noncancerous tissues. Furthermore, up-regulation of HULC was correlated with grading and overall survival. Meanwhile, HULC could promote cell proliferation, migration, and invasion in vitro and inhibit cisplatin-induced apoptosis. Moreover, we show that HULC specifically binds to Y-box binding protein 1 (YB-1) protein both in vitro and in vivo. YB-1 is a major component of translationally inactive messenger ribonucleoprotein particles which keeps mRNA in a silent state. Our study further demonstrated that HULC could promote the phosphorylation of YB-1 protein, which leads to the release of YB-1 from its bound mRNA. As a consequence, translation of silenced oncogenic mRNAs would be activated, including cyclin D1, cyclin E1, and matrix metalloproteinase 3. In addition, we found that HULC promotes the phosphorylation of YB-1 protein mainly through extracellular signal-regulated kinase.
  
  
  
  We demonstrate that HULC promotes the phosphorylation of YB-1 through the extracellular signal-regulated kinase pathway, in turn regulates the interaction of YB-1 with certain oncogenic mRNAs, and consequently accelerates the translation of these mRNAs in the process of tumorigenesis. (Hepatology 2017;65:1612-1627).
authors.affiliation: State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Li
authors.affiliation: State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.|Institute of Cancer Stem Cells, Cancer Center, Dalian Medical University, Dalian, China.
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Liu
authors.affiliation: Liver Surgery Department, Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, and Institute of Biomedical Sciences, Fudan University, Shanghai, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Liver Surgery Department, Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, and Institute of Biomedical Sciences, Fudan University, Shanghai, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Hu
authors.affiliation: State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
authors.forename: Dongdong
authors.initials: D
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Qiao
authors.affiliation: State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.|Laboratory of Molecular Oncology, Beijing University Cancer Hospital and Institute, Beijing, China.|Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, China.
authors.forename: Qimin
authors.initials: Q
authors.lastname: Zhan
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000209:etiology* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D002453:Cell Cycle; D049109:Cell Proliferation; D002681:China / Q000453:epidemiology; D019938:Cyclin D1 / Q000378:metabolism; D019927:Cyclin E; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005260:Female; D056945:Hep G2 Cells; D006801:Humans; D008099:Liver / Q000473:pathology; D008113:Liver Neoplasms / Q000209:etiology* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D008297:Male; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D008875:Middle Aged; D015513:Oncogene Proteins; D010766:Phosphorylation; D062085:RNA, Long Noncoding / Q000378:metabolism*; D051840:Y-Box-Binding Protein 1 / Q000378:metabolism*
chemical_list: C530104:CCND1 protein, human; C475820:CCNE1 protein, human; D019927:Cyclin E; C574685:HULC long non-coding RNA, human; D015513:Oncogene Proteins; D062085:RNA, Long Noncoding; D051840:Y-Box-Binding Protein 1; C070856:YBX1 protein, human; D019938:Cyclin D1; D048049:Extracellular Signal-Regulated MAP Kinases; D019278:Matrix Metalloproteinase 3