title: Protumorigenic role of Timeless in hepatocellular carcinoma.
abstract: The mammalian timeless (TIM) protein interacts with proteins of the endogenous clock and essentially contributes to the circadian rhythm. In addition, TIM is involved in maintenance of chromosome integrity, growth control and development. Thus, we hypothesized that TIM may exert a potential protumorigenic function in human hepatocarcinogenesis. TIM was overexpressed in a subset of human HCCs both at the mRNA and the protein level. siRNA-mediated knockdown of TIM reduced cell viability due to the induction of apoptosis and G2 arrest. The latter was mediated via CHEK2 phosphorylation. In addition, siRNA-treated cells showed a significantly reduced migratory capacity and reduced expression levels of various proteins. Mechanistically, TIM directly interacts with the eukaryotic elongation factor 1A2 (EEF1A2), which binds to actin filaments to promote tumor cell migration. siRNA-mediated knockdown of TIM reduced EEF1A2 protein levels thereby affecting ribosomal protein biosynthesis. Thus, overexpression of TIM exerts oncogenic function in human HCCs, which is mediated via CHEK2 and EEF1A2.
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, D-69120 Heidelberg, Germany.
authors.forename: Nahla
authors.initials: N
authors.lastname: Elgohary
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, D-69120 Heidelberg, Germany.
authors.forename: Rossella
authors.initials: R
authors.lastname: Pellegrino
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, D-69120 Heidelberg, Germany.
authors.forename: Olaf
authors.initials: O
authors.lastname: Neumann
authors.affiliation: Department of Medical Oncology (NCI), Cairo University, Cairo 11796, Egypt.
authors.forename: Heba M
authors.initials: HM
authors.lastname: Elzawahry
authors.affiliation: Department of Medical Oncology (NCI), Cairo University, Cairo 11796, Egypt.
authors.forename: Magdy M
authors.initials: MM
authors.lastname: Saber
authors.affiliation: Department of Medical Oncology (NCI), Cairo University, Cairo 11796, Egypt.
authors.forename: Ahmed A
authors.initials: AA
authors.lastname: Zeeneldin
authors.affiliation: Genome Analytics, Helmholtz Centre for Infection Research, D-38124 Braunschweig, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Geffers
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, D-69120 Heidelberg, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Ehemann
authors.affiliation: Department of General Surgery, University Hospital Heidelberg, D-69120 Heidelberg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Schemmer
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, D-69120 Heidelberg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Schirmacher
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, D-69120 Heidelberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Longerich
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D063646:Carcinogenesis / Q000235:genetics*; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D064447:Checkpoint Kinase 2 / Q000096:biosynthesis; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D020648:Peptide Elongation Factor 1 / Q000096:biosynthesis; D034741:RNA, Small Interfering
chemical_list: D018797:Cell Cycle Proteins; C503234:EEF1A2 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D020648:Peptide Elongation Factor 1; D034741:RNA, Small Interfering; C509769:TIMELESS protein, human; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human