Protumorigenic role of Timeless in hepatocellular carcinoma

Elgohary,Nahla; Pellegrino,Rossella; Neumann,Olaf; Elzawahry,Heba M.; Saber,Magdy M.; Zeeneldin,Ahmed A.; Geffers,Robert; Ehemann,Volker; Schemmer,Peter; Schirmacher,Peter; Longerich,Thomas

doi:10.3892/ijo.2014.2751

Protumorigenic role of Timeless in hepatocellular carcinoma

Authors:
- Nahla Elgohary
- Rossella Pellegrino
- Olaf Neumann
- Heba M. Elzawahry
- Magdy M. Saber
- Ahmed A. Zeeneldin
- Robert Geffers
- Volker Ehemann
- Peter Schemmer
- Peter Schirmacher
- Thomas Longerich
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Affiliations: Institute of Pathology, University Hospital Heidelberg, D-69120 Heidelberg, Germany, Department of Medical Oncology (NCI), Cairo University, Cairo 11796, Egypt, Genome Analytics, Helmholtz Centre for Infection Research, D-38124 Braunschweig, Germany, Department of General Surgery, University Hospital Heidelberg, D-69120 Heidelberg, Germany
Published online on: November 14, 2014 https://doi.org/10.3892/ijo.2014.2751
Pages: 597-606

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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.

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