Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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Translation Initiation Factor-2S2 (eIF2S2) Contributes to Cervical Carcinogenesis by Inhibiting the TGF-β/SMAD4 Signaling Pathway

  • Juthika Kundu (Lika shing applied virology institute, Department of Medical Microbiology and Immunology, University of Alberta) ;
  • Hobin Yang (College of Pharmacy, Kyungsung University) ;
  • Saerom Moon (College of Pharmacy, Duksung Women's University) ;
  • Mi Ran Byun (College of Pharmacy, Daegu Catholic University) ;
  • Young Kee Shin (Laboratory of Molecular Pathology and Cancer Genomics, Research Institute of Pharmaceutical Sciences and College of Pharmacy, Seoul National University) ;
  • Kyoung Song (College of Pharmacy, Duksung Women's University) ;
  • Joon-Seok Choi (College of Pharmacy, Daegu Catholic University)
  • Received : 2024.01.30
  • Accepted : 2024.09.02
  • Published : 2024.11.01
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Abstract

The deregulation of protein translational machinery and the oncogenic role of several translation initiation factors have been extensively investigated. This study aimed to investigate the role of eukaryotic translation initiation factor 2S2 (eIF2S2, also known as eIF2β) in cervical carcinogenesis. Immunohistochemical analysis of human cervical carcinoma tissues revealed a stage-specific increase in eIF2S2 expression. The knockdown of eIF2S2 in human cervical cancer (SiHa) cells significantly reduced growth and migration properties, whereas its overexpression demonstrated the opposite effect. Immunoprecipitation and Bimolecular fluorescence complementation (BiFC) assay confirmed the previous photo array finding of the interaction between eIF2S2 and SMAD4 to understand the tumorigenic mechanism of eIF2S2. The results indicated that the N-terminus of eIF2S2 interacts with the MH-1 domain of SMAD4. The interaction effect between eIF2S2 and SMAD4 was further evaluated. The knockdown of eIF2S2 increased SMAD4 expression in cervical cancer cells without changing SMAD4 mRNA expression, whereas transient eIF2S2 overexpression reduced SMAD4 expression. This indicates the possibility of post-translational regulation of SMAD4 expression by eIF2S2. Additionally, eIF2S2 overexpression was confirmed to weaken the expression and/or promoter activity of p15 and p27, which are SMAD4-regulated antiproliferative proteins, by reducing SMAD4 levels. Therefore, our study indicated the pro-tumorigenic role of eIF2S2, which diminishes both SMAD4 expression and function as a transcriptional factor in cervical carcinogenesis.

Keywords

Acknowledgement

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (No. 2022R1C1C1009883, No. 2021R1F1A1057411), as well as by the Priority Research Centers Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science, and Technology (2016R1A6A1A03007648). Additionally, it received support from the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education, Science, and Technology (NRF-2014R1A1A).

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