An internal ribosome entry site in the 5' untranslated region of epidermal growth factor receptor allows hypoxic...

Area of Science:

• Molecular Biology
• Cancer Research
• Translational Control

Background:

• Epidermal growth factor receptor (EGFR) expression drives cancer progression and is targeted by anti-cancer drugs.
• EGFR inhibition causes side effects due to its normal cellular functions.
• Oncogenes, including EGFR, are often expressed in hypoxic tumor interiors via unknown translational control mechanisms.

Purpose of the Study:

• To elucidate the mechanism maintaining EGFR expression under hypoxia.
• To investigate the role of the EGFR 5' untranslated region (UTR) in translational control.
• To identify factors involved in EGFR translational regulation under hypoxic conditions.

Main Methods:

• Utilized reporter gene assays to assess EGFR 5' UTR activity.
• Investigated internal ribosome entry site (IRES) activity within the EGFR 5' UTR.
• Examined the role of eukaryotic initiation factor 4A (eIF4A) using the inhibitor hippuristanol.
• Assessed protein expression levels under varying conditions, including hypoxia.

Main Results:

• Demonstrated that the human EGFR 5' UTR can initiate downstream open reading frame expression via an internal ribosome entry site (IRES).
• Ruled out cryptic promoter activity or splicing as causes for this initiation.
• Showed that hippuristanol, an eIF4A inhibitor, reduced EGFR 5' UTR-driven reporter activity and EGFR protein levels.
• Confirmed that EGFR IRES-driven reporter gene expression is maintained under hypoxia despite decreased global translation.

Conclusions:

• The EGFR 5' UTR contains a functional internal ribosome entry site (IRES) that drives translation initiation.
• This EGFR IRES-mediated translation is dependent on eukaryotic initiation factor 4A (eIF4A).
• The EGFR IRES provides a mechanism for sustained EGFR expression in hypoxic tumor environments, contributing to cancer progression.