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DDX3 modulates the tumor microenvironment via its role in endoplasmic reticulum-associated translation

Hung-Hsi Chen1, Hsin-I Yu1, Rudy Rudy1

  • 1Institute of Biomedical Sciences, Academia Sinica, 128 Academy Road Section 2, Nankang, Taipei 11529, Taiwan.

Iscience
|September 27, 2021
PubMed

Insights

The RNA helicase DDX3 protein targets amphiregulin (AREG) mRNA for translation, influencing oral cancer progression and the tumor microenvironment (TME). Targeting DDX3 may offer a therapeutic strategy against oral squamous cell carcinoma (OSCC).

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Biology

Background:

  • Oral squamous cell carcinoma (OSCC) is a significant global health concern.
  • The tumor microenvironment (TME) plays a critical role in OSCC progression.
  • RNA helicase DDX3 is implicated in various cellular processes, including cancer.

Purpose of the Study:

  • To investigate the role of RNA helicase DDX3 in regulating secreted signaling factors in OSCC.
  • To identify translational targets of DDX3 in OSCC.
  • To elucidate the mechanism by which DDX3 influences the TME in OSCC.

Main Methods:

  • Antibody arrays to profile secreted factors.
  • Ribo-seq to identify translational targets.
  • Proteomics to identify interacting partners.
  • Immunofluorescence to determine subcellular localization.

Main Results:

  • DDX3 modulates secreted signaling factors in OSCC cells, with amphiregulin (AREG) identified as a translational target.
  • DDX3 regulates AREG translation via its 3'-untranslated region.
  • DDX3 interacts with the signal recognition particle (SRP) and co-localizes with SRP54 near the endoplasmic reticulum.
  • DDX3 and SRP54 are essential for targeting AREG mRNA to membrane-bound polyribosomes, influencing TME reprogramming.
  • OSCC-associated mutant DDX3 enhances AREG expression, highlighting its role in tumor progression.

Conclusions:

  • DDX3 controls AREG translation through an SRP-dependent, ER-associated mechanism, impacting OSCC progression and TME.
  • Targeting DDX3 may represent a novel therapeutic strategy to inhibit tumor-promoting functions in the OSCC TME.
Keywords:
CancerCell biologyMolecular biology

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