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

• Published in: iScience Vol. 24; no. 9; p. 103086
• Main Authors: Chen, Hung-Hsi, Yu, Hsin-I, Rudy, Rudy, Lim, Sim-Lin, Chen, Yi-Fen, Wu, Shu-Hsing, Lin, Shu-Chun, Yang, Muh-Hwa, Tarn, Woan-Yuh
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 24.09.2021; Elsevier
• Subjects: Cancer; Cell biology; Molecular biology; Cell biology; Molecular biology; Cancer
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2021.103086

Using antibody arrays, we found that the RNA helicase DDX3 modulates the expression of secreted signaling factors in oral squamous cell carcinoma (OSCC) cells. Ribo-seq analysis confirmed amphiregulin (AREG) as a translational target of DDX3. AREG exerts important biological functions in cancer, including promoting cell migration and paracrine effects of OSCC cells and reprogramming the tumor microenvironment (TME) of OSCC in mice. DDX3-mediated translational control of AREG involves its 3′-untranslated region. Proteomics identified the signal recognition particle (SRP) as an unprecedented interacting partner of DDX3. DDX3 and SRP54 were located near the endoplasmic reticulum, regulated the expression of a common set of secreted factors, and were essential for targeting AREG mRNA to membrane-bound polyribosomes. Finally, OSCC-associated mutant DDX3 increased the expression of AREG, emphasizing the role of DDX3 in tumor progression via SRP-dependent, endoplasmic reticulum-associated translation. Therefore, pharmacological targeting of DDX3 may inhibit the tumor-promoting functions of the TME. [Display omitted] •DDX3-AREG axis promotes cancer progression through microenvironment remodeling•DDX3 activates AREG translation via binding to its 3′ UTR•DDX3 interacts with the signal recognition particle (SRP)•DDX3-SRP-mediated mRNA recruitment assists ER-associated translation Molecular biology; Cell biology; Cancer