Abstract Increased protein synthesis enables proliferation of established tumors. However, how mRNA translation contributes to early tumorigenesis remains unclear. Following oncogene activation, hepatocytes enter a non-proliferative/senescent-like phase characterised by deposition of extracellular matrix (ECM) niches which then promote subsequent progression to proliferating hepatocellular carcinoma (HCC). We demonstrate that removal of eIF4A2, a negative regulator of mRNA translation, upregulates synthesis of membrane/secretory proteins. This leads to a compensatory increase of integrin degradation which, in turn, compromises generation of ECM-rich tumour initiation niches and progression to proliferating HCC. Conversely, pharmacological inhibition of mRNA translation following eIF4A2 deletion restores ECM deposition and reinstates HCC progression. Our results highlight how the way in which cells respond to dysregulated mRNA translation in early tumorigenesis influences cancer outcomes. One-Sentence Summary Enhancing rates of secretory protein synthesis during early oncogenesis retards cancer initiation by inhibiting ECM deposition.

The eIF4A2 negative regulator of mRNA translation promotes extracellular matrix deposition to accelerate hepatocellular carcinoma initiation