Gonzalez, A.; Ataman, M.; Mironov, A.; Schlusser, N.; Pandey, M.; Schmidt, A.; Coto-Llerena, M.; Piscuoglio, S.; Mittal, N.; Zavolan, M.

Hepatocellular carcinoma (HCC) is one the most lethal cancer types. While infections with hepatitis B or hepatitis C viruses remain the primary risk factors for HCC development worldwide, metabolic disease-associated steatohepatitis has become the fastest growing etiology of HCC, particularly in the West. Our study characterizes, for the first time, the remodeling of the translation landscape in steatohepatitis-associated HCC using ribosome profiling and mass spectrometry techniques. In striking contrast with the transcriptional alterations, which do not show strong dependence on associated co-morbidity, translational alterations are broader in the steatohepatitis compared to the viral background. These alterations affect hundreds of genes, whose products are often involved in subcellular protein localization. By quantifying the relationship between the ribosome occupancy of upstream or downstream open reading frames (uORFs or dORFs) and coding regions (CDSs), we provide evidence of uORFs attenuating the translation efficiency of CDSs in HCC. We also identify numerous novel translated regions, including from RNAs currently annotated as non-coding, some yielding peptides that can be reproducibly identified in mass spectrometry datasets. Our study thus provides novel molecular data on HCC with a focus on the steatohepatitis etiology, reveals unexpectedly extensive translational control in this co-morbidity, and gives multiple hints and candidate targets for follow-up experiments.