Abstract Despite extensive genomic exploration, the mechanisms that initiate malignancy remain obscure. We addressed this issue by studying how chronic liver diseases progress to hepatocellular carcinoma (HCC). We focused our studies on the role of p62/SQSTM1, whose accumulation is a hallmark of premalignant liver disease. Using mice, we found that hepatocyte-specific p62 ablation inhibits HCC development in four distinct models, with strongest effect exerted in etiologies involving mTORC1 activation. Forced p62 expression in autophagy-competent livers suffices for HCC induction. Amongst p62 activities including aggregate formation, binding ubiquitinated proteins, mTORC1 stimulation and transcription factor activation, most critical is the NRF2 pathway, which is mutationally activated in 14% of human HCCs. We propose that environmentally-induced p62-dependent NRF2 signaling is a key early event inHCC pathogenesis that together with mTORC1 promotes survival and expansion of superoxide-accumulating HCC-initiating cells. Indeed, high p62 expression in preneoplastic human liver predicts rapid HCC recurrence after curative ablation. Citation Format: Michael Karin. p62/SQSTM1 accumulation links chronic tissue damage to malignant progression in liver and pancreas. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr IA08.
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