Mechanism of progression of hepatocellular carcinoma
Activation of hepatic stellate cells (HSCs) contributes to the development chronic inflammation and hepatocellular carcinoma (HCC) by shaping a pro-tumorigenic microenvironment. In addition, inactivation of p62 leads to enhanced hepatocarcinogenesis.
The researchers demonstrate the signaling mechanism by which it prevents activation of inflammation. p62 activates the interferon (IFN) cascade by promoting STING ubiquitination by tripartite motif protein 32 (TRIM32) in HSCs. p62, binding neighbor of BRCA1 gene 1 (NBR1) and STING, triggers the IFN cascade by displacing NBR1, which normally prevents the interaction of TRIM32 with STING and its subsequent activation.
Furthermore, NBR1 also antagonizes STING by promoting its trafficking to the endosome-lysosomal compartment for degradation independent of autophagy. Thus, researchers show that NBR1 is a synthetic vulnerability of p62 deficiency in HSCs by opposingly regulating the STING-interferon cascade.
They show that NBR1 ablation results in the accumulation of STING and its ability to activate IFN signaling, antagonizing the effect of p62 deficiency, which increases anti-tumor immunity in HCC.
https://www.cell.com/molecular-cell/fulltext/S1097-2765(24)00782-2
