p62/SQSTM1—Dr. Jekyll and Mr. Hyde that prevents oxidative stress but promotes liver cancer

Abstract

p62/SQSTM1 is a multifunctional signaling hub and autophagy adaptor with many binding partners, which allow it to activate mTORC1-dependent nutrient sensing, NF-κB-mediated inflammatory responses and the NRF2-activated antioxidant defense. p62 recognizes polyubiquitin chains via its C-terminal domain and binds to LC3 via its LIR motif, thereby promoting the autophagic degradation of ubiquitinated cargos. p62 accumulates in many human liver diseases, including non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC), where it is a component of Mallory-Denk bodies and intracellular hyaline bodies. Chronic p62 elevation contributes to HCC development by preventing oncogene-induced senescence and death of cancer-initiating cells and enhancing their proliferation. In this review, we discuss p62-mediated signaling pathways and their roles in liver pathophysiology, especially NASH and HCC.

Genetic disruption of NRF2 promotes the development of necroinflammation and liver fibrosis in a mouse model of HFE-hereditary hemochromatosis

“…Clinical cofactors influence disease progression and genetic factors may also play a role [1], [3]. In rodents, the ability of iron to stimulate the progression of experimentally-induced hepatic fibrosis has been reported; alcoholic liver fibrosis is potentiated by dietary iron [26] and carbon tetrachloride-induced liver fibrogenesis is exacerbated in mice fed carbonyl iron [27] and in hemojuvelin knockout mice [28]. Conversely, an iron-deficient diet attenuates the development of liver fibrosis after treatment of rats with thioacetamide or bile-duct ligation [29].…”

Relevance of FXR-p62/SQSTM1 pathway for survival and protection of mouse hepatocytes and liver, especially with steatosis

“…Taken together, we think that the hepatocytes with autonomic/strong proliferative capability can be stimulated with some kinds of trigger such as “metabolic switch”, whereas that of healthy hepatocytes whose proliferation is not driven autonomically/strongly cannot be stimulated by the metabolic changes alone. Similar to FXR, the association of p62/SQSTM1 with tumor have been reported [30, 33]. The anti-oxidant and pro-survival properties of p62/SQSTM1, is surely expected to prevent oxidative stress, cell death (injury) and inflammation in normal hepatocytes/liver.…”

“…Recently, a novel target gene of FXR was identified in the regulation of p62/SQSTM1 gene expression [29]. The anti-adipogenic effect of FXR also has been reported in hepatocytes [30]. FXR therefore has been a potent therapeutic target against NAFLD including NASH [28].…”

Tumor SQSTM1 (p62) expression and T cells in colorectal cancer

“…17,[20][21][22] The SQSTM1 (sequestosome 1, p62) protein is a ubiquitin-binding scaffold molecule that plays a key role in autophagic degradation of ubiquitinated proteins, [23][24][25][26][27][28][29] and the degradation of SQSTM1 with tumor-related antigen may promote T-cell-mediated immunity. [30][31][32] Colorectal cancer represents a heterogeneous group of neoplasms resulting from genomic and epigenomic alterations, which influence and are influenced by tumor-host interactions.…”