p62, Upregulated during Preneoplasia, Induces Hepatocellular Carcinogenesis by Maintaining Survival of Stressed HCC-Initiating Cells

Abstract

Summary p62 is a ubiquitin-binding autophagy receptor and signaling protein that accumulates in premalignant liver diseases and most hepatocellular carcinomas (HCC). Although p62 was proposed to participate in formation of benign adenomas in autophagy-deficient livers, its role in HCC initiation was not explored. Here we show that p62 is necessary and sufficient for HCC induction in mice and that its high expression level in non-tumor human liver predicts rapid HCC recurrence after curative ablation. High p62 expression is needed for activation of NRF2 and mTORC1, induction of c-Myc and protection of HCC-initiating cells from oxidative stress-induced death.

Recent insights into the function of autophagy in cancer

“…Adenovirus-mediated overexpression of p62 in hepatocytes in vivo in the absence of any other oncogenic stimuli drives HCC through the activation of mTORC1 in a manner that is independent of p62's role as a cargo receptor in autophagy. These results establish for the first time that the ability of p62 to activate mTORC1 (along with NRF2) in hepatocytes in vivo is a new critical driver of liver cancer initiation (Umemura et al 2016). In contrast, reduction of p62 in stroma promotes tumorigenesis of prostate cancer through interleukin-6 (IL6) production (Valencia et al 2014).…”

“…In support of this concept, accumulation of p62 has been observed in premalignant liver disease, and high expression of p62 in hepatocellular carcinoma (HCC) predicts poor prognosis (Umemura et al 2016). In multiple physiologically relevant HCC mouse models, p62 is necessary for the activation of mTORC1 in HCCs driven by TSC2 deficiency (Umemura et al 2016). A role for p62 in promoting NFR2 activation and HCC has also been identified (Saito et al 2016).…”

“…In addition to its role as a cargo adapter, p62 also serves as a signaling adaptor for TRAF6, KEAP1, and components of the mTORC1 complex, promoting survival and proliferative functions, possibly explaining the tumor promotion observed upon its accumulation. In support of this concept, accumulation of p62 has been observed in premalignant liver disease, and high expression of p62 in hepatocellular carcinoma (HCC) predicts poor prognosis (Umemura et al 2016). In multiple physiologically relevant HCC mouse models, p62 is necessary for the activation of mTORC1 in HCCs driven by TSC2 deficiency (Umemura et al 2016).…”

Hepatoblastoma modeling in mice places Nrf2 within a cancer field established by mutant β-catenin

“…Support for this concept derives from studies showing that hepatic injury provokes activation of β-catenin (49), Myc (50,51), and Nrf2 (52) and that hepatotoxins accelerate oncogene-driven hepatocarcinogenesis (53). Indeed, very recent data demonstrate that p62/sqstm1, a known Nrf2 target that was elevated 3-to 4-fold in livers expressing β-catenin, constitutes part of such a field that sensitizes livers to diethylnitrosamine-induced HCC (54). Collectively, these data support the idea that a subset of HBs may evolve from hepatic cells that spontaneously acquire oncogenic mutations over time that drive tumor development in a normal liver, while others may have an etiology rooted in oxidative stress emanating from prior hepatic injury or inflammation and develop from cells that survive and outgrow their "less fit" neighbors.…”

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

“…Autophagic activity in tumor cells may enhance extracellular release of immune mediators and cross-presentation of tumor-associated antigens to T cells, thereby potentiating immune response to tumor cells. [6][7][8][9][10][11][12][13][14][15][16][17][18][19] Emerging evidence attests to a key role of tumor autophagic activity in modulating functions of T cells such as CD8…”