Sequestosome 1/p62-related pathways as therapeutic targets in hepatocellular carcinoma

ABSTRACT

Introduction: Protein sequestosome 1/p62 (p62) plays a crucial role in vital complex and interacting signaling pathways in normal and neoplastic cells. P62 is involved in autophagy, defense against oxidative stress via activation of the Keap1/Nrf2 system, in protein aggregation and sequestration, and in apoptosis. Autophagy contributes to cell survival and proliferation by eliminating damaged organelles, potentially toxic protein aggregates and invading microorganisms, and by providing nutrients under starvation conditions. The same holds true for oxidative stress defense, which may prevent genomic alterations and tumor initiation but also protect established tumor cells and promote tumor progression. Cross-talk between autophagy and apoptosis is regulated by a signaling network with the involvement of p62.

Areas covered: The review deals with structure, function, and regulation of p62 and its role in liver carcinogenesis. Emphasis is placed on mechanisms leading to overexpression of p62 and its accumulation as inclusion bodies in HCC and on the impact of p62-dependent signaling pathways in tumor cells with the aim to explore the possible role of p62 as the therapeutic target.

Expert opinion: Depending on the context, targeting p62 or interference with related pathways, such as autophagy, is a potential therapeutic strategy in HCC. However, the heterogeneity of this tumor entity and the complexity and mutual interactions of the p62-dependent pathways involved are challenges for a targeted therapy since interference with p62-mediated regulatory processes could result likewise in inhibition of tumorigenesis and in its promotion and thus provoke harmful side effects. Therapy-related patient stratification based on reliable markers to better define pathogenic principles of the tumor is a necessity when this type of treatment is considered.

KEYWORDS:

• Sequestosome1/p62
• hepatocellular carcinoma (HCC)
• signaling pathways
• autophagy
• apoptosis
• oxidative stress
• inclusion bodies
• Mallory-Denk bodies
• intracellular hyaline bodies

Article Highlights

• Association, function, and regulation of p62 regarding HCC are reviewed.

• p62 is a multidomain, multifunctional protein, which is involved in a variety of vital and interacting pathways in neoplastic and non-neoplastic cells, including autophagy, apoptosis, defense against oxidative stress and metabolic reprogramming.

• p62 overexpression and accumulation as the constituent of inclusion bodies in HCC (e.g. IHBs, MDBs) indicate deficient autophagy and are signs of poor prognosis and increased risk of post-therapeutic recurrence.

• Interference with p62-related pathways may, on one hand, prevent genome damage and carcinogenesis but, on the other, support survival of neoplastic cells.

• Therapeutic targeting aimed at inhibition of p62-dependent signaling pathways is, therefore, a ‘double-edged sword’ and may even promote tumor progression.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

This paper was not funded.