# Role of p62/SQSTM1 in obesity-induced liver cancer

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2020 · $726,246

## Abstract

Abstract
 This is an application for continuation of a project whose long-term goal is the identification of the
mechanisms through which obesity and hypernutrition enhance cancer risk. Obesity manifests one of its
strongest tumor-promoting effects in hepatocellular carcinoma (HCC), the major primary liver cancer,
whose US incidence has increased by 300% during the past 20 years. This increase is due to the obesity
epidemic that is still spreading throughout our country. We therefore chose to address the important and
general question regarding the mechanisms by which obesity increase cancer risk by studying the
relationships between obesity and HCC development. In the previous project period, we developed new
models for studying obesity-induced HCC and used them to establish the role of inflammation and ER
stress in the progression of non-alcoholic steatohepatitis (NASH) to HCC. During these studies, we had
uncovered the key pathogenic function of the autophagy receptor and signaling adaptor p62/SQSTM1, a
protein that accumulates in NASH and several other chronic liver diseases, all of which increase HCC risk.
We have validated the relevance of p62/SQSTM1 to the pathogenesis of human HCC and shown that its
elevated expression in the non-tumor liver provides a strong prediction of HCC recurrence after curative
ablation. Since all of this work was done in collaboration with Dr. Jorge Moscat, a pioneer in studying p62
function, we have decided to formalize our joint effort and pursue a more in-depth investigation of p62
involvement in obesity-induced HCC through the multi-investigator R01 mechanism. We propose to further
investigate how p62 exerts its HCC-inducing activity by defining the tumorigenic function of various p62
structural motifs that mediate its interactions with other proteins. In particular, we will focus on the role of
NRF2, an activator of the anti-oxidant response, and mTORC1, a major metabolism regulating protein
kinase complex, as downstream effectors of p62-dependent liver tumorigenesis. We will also conduct
unbiased metabolomic analysis to decipher the role of NRF2- and mTORC1-regulated metabolic pathways
in obesity-induced HCC development. In addition, we will use state-of-the-art high throughput screens to
search for small molecule inhibitors that target p62-driven NRF2 and mTORC1 activation and thereby
prevent obesity-induced HCC development or inhibit the growth and progression of such tumors. In
addition to greatly improving our understanding of the mechanisms through which obesity induces HCC
development, this investigation may lead to new preventive and therapeutic strategies.

## Key facts

- **NIH application ID:** 9844458
- **Project number:** 5R01CA211794-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Michael Karin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $726,246
- **Award type:** 5
- **Project period:** 2017-02-15 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9844458

## Citation

> US National Institutes of Health, RePORTER application 9844458, Role of p62/SQSTM1 in obesity-induced liver cancer (5R01CA211794-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9844458. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*