# The role of DNAJB1-PKAc-β-catenin axis in fibrolamellar HCC

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2024 · $618,809

## Abstract

Abstract
This multiple-PI application proposes investigations of cellular and molecular mechanisms of Fibrolamellar
Hepatocellular Carcinoma, FLC. FLC is a disease that occurs in children, adolescents and in young adults
without a history of other liver disorders such as fibrosis or cirrhosis. Numerous studies in FLC patients and in
animal models clearly showed that FLC is caused by a fusion protein kinase DNAJB1-PKAc which is sufficient
to induce liver cancer resembling FLC in mouse models. We found that the fusion kinase DNAJB1-PKAc
phosphorylates b-catenin at Ser675 in FLC patients and in FLC-derived spheroid cells. This phosphorylation
leads to elevation of the b-catenin-TCF4 complex which might activate multiple cancer genes via two pathways:
interaction with and activation of unique chromosomal regions (Cancer-Enhancing Genomic Regions or
Aggressive Liver Cancer Domains, CEGRs/ALCDs) and via direct activation of the promoters of genes involved
in metabolic rewiring. The main hypothesis of this application is that the DNAJB1-PKAc-b-catenin axis is a critical
mediator of FLC pathology via activation of CEGRs/ALCDs-dependent neuronal genes, oncogenes and
collagens as well as genes involved in pathological metabolic changes. Three Specific Aims are designed to test
this hypothesis. Specific Aim 1 will examine the role of the DNAJB1-PKAc-b-catenin pathway in activation of
CEGRs/ALCDs-dependent cancer genes in FLC. The focus of these studies is on the FLC patients who have
relapsed tumor and lung metastases which are potentially caused by activation of DNAJB1-PKAc-b-catenin-
dependent neuronal pathways. Specific Aim 2 will investigate the role of the DNAJB1-PKAc-b-catenin-TCF4
axis in FLC using a mouse model of FLC. We have generated an FLC mouse model, in which DNAJB1-PKAc
protein is created and expressed at high levels at 4 months after injections of gRNAs. We will examine
development of pathological changes in the liver and investigate the DNAJB1-PKAc-b-catenin-TCF4 pathway at
different stages of FLC. We will inhibit b-catenin by PRI-724 in the FLC mouse model, examine development of
FLC, and determine downstream molecular mediators. Specific Am 3 will determine the role of the DNAJB1-
PKAc-b-catenin-TCF4 axis in rewiring of metabolic pathways in FLC. Our preliminary data suggest that the urea
cycle and associated metabolic processes are rewired toward increased collagen synthesis and maturation in
FLC, and the treatment of FLC spheroids with PRI-724 reverts these changes. Therefore, we will test the
hypothesis that the DNAJB1-PKAc-β-catenin-TCF4 axis is a critical event for metabolic rewiring and will also
determine the impact of metabolic rewiring on FLC proliferation and survival. Thus, this project will elucidate
mechanisms of FLC and develop a background for b-catenin-based therapy.

## Key facts

- **NIH application ID:** 10814969
- **Project number:** 5R01CA278834-02
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Soona Shin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $618,809
- **Award type:** 5
- **Project period:** 2023-04-01 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10814969

## Citation

> US National Institutes of Health, RePORTER application 10814969, The role of DNAJB1-PKAc-β-catenin axis in fibrolamellar HCC (5R01CA278834-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10814969. Licensed CC0.

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