# Association of TP53 with Defective Long Chain 3-Hydroxy acyl-CoA Dehydrogenase Induced Non-Cirrhotic Hepatocellular Carcinoma

## TL;DR

This study shows that a defective enzyme in fatty acid oxidation can lead to liver cancer without cirrhosis, offering new insights into its causes and detection.

## Contribution

The study identifies defective LCHAD as a novel cause of non-cirrhotic hepatocellular carcinoma.

## Key findings

- Defective LCHAD leads to liver cancer without cirrhosis in a mouse model.
- The p53 and MDM2 proteins play a key role in this type of liver cancer.
- Proteomic analysis revealed potential molecular markers for early detection.

## Abstract

Researchers have studied how an energy process called fatty acid oxidation may contribute to liver cancer. They have used a unique mouse model that has a defective enzyme for fatty acid oxidation and found that some of the mice developed liver cancer without the typical hardening of tissue or scarring, or cirrhosis, which is usually present in liver cancer. This finding is important because it identifies a unique manner that liver cancer can start in some patients, which makes it harder to detect and treat patients using standard tools and methods. To address this challenge, the researchers used a protein analysis technique (proteomics) and software (Ingenuity Pathway Analysis) to identify specific molecular clues or markers. These results could lead to better strategies for identifying and treating liver cancer patients who do not have cirrhosis.

Background and Aims: Little is known about metabolic dysfunction-associated steatotic liver disease (MASLD) as a risk factor for hepatocellular carcinoma (HCC) in non-cirrhotic (HCC-NC) patients. In-house developed mouse models with defective lipid-metabolizing enzyme long-chain 3-hydroxy acyl-CoA dehydrogenase (LCHAD), coded by hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit alpha (HADHA) gene, result in MASLD (steatosis) without cirrhosis leading to HCC-NC. The aims of the current investigations are to assess molecular markers and the associated molecular events that may lead to HCC-NC. Methods: cDNA array study of HCC patients was conducted to assess the expression of HADHA transcripts. Differentially expressed proteins identified between wild-type (WT) and heterozygous mice with no cancer (HT) from a previous study were subjected to Ingenuity Pathway Analysis (IPA). Western blotting was performed to assess the expression of proteins. Results: IPA of the differentially expressed proteins between WT and HT mice results in two biological networks (network 1 and network 2), which pointed to an important role of p53 in HCC-NC. Validation of the levels of MDM2 and p53 also highlights the role of MDM2-p53 axis in HCC-NC. All the focus molecules in network 1 and network 2 are either presented as tumor suppressor/promoter of carcinogenesis or serum markers for early HCC diagnosis. The hepatotoxicity report from IPA further identified four functional groups including liver steatosis, glutathione depletion, hepatocellular carcinoma, and liver hyperplasia/hyperproliferation. Conclusions: This study suggests that impaired fatty oxidation may play a role in the development of HCC associated with steatosis but without cirrhosis (HCC-NC). Defective LCHAD is a novel etiology for HCC.