Basic Study
Copyright ©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Clin Oncol. Jan 24, 2024; 15(1): 130-144
Published online Jan 24, 2024. doi: 10.5306/wjco.v15.i1.130
Fatty acid binding protein 5 is a novel therapeutic target for hepatocellular carcinoma
Yan Li, William Lee, Zhen-Gang Zhao, Yi Liu, Hao Cui, Hao-Yu Wang
Yan Li, Zhen-Gang Zhao, Yi Liu, Hao Cui, Hao-Yu Wang, Department of Gastroenterology, Tianjin Third Central Hospital, Tianjin 300170, China
William Lee, Biomedical Engineering, Texas A&M University, College Station, TX 77843, United States
Co-first authors: Yan Li and William Lee.
Author contributions: Li Y conceived and designed the study; Li Y, Lee W, Zhao ZG, Liu Y, Cui H, and Wang HY performed the experiments and analyzed the data; Li Y, Lee W, Zhao ZG, Liu Y, Cui H, and Wang HY interpreted the data; Li Y and Lee W drafted the manuscript; Liu Y, Cui H, and Wang HY revised the manuscript; All authors approved the final version of the article. Lee W contributed primarily to the bioinformatics analysis and therefore Lee W and Li Y contributed equally to the study. Li Y conceived and designed the study, performed the experiments, analyzed and interpreted the data, drafted and revised the manuscript. Lee W contributed to the bioinformatics analysis, data analysis and interpretation, as well as manuscript drafting and revision. Both authors have made substantial contributions to the study and are therefore qualified as co-first authors of the paper.
Supported by Tianjin Key Medical Discipline Construction Project, No. TJYXZDXK-034A.
Institutional review board statement: This study was approved by the Institutional Review Board (IRB) of Tianjin Third Central Hospital.
Conflict-of-interest statement: All authors have seen and agreed with the contents of the manuscript and there is no conflict of interest to declare.
Data sharing statement: For this bioinformatics analysis, we acquired the TCGA data and LIHC data as well as the data for other cancer patients from cBioPortal (https://www.cbioportal.org/). The bioinformatic platform GEPIA2 also used the TCGA datasets for the built-in analysis. No additional data are available.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Yan Li and William Lee, MD, Chief Physician, Department of Gastroenterology, Tianjin Third Central Hospital, No. 83 Jintang Road, Hedong District, Tianjin 300170, China. li13821177880@126.com
Received: August 30, 2023
Peer-review started: August 30, 2023
First decision: November 20, 2023
Revised: December 2, 2023
Accepted: December 25, 2023
Article in press: December 25, 2023
Published online: January 24, 2024
Abstract
BACKGROUND

Hepatocellular carcinoma (HCC) is an aggressive subtype of liver cancer and is one of the most common cancers with high mortality worldwide. Reprogrammed lipid metabolism plays crucial roles in HCC cancer cell survival, growth, and evolution. Emerging evidence suggests the importance of fatty acid binding proteins (FABPs) in contribution to cancer progression and metastasis; however, how these FABPs are dysregulated in cancer cells, especially in HCC, and the roles of FABPs in cancer progression have not been well defined.

AIM

To understand the genetic alterations and expression of FABPs and their associated cancer hallmarks and oncogenes in contributing to cancer malignancies.

METHODS

We used The Cancer Genome Atlas datasets of pan cancer and liver hepatocellular carcinoma (LIHC) as well as patient cohorts with other cancer types in this study. We investigated genetic alterations of FABPs in various cancer types. mRNA expression was used to determine if FABPs are abnormally expressed in tumor tissues compared to non-tumor controls and to investigate whether their expression correlates with patient clinical outcome, enriched cancer hallmarks and oncogenes previously reported for patients with HCC. We determined the protein levels of FABP5 and its correlated genes in two HCC cell lines and assessed the potential of FABP5 inhibition in treating HCC cells.

RESULTS

We discovered that a gene cluster including five FABP family members (FABP4, FABP5, FABP8, FABP9 and FABP12) is frequently co-amplified in cancer. Amplification, in fact, is the most common genetic alteration for FABPs, leading to overexpression of FABPs. FABP5 showed the greatest differential mRNA expression comparing tumor with non-tumor tissues. High FABP5 expression correlates well with worse patient outcomes (P < 0.05). FABP5 expression highly correlates with enrichment of G2M checkpoint (r = 0.33, P = 1.1e-10), TP53 signaling pathway (r = 0.22, P = 1.7e-5) and many genes in the gene sets such as CDK1 (r = 0.56, P = 0), CDK4 (r = 0.49, P = 0), and TP53 (r = 0.22, P = 1.6e-5). Furthermore, FABP5 also correlates well with two co-expressed oncogenes PLK1 and BIRC5 in pan cancer especially in LIHC patients (r = 0.58, P = 0; r = 0.58, P = 0; respectively). FABP5high Huh7 cells also expressed higher protein levels of p53, BIRC5, CDK1, CDK2, and CDK4 than FABP5low HepG2 cells. FABP5 inhibition more potently inhibited the tumor cell growth in Huh7 cells than in HepG2 cells.

CONCLUSION

We discovered that FABP5 gene is frequently amplified in cancer, especially in HCC, leading to its significant elevated expression in HCC. Its high expression correlates well with worse patient outcome, enriched cancer hallmarks and oncogenes in HCC. FABP5 inhibition impaired the cell viability of FABP5high Huh7 cells. All these support that FABP5 is a novel therapeutic target for treating FABP5high HCC.

Keywords: Hepatocellular carcinoma, Fatty acid binding protein, Novel target, Amplification, Correlated expression

Core Tip: Several recent studies reported that fatty acid binding proteins (FABPs) contribute to reprogrammed lipid metabolism and cancer progression; however, how these FABPs are dysregulated in cancer, especially in hepatocellular carcinoma (HCC), has not been carefully addressed. We discovered that a FABP gene cluster including FABP5 are frequently amplified in cancer. FABP5 is significantly upregulated in HCC and its high expression correlates well with worse patient outcomes, enrichment of top enriched cancer hallmarks involved in cell cycle progression, and two oncogenes PLK1 and BIRC5 in HCC. FABP5 inhibition impaired the cell viability of FABP5high HCC cells. Our data supported that FABP5 is a novel therapeutic target for treating HCC.