Liu R, Li JC, Li SD, Li JD, He RQ, Chen G, Feng ZB, Wei JL. Deciphering the oncogenic role of Rac family small GTPase 3 in hepatocellular carcinoma through multiomics integration. World J Hepatol 2025; 17(7): 106151 [DOI: 10.4254/wjh.v17.i7.106151]
Corresponding Author of This Article
Zhen-Bo Feng, MD, Professor, Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, No. 6 Shuangyong Road, Nanning 530021, Guangxi Zhuang Autonomous Region, China. fengzhenbo_gxmu@163.com
Research Domain of This Article
Anatomy & Morphology
Article-Type of This Article
Basic Study
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (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: http://creativecommons.org/licenses/by-nc/4.0/
World J Hepatol. Jul 27, 2025; 17(7): 106151 Published online Jul 27, 2025. doi: 10.4254/wjh.v17.i7.106151
Deciphering the oncogenic role of Rac family small GTPase 3 in hepatocellular carcinoma through multiomics integration
Run Liu, Jin-Cheng Li, Shi-De Li, Jian-Di Li, Rong-Quan He, Gang Chen, Zhen-Bo Feng, Jia-Liang Wei
Run Liu, Shi-De Li, Jian-Di Li, Gang Chen, Zhen-Bo Feng, Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
Jin-Cheng Li, Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
Shi-De Li, Department of Information Management and Information System, School of Information and Management, Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
Rong-Quan He, Jia-Liang Wei, Department of Medical Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
Co-first authors: Run Liu and Jin-Cheng Li.
Co-corresponding authors: Zhen-Bo Feng and Jia-Liang Wei.
Author contributions: Liu R and Li JC performed the internal immunohistochemical sample collection and experimental procedures, drafted the initial manuscript; Li SD, Li JD, He RQ, and Chen G conducted public data acquisition, curation, and statistical analysis; Feng ZB, Wei JL, He RQ, and Chen G critically revised the manuscript for substantial intellectual content; Feng ZB and Wei JL conceived and designed the study; all authors have read and approved the final version of the manuscript.
Supported by National Natural Science Foundation of China, No. 82260581.
Institutional review board statement: The study was reviewed and approved by The First Affiliated Hospital of Guangxi Medical University Institutional Review Board (No. 2022-KT-NSFC-127).
Conflict-of-interest statement: The authors declare that they have no competing interests.
Data sharing statement: Data and material will be available on reasonable request.
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: Zhen-Bo Feng, MD, Professor, Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, No. 6 Shuangyong Road, Nanning 530021, Guangxi Zhuang Autonomous Region, China. fengzhenbo_gxmu@163.com
Received: March 5, 2025 Revised: April 26, 2025 Accepted: June 11, 2025 Published online: July 27, 2025 Processing time: 142 Days and 21.2 Hours
Abstract
BACKGROUND
Hepatocellular carcinoma (HCC) remains a lethal malignancy due to its molecular complexity and chemoresistance. Rac family small GTPase 3 (RAC3), a tumorigenic GTPase understudied in HCC, drives recurrence via E2F transcription factor 1 (E2F1)-mediated transcriptional activation. This study integrates multiomics and clustered regularly interspaced short palindromic repeats (CRISPR) screening to delineate RAC3’s roles. RAC3 overexpression correlates with advanced HCC and patient age, while its knockout suppresses proliferation. Mechanistically, RAC3 dysregulates cell-cycle checkpoints through E2F1 binding. Pharmacological RAC3 inhibition disrupts tumor growth and synergizes with chemotherapy to overcome resistance.
AIM
To explore RAC3’s expression, clinical links, and HCC mechanisms via multiomics and functional genomics.
METHODS
Multiomic integration of The Cancer Genome Atlas (TCGA), Gene Expression Omnibus, and Genotype-Tissue Expression datasets was performed to analyze RAC3 mRNA expression. Immunohistochemistry quantified RAC3 protein in 108 HCC/adjacent tissue pairs. Kaplan–Meier/Cox regression assessed prognostic significance using TCGA data. CRISPR screening validated RAC3’s necessity for HCC proliferation. Functional enrichment identified associated pathways; hTFtarget/JASPAR predicted transcription factors, validated via chromatin immunoprecipitation sequencing (ChIP-seq).
RESULTS
RAC3 exhibited significant mRNA and protein overexpression in HCC tissues, which was correlated with advanced tumor stages and reduced overall survival rates (hazard ratio = 1.82, 95%CI: 1.31–2.53). Genetic ablation of RAC3 suppressed HCC cell proliferation across 16 cell lines. Pathway analysis revealed RAC3’s predominant involvement in cell-cycle regulation, DNA replication, and nucleocytoplasmic transport. Mechanistic investigations identified E2F1 as a pivotal upstream transcriptional regulator, and ChIP-seq analysis validated its direct binding to the RAC3 promoter region. These findings suggest that RAC3 drives HCC progression through E2F1-mediated cell-cycle dysregulation.
CONCLUSION
This study identified RAC3 as a key HCC oncogenic driver; its overexpression links to poor prognosis/resistance. Targeting the RAC3/E2F1 axis offers a new therapy, which highlights RAC3 as a biomarker/target.
Core Tip: This study identifies Rac family small GTPase 3 (RAC3) as a critical oncogenic driver in hepatocellular carcinoma (HCC) through multi functional validation. RAC3 overexpression correlates with advanced tumor stage and poor prognosis (hazard ratio = 1.82), while clustered regularly interspaced short palindromic repeats screening confirms its necessity for HCC proliferation. Mechanistically, E2F transcription factor 1 transcriptionally activates RAC3, which drives cell-cycle dysregulation. These findings position RAC3 as a promising therapeutic target for combating chemotherapy resistance in HCC.
