Overexpression and clinicopathological significance of cullin-2 in hepatocellular carcinoma progression

doi:10.4254/wjh.v18.i3.117134

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Mar 27, 2026 (publication date) through Mar 26, 2026

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World Journal of Hepatology

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1948-5182

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Copyright: ©Author(s) 2026. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution-NonCommercial (CC BY-NC 4.0) license. No commercial re-use. See permissions. Published by Baishideng Publishing Group Inc.

World J Hepatol. Mar 27, 2026; 18(3): 117134
Published online Mar 27, 2026. doi: 10.4254/wjh.v18.i3.117134

Overexpression and clinicopathological significance of cullin-2 in hepatocellular carcinoma progression

Pan Tang, Qiu-Hong Nong, Kun-Hua Xiong, Huan-Huan Tang, Bei-Bei Huang, Guang-Lei Huang, Qi Li, Shi-Pei He, Gang Chen, Zhen-Bo Feng, Jian-Di Li

Pan Tang, Qiu-Hong Nong, Kun-Hua Xiong, Huan-Huan Tang, Bei-Bei Huang, Guang-Lei Huang, Qi Li, Shi-Pei He, Gang Chen, Zhen-Bo Feng, Jian-Di Li, Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China

Co-first authors: Pan Tang and Qiu-Hong Nong.

Co-corresponding authors: Zhen-Bo Feng and Jian-Di Li.

Author contributions: Tang P, Nong QH, Feng ZB, and Li JD contributed to the conception and design of the study; Tang P, Nong QH, Xiong KH, Tang HH, Huang BB, Huang GL, Li Q, and He SP contributed to the acquisition, analysis, or interpretation of data; Feng ZB, Li JD, and Chen G contributed to the supervision, editing of the content, and writing of the final version of the manuscript; all authors have read and approved the final manuscript. Tang P and Nong QH contributed equally to this work as co-first authors. We designate Feng ZB and Li JD as joint corresponding authors for the following reasons: As the graduate supervisor of the first author, Feng ZB led the entire process of the study, including overall project design, selection of key experimental indicators, guidance on core experimental operations, and systematic literature research, providing important academic leadership and resource support for the smooth implementation of the research. As the research mentor, Li JD offered direct and detailed guidance in key late-stage research steps such as data calculation, advanced statistical analysis, scientific figure preparation, and in-depth interpretation of experimental results, playing an indispensable role in ensuring the rigor of the research conclusions and the quality of result presentation. Both supervisors made equally significant contributions to this study from different stages and dimensions, and bear core responsibility for the integrity and scientific validity of the research.

Supported by National Natural Science Foundation of China, No. 82260581; Innovation Project of Guangxi Graduate Education, No. JGY2023068; Guangxi Medical University “Four New” Project, No. SX202403; Guangxi Medical University Special Project on Educational and Teaching Reform for Clinical Disciplines, No. 2025LCJG02; Guangxi Medical University Digital Textbook Construction Project, No. Gxmuszjc2515; China Undergraduate Innovation and Entrepreneurship Training Program, No. 202510598040; and Future Academic Star of Guangxi Medical University, No. WLXSZX25B079.

Institutional review board statement: This study was reviewed and approved by the Medical Ethics Committee of the First Affiliated Hospital of Guangxi Medical University (Approval No. 2022-KT-NSFC-127). All procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Conflict-of-interest statement: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Data sharing statement: The data supporting this study can be obtained from the corresponding author upon reasonable request.

Corresponding author: Jian-Di Li, Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, No. 6 Shuangyong Road, Nanning 530021, Guangxi Zhuang Autonomous Region, China. jiandi_li_gxmu@163.com

Received: December 1, 2025
Revised: December 23, 2025
Accepted: February 4, 2026
Published online: March 27, 2026
Processing time: 116 Days and 19.4 Hours

Abstract

BACKGROUND

Hepatocellular carcinoma (HCC) is a life-threatening malignant tumor with complex pathogenesis and limited treatment. The core clinical protocols include surgical resection, liver transplantation, local ablation, transcatheter arterial chemoembolization, targeted therapy, immunotherapy, and systemic chemotherapy. As a core component of the Cullin-RING E3 ubiquitin ligase complex, Cullin-2 (CUL2) plays a key role in cell cycle regulation. However, its clinical significance and molecular mechanisms in HCC remain unclear.

AIM

To systematically elucidate the expression pattern, clinical significance, and molecular mechanism of CUL2 in HCC, evaluate its potential as a diagnostic biomarker and therapeutic target, this study integrated large-scale omics data and clustered regularly interspaced short palindromic repeats (CRISPR) screening technology.

METHODS

CUL2 protein expression in 125 HCC tissue specimens was assessed via immunohistochemistry. We integrated global HCC microarray and high-throughput sequencing datasets from a multicenter cohort (9283 specimens: 5204 HCC and 4079 non-tumor tissues) for CUL2 mRNA expression analysis. Single-cell RNA sequencing and spatial transcriptomics were employed to characterize CUL2 expression patterns. The correlation between CUL2 expression and clinicopathological parameters was analyzed in the Cancer Genome Atlas-LIHC cohort (n = 371). Gene set enrichment analysis (GSEA) was performed using Hallmark, Kyoto Encyclopedia of Genes and Genomes, and Gene Ontology gene sets. CRISPR functional screening and gene co-expression network analysis were applied to elucidate molecular mechanisms.

RESULTS

CUL2 was significantly overexpressed in HCC tissues at both mRNA and protein levels. Integrated multicenter analysis (n = 5204) confirmed marked CUL2 mRNA up-regulation (standardized mean difference = 0.70, P < 0.05) with moderate diagnostic value (area under the curve = 0.78). Patients with high CUL2 expression showed significantly reduced overall survival (approximately 4.1 years shorter, P = 0.0011). CUL2 expression correlated with clinicopathological features, including tumor stage. GSEA revealed significant enrichment of E2F targets, G2/M checkpoint, and MYC signaling pathways in CUL2-high tumors. CRISPR-mediated CUL2 knockout inhibited growth in 20 of 21 HCC cell lines. Co-expression analysis identified 190 CUL2-correlated genes enriched in nuclear division, cell cycle transition, and nucleocytoplasmic transport pathways, indicating CUL2 promotes HCC progression through proliferation and migration-related mechanisms.

CONCLUSION

CUL2 is significantly overexpressed in HCC tissues, which highlights its potential as a molecular biomarker and a promising therapeutic target for HCC management.

Keywords: Hepatocellular carcinoma; Cullin 2; Molecular biomarker; Molecular mechanisms; Prognosis; Targeted therapy

Core Tip: Cullin-2 (CUL2) is highly expressed in mRNA and protein levels in hepatocellular carcinoma (HCC). Multicenter analysis (n = 5204) confirmed its high expression (standardized mean difference = 0.70) and diagnostic value (area under the curve = 0.78). The overall survival of patients with high expression was shortened by about 4.1 years. Functional enrichment showed that it was associated with E2F, G2/M and MYC pathways and promoted cell cycle progression. Knockout of CUL2 significantly inhibited the growth of HCC cells, indicating that CUL2 drives HCC progression through proliferation and migration.