Clinical and Translational Research
Copyright ©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Clin Oncol. Jan 24, 2024; 15(1): 62-88
Published online Jan 24, 2024. doi: 10.5306/wjco.v15.i1.62
Identification of the key genes and mechanisms associated with transcatheter arterial chemoembolisation refractoriness in hepatocellular carcinoma
Jie-Zhuang Huang, Jian-Di Li, Gang Chen, Rong-Quan He
Jie-Zhuang Huang, Rong-Quan He, Department of Medical Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
Jian-Di Li, Gang Chen, Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
Author contributions: Huang JZ and Li JD took part in data collection, statistical analysis, interpretation and paper drafting; He RQ and Chen G were responsible for study design, statistical analysis guidance and paper correction.
Supported by Guangxi Higher Education Undergraduate Teaching Reform Project, No. 2021JGA142; Guangxi Educational Science Planning Key Project, No. 2022ZJY2791; Guangxi Medical University Education and Teaching Reform Project, No. 2021XJGA02; and Guangxi Zhuang Autonomous Region Health Commission Self-financed Scientific Research Project, No. Z20201147.
Institutional review board statement: The study did not involve any human or animal related experiments, so no statement of ethics will be provided.
Informed consent statement: The letter is to state that “informed consent” is not apply for our manuscript because the data of this study are from the public database TCGA, GEO and GTEx database.
Conflict-of-interest statement: We have no financial relationships to disclose.
Data sharing statement: The datasets analysed in this study are publicly available in the TCGA (https://portal.gdc.cancer.gov/), GEO (https://www.ncbi.nlm.nih.gov/geo/) and GTEx (https://gtexportal.org/home/) databases.
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: Rong-Quan He, MD, PhD, Doctor, Researcher, Department of Medical Oncology, The First Affiliated Hospital of Guangxi Medical University, No. 6 Shuangyong Road, Nanning 530021, Guangxi Zhuang Autonomous Region, China. herongquan@gxmu.edu.cn
Received: October 23, 2023
Peer-review started: October 23, 2023
First decision: November 23, 2023
Revised: December 12, 2023
Accepted: December 28, 2023
Article in press: December 28, 2023
Published online: January 24, 2024
Abstract
BACKGROUND

Transcatheter arterial embolisation (TACE) is the primary treatment for intermediate-stage hepatocellular carcinoma (HCC) patients while some HCC cases have shown resistance to TACE.

AIM

To investigate the key genes and potential mechanisms correlated with TACE refractoriness in HCC.

METHODS

The microarray datasets of TACE-treated HCC tissues, HCC and non-HCC tissues were collected by searching multiple public databases. The respective differentially expressed genes (DEGs) were attained via limma R package. Weighted gene co-expression network analysis was employed for identifying the significant modules related to TACE non-response. TACE refractoriness-related genes were obtained by intersecting up-regulated TACE-associated and HCC-associated DEGs together with the genes in significant modules related to TACE non-response. The key genes expression in the above two pairs of samples was compared respectively via Wilcoxon tests and standard mean differences model. The prognostic value of the key genes was evaluated by Kaplan-Meier curve. Multivariate analysis was utilised to investigate the independent prognostic factor in key genes. Single-cell RNA (scRNA) sequencing analysis was conducted to explore the cell types in HCC. TACE refractoriness-related genes activity was calculated via AUCell packages. The CellChat R package was used for the investigation of the cell–cell communication between the identified cell types.

RESULTS

HCC tissues of TACE non-responders (n = 66) and TACE responders (n = 81), HCC (n = 3941) and non-HCC (n = 3443) tissues were obtained. The five key genes, DLG associated protein 5 (DLGAP5), Kinesin family member 20A (KIF20A), Assembly factor for spindle microtubules (ASPM), Kinesin family member 11 (KIF11) and TPX2 microtubule nucleation factor (TPX2) in TACE refractoriness-related genes, were identified. The five key genes were all up-regulated in the TACE non-responders group and the HCC group. High expression of the five key genes predicted poor prognosis in HCC. Among the key genes, TPX2 was an independent prognostic factor. Four cell types, hepatocytes, embryonic stem cells, T cells and B cells, were identified in the HCC tissues. The TACE refractoriness-related genes expressed primarily in hepatocytes and embryonic stem cells. Hepatocytes, as the providers of ligands, had the strongest interaction with embryonic stem cells that provided receptors.

CONCLUSION

Five key genes (DLGAP5, KIF20A, ASPM, KIF11 and TPX2) were identified as promoting refractory TACE. Hepatocytes and embryonic stem cells were likely to boost TACE refractoriness.

Keywords: Hepatocellular carcinoma, Transcatheter arterial embolisation refractoriness, Weighted gene co-expression network analysis, Single-cell RNA sequencing, AUCell, CellChat

Core Tip: This is a study that explored the key genes and mechanisms related to transcatheter arterial chemoembolisation (TACE) refractoriness in hepatocellular carcinoma. Through the combination of tissue microarrays and RNA-seq with single-cell RNA sequencing, the TACE refractoriness-related genes were identified and five key genes (DLGAP5, KIF20A, ASPM, KIF11 and TPX2) associated with TACE refractoriness were revealed. The TACE refractoriness-related genes were found to mainly express in hepatocytes and embryonic stem cells. Hepatocytes providing ligands had the strongest interaction with embryonic stem cells as receptors providers.