Clinical and Translational Research
Copyright ©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Oncol. Sep 15, 2023; 15(9): 1567-1594
Published online Sep 15, 2023. doi: 10.4251/wjgo.v15.i9.1567
Cellular senescence throws new insights into patient classification and pharmacological interventions for clinical management of hepatocellular carcinoma
Hou-Hong Wang, Wen-Li Chen, Ya-Yun Cui, Hui-Hui Gong, Heng Li
Hou-Hong Wang, Wen-Li Chen, Department of General Surgery, The Affiliated Bozhou Hospital of Anhui Medical University, Bozhou 236800, Anhui Province, China
Ya-Yun Cui, Department of Cancer Radiotherapy, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China (Anhui Provincial Cancer Hospital), Hefei 230000, Anhui Province, China
Hui-Hui Gong, Faculty of Health and Life Sciences, Oxford Brookes University, Oxford OX3 0BP, United Kingdom
Heng Li, Department of Comprehensive Surgery, Anhui Provincial Cancer Hospital, West District of The First Affiliated Hospital of USTC, Hefei 230000, Anhui Province, China
Author contributions: Wang HH and Chen WL contributed equally to this work; Li H conceived and designed the study; Wang HH and Chen WL conducted most of the experiments and data analysis, and wrote the manuscript; Cui YY and Gong HH participated in collecting data and helped to draft the manuscript; All authors reviewed and approved the manuscript.
Supported by Project of Bozhou Municipal Health Commission, No. bzwj2022A001; Project of Bozhou Science and Technology Bureau, No. bzzc2022008; and Scientific Research Fund of Bozhou Hospital, Anhui Medical University, No. by2022001.
Institutional review board statement: The study was approved by the Ethics Committee of The Affiliated Bozhou Hospital of Anhui Medical University, No. 2022-17.
Informed consent statement: All study participants or their legal guardian provided informed written consent about personal and medical data collection prior to study enrolment.
Conflict-of-interest statement: The authors declare no conflicts of interest.
Data sharing statement: The data used to support the findings of this study are included within the supplementary information files.
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: Heng Li, Doctor, Professor, Department of Comprehensive Surgery, Anhui Provincial Cancer Hospital, West District of The First Affiliated Hospital of USTC, No. 17 Lujiang Road, Hefei 230000, Anhui Province, China. jxna36@163.com
Received: February 13, 2023
Peer-review started: February 13, 2023
First decision: May 23, 2023
Revised: July 10, 2023
Accepted: August 6, 2023
Article in press: August 6, 2023
Published online: September 15, 2023
ARTICLE HIGHLIGHTS
Research background

Cellular senescence, a state of stable growth arrest, is intertwined with human cancers. Due to the highly heterogeneous malignancy at the molecular and histological levels, characterization of cellular-senescence-based classification might facilitate the personalized treatment of hepatocellular carcinoma (HCC).

Research motivation

Nonetheless, the heterogeneity of cellular-senescence-related features makes the definition and targeting of treatment-induced senescent cells challenging.

Research objectives

This study aimed to characterize cellular-senescence-based phenotypes in HCC, and identify a novel cellular-senescence-related therapeutic target.

Research methods

We enrolled two HCC datasets, TCGA-LIHC and International Cancer Genome Consortium (ICGC). Unsupervised clustering was executed to probe tumor heterogeneity based upon cellular senescence genes. Least absolute shrinkage and selection operator algorithm was utilized to define a cellular-senescence-relevant scoring system. TRNP1 expression was measured in HCCs and normal tissues through immunohistochemistry, immunoblotting and quantitative real-time polymerase chain reaction. The influence of TRNP1 on HCC senescence and growth was proven via a series of experiments.

Research results

TCGA-LIHC patients were classified as three cellular senescence subtypes, named C1–3. The robustness and reproducibility of these subtypes were proven in the ICGC cohort. C2 had the worst overall survival, C1 the next, and C3 the best. C2 presented the highest levels of immune checkpoints, abundance of immune cells, and immunogenetic indicators. Thus, C2 might respond to immunotherapy. C2 had the lowest somatic mutation rate, while C1 presented the highest copy number variations. A cellular-senescence-relevant gene signature was generated, which can predict patient survival, and chemo- or immunotherapeutic response. Experimentally, it was proven that TRNP1 presented with remarkable upregulation in HCCs. TRNP1 knockdown induced apoptosis and senescence of HCC cells and attenuated tumor growth.

Research conclusions

These findings provide a systematic framework for assessing cellular senescence in HCC, which decode the tumor heterogeneity and tailor the pharmacological interventions to improve clinical management.

Research perspectives

Cellular senescence, a state of stable growth arrest, is implicated in human cancers. Nevertheless, characterization of cellular-senescence-associated phenotypes in HCC is still indistinct. Here, we proposed a novel cellular-senescence-based classification for HCC and identified TRNP1 as a novel therapeutic target.