Letter to the Editor
Copyright ©The Author(s) 2025. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jun 7, 2025; 31(21): 103184
Published online Jun 7, 2025. doi: 10.3748/wjg.v31.i21.103184
Mechanisms underlying hepatocellular carcinoma progression through N6-methyladenosine modifications of long non-coding RNA
Ning Wang, Fei-Tian Min, Wei-Bo Wen, Huan-Tian Cui
Ning Wang, Fei-Tian Min, Wei-Bo Wen, Huan-Tian Cui, The First School of Clinical Medicine, Yunnan University of Chinese Medicine, Kunming 650000, Yunnan Province, China
Co-corresponding authors: Wei-Bo Wen and Huan-Tian Cui.
Author contributions: Wang N wrote the initial manuscript draft; Min FT did the literature review; Cui HT designed the overall concept and outline of the manuscript; Wen WB did literature review and critical revision of the manuscript; Cui HT contributed to the editing of the manuscript. All authors have read and approved the final manuscript. Both Wen WB and Cui HT have made crucial and indispensable contributions towards the completion of the project and thus qualified as the co-corresponding authors of the paper.
Supported by National Natural Science Foundation of China, No. 82405223; and Yunling Scholars Program, No. XDYC-YLXZ-2022-0027.
Conflict-of-interest statement: The authors declare that they have no conflicts of interest.
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: Huan-Tian Cui, PhD, The First School of Clinical Medicine, Yunnan University of Chinese Medicine, No. 1076 Yuhua Road, Chenggong District, Kunming 650000, Yunnan Province, China. 1762316411@qq.com
Received: November 19, 2024
Revised: March 26, 2025
Accepted: April 22, 2025
Published online: June 7, 2025
Processing time: 199 Days and 16.9 Hours
Abstract

Hepatocellular carcinoma (HCC) is a highly lethal malignancy with limited treatment options, particularly for patients with advanced stages of the disease. Sorafenib, the standard first-line therapy, faces significant challenges due to the development of drug resistance. Yu et al explored the mechanisms by which lncRNA KIF9-AS1 regulates the stemness and sorafenib resistance in HCC using a combination of cell culture, transfection, RNA immunoprecipitation, co-immunoprecipitation, and xenograft tumor models. They demonstrate that N6-methyladenosine-modified long non-coding RNA KIF9-AS1 acts as an oncogene in HCC. This modification involves methyltransferase-like 3 and insulin-like growth factor 2 mRNA-binding protein 1, which play critical roles in regulating KIF9-AS1. Furthermore, KIF9-AS1 stabilizes and upregulates short stature homeobox 2 by promoting its deubiquitination through ubiquitin-specific peptidase 1, thereby enhancing stemness and contributing to sorafenib resistance in HCC cells. These findings provide a theoretical basis for KIF9-AS1 as a diagnostic marker and therapeutic target for HCC, highlighting the need for further investigation into its clinical application potential.

Keywords: Hepatocellular carcinoma; Stemness; Sorafenib resistance; Long non-coding RNA KIF9-AS1; Short stature homeobox 2; N6-methyladenosine

Core Tip: Yu et al present evidence showing that m6A-modified long non-coding RNA KIF9-AS1 drives the progression of hepatocellular carcinoma (HCC) and reveal novel molecular mechanisms underlying this process. The m6A modification, mediated by modification involves methyltransferase-like 3 and insulin-like growth factor insulin-like growth factor 2 mRNA-binding protein 1, stabilizes and upregulates KIF9-AS1 expression. In turn, KIF9-AS1 enhances the stability and expression of SHOX2 by promoting its deubiquitination via ubiquitin-specific peptidase 1, which strengthens stemness and contributes to sorafenib resistance in HCC cells. Future studies should further validate KIF9-AS1 as a potential diagnostic biomarker for HCC and explore its therapeutic applications in HCC treatment.