Basic Study
Copyright ©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Dec 28, 2024; 30(48): 5174-5190
Published online Dec 28, 2024. doi: 10.3748/wjg.v30.i48.5174
N6-methyladenosine-modified long non-coding RNA KIF9-AS1 promotes stemness and sorafenib resistance in hepatocellular carcinoma by upregulating SHOX2 expression
Yong Yu, Xiang-Hong Lu, Jin-Song Mu, Jiang-Yun Meng, Jiang-Shan Sun, Hai-Xu Chen, Yang Yan, Ke Meng
Yong Yu, Jiang-Yun Meng, Jiang-Shan Sun, Ke Meng, Department of Gastroenterology and Hepatology, The First Medical Center, Chinese People’s Liberation Army General Hospital, Beijing 100853, China
Xiang-Hong Lu, Department of Intensive Care Medicine, The First Medical Center, Chinese People’s Liberation Army General Hospital, Beijing 100853, China
Jin-Song Mu, Department of Intensive Care Medicine, The Fifth Medical Center, Chinese People’s Liberation Army General Hospital, Beijing 100039, China
Hai-Xu Chen, Institute of Geriatrics and National Clinical Research Center of Geriatrics Disease, The Second Medical Center, Chinese People’s Liberation Army General Hospital, Beijing 100853, China
Yang Yan, Department of General Surgery, The First Medical Center, Chinese People’s Liberation Army General Hospital, Beijing 100853, China
Co-first authors: Yong Yu and Xiang-Hong Lu.
Co-corresponding authors: Yang Yan and Ke Meng.
Author contributions: Yu Y and Lu XH jointly wrote the manuscript; Yu Y drafting the initial version; Lu XH making substantial revisions and additions to ensure accuracy and consistency; Yu Y and Lu XH made equal contributions in study design, data analysis, and manuscript preparation, and they contributed equally to this work as co-first authors. Yu Y, Mu JS, Yan Y, and Meng K designed and coordinated the study; Lu XH, Meng JY, Sun JS, and Chen HX performed the experiments and acquired and analyzed the data; Mu JS, Yan Y, and Meng K revised the manuscript; and all authors approved the final version of the article. Yan Y and Meng K designed, financed and coordinated the study and contributed equally to this work as co-corresponding authors.
Supported by the National Natural Science Foundation of China, No. 82271628.
Institutional review board statement: This study was reviewed and approved by the Medical Ethics Committee of the Fifth Medical Center of the Chinese People’s Liberation Army General Hospital, approval No. KY-2024-5-75-1.
Institutional animal care and use committee statement: All animal experiments were approved by the Institutional Animal Care Committee of the Fifth Medical Center of the Chinese People’s Liberation Army General Hospital, No. IACUC-2019-0025.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: All the data obtained in the current study are available from the corresponding authors upon reasonable request.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
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: Ke Meng, MD, Department of Gastroenterology and Hepatology, The First Medical Center, Chinese People’s Liberation Army General Hospital, No. 28 Fuxing Road, Haidian District, Beijing 100853, China. mengke301@126.com
Received: June 20, 2024
Revised: September 26, 2024
Accepted: November 8, 2024
Published online: December 28, 2024
Processing time: 161 Days and 21.8 Hours
Abstract
BACKGROUND

Hepatocellular carcinoma (HCC) is a prevalent and aggressive tumor. Sorafenib is the first-line treatment for patients with advanced HCC, but resistance to sorafenib has become a significant challenge in this therapy. Cancer stem cells play a crucial role in sorafenib resistance in HCC. Our previous study revealed that the long non-coding RNA (lncRNA) KIF9-AS1 is an oncogenic gene in HCC. However, the role of KIF9-AS1 in drug resistance and cancer stemness in HCC remains unclear. Herein, we aimed to investigate the function and mechanism of the lncRNA KIF9-AS1 in cancer stemness and drug resistance in HCC.

AIM

To describe the role of the lncRNA KIF9-AS1 in cancer stemness and drug resistance in HCC and elucidate the underlying mechanism.

METHODS

Tumor tissue and adjacent non-cancerous tissue samples were collected from HCC patients. Sphere formation was quantified via a tumor sphere assay. Cell viability, proliferation, and apoptosis were evaluated via Cell Counting Kit-8, flow cytometry, and colony formation assays, respectively. The interactions between the lncRNA KIF9-AS1 and its downstream targets were confirmed via RNA immunoprecipitation and coimmunoprecipitation. The tumorigenic role of KIF9-AS1 was validated in a mouse model.

RESULTS

Compared with that in normal controls, the expression of the lncRNA KIF9-AS1 was upregulated in HCC tissues. Knockdown of KIF9-AS1 inhibited stemness and attenuated sorafenib resistance in HCC cells. Mechanistically, N6-methyladenosine modification mediated by methyltransferase-like 3/insulin-like growth factor 2 mRNA-binding protein 1 stabilized and increased the expression of KIF9-AS1. Additionally, KIF9-AS1 increased the stability and expression of short stature homeobox 2 by promoting ubiquitin-specific peptidase 1-induced deubiquitination. Furthermore, depletion of KIF9-AS1 alleviated sorafenib resistance in a xenograft mouse model of HCC.

CONCLUSION

The N6-methyladenosine-modified lncRNA KIF9-AS1 promoted stemness and sorafenib resistance in HCC by upregulating short stature homeobox 2 expression.

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

Core Tip: Hepatocellular carcinoma (HCC) is a highly aggressive tumor with a poor prognosis. Our previous investigation revealed that knockdown of the long non-coding RNA KIF9-AS1 suppressed HCC progression. However, the role of KIF9-AS1 in cancer stemness and drug resistance in HCC remains unclear. This study revealed that N6-methyladenosine modification of KIF9-AS1 promotes stemness and sorafenib resistance in HCC by upregulating short stature homeobox 2 expression. This finding provides new insights into the role of KIF9-AS1 in HCC pathogenesis and highlights its potential as a biomarker and therapeutic target.