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World J Gastroenterol. Nov 7, 2026; 32(41): 121890
Published online Nov 7, 2026. doi: 10.3748/wjg.121890
Epitranscriptomic regulation of the COX-2/PGE2 axis by hnRNPA2B1 promotes esophageal squamous cell carcinoma progression
Jiao-Qian Lu, Xue-Fen Fang, Xiao-Xiong Guo, Miao Liu, Ji-Hong Lin, Hua-Long Zheng, Can-Mei Zhong, Qiu-Yan Lin, Xiao-Yun Huang, Xiao-Zhong Wang, Hao Tian, Jian-Wen Que, Feng-Lin Chen, Bi-Yun Zheng
Jiao-Qian Lu, Xue-Fen Fang, Xiao-Xiong Guo, Can-Mei Zhong, Qiu-Yan Lin, Xiao-Yun Huang, Xiao-Zhong Wang, Feng-Lin Chen, Bi-Yun Zheng, Department of Gastroenterology, Fujian Medical University Union Hospital, Fuzhou 350001, Fujian Province, China
Jiao-Qian Lu, Xue-Fen Fang, Xiao-Xiong Guo, Hua-Long Zheng, Can-Mei Zhong, Qiu-Yan Lin, Xiao-Yun Huang, Xiao-Zhong Wang, Feng-Lin Chen, Bi-Yun Zheng, Department of Gastroenterology, Fujian Clinical Research Center for Digestive System Tumors and Upper Gastrointestinal Disease, Fuzhou 350001, Fujian Province, China
Miao Liu, Department of Gastrointestinal Endoscopy Nursing, Fujian Medical University Union Hospital, Fuzhou 350001, Fujian Province, China
Ji-Hong Lin, Department of Thoracic Surgery, Fujian Medical University Union Hospital, Fuzhou 350001, Fujian Province, China
Hua-Long Zheng, Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou 350001, Fujian Province, China
Hao Tian, Eye Center, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China
Jian-Wen Que, Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, United States
Co-first authors: Jiao-Qian Lu and Xue-Fen Fang.
Co-corresponding authors: Feng-Lin Chen and Bi-Yun Zheng.
Author contributions: Lu JQ and Fang XF contributed equally as co-first authors; Zheng BY and Chen FL conceptualized and supervised the study as co-corresponding authors; Lu JQ, Fang XF, Guo XX, Liu M, Zheng HL, Zhong CM, Lin QY, Huang XY, Wang XZ, Tian H, Que JW, Chen FL, and Zheng BY developed the methodology; Lu JQ, Fang XF, Guo XX, Liu M, Lin JH, Zheng HL, and Zhong CM performed the investigation; Lu JQ, Fang XF, Guo XX, Liu M, and Zheng BY conducted formal analysis and curated the data; Chen FL, Que JW, and Zheng BY provided resources; Lu JQ and Zheng BY drafted the manuscript; Que JW, Chen FL, and Zheng BY reviewed and edited the manuscript; all authors approved the final version of the article.
AI contribution statement: AI tools were not used to generate scientific data, perform data analysis, or draw scientific conclusions. The authors take full responsibility for the integrity, accuracy, and scientific content of the manuscript.
Supported by National Natural Science Foundation of China Young Scientists Fund, No. 82203308; National Natural Science Foundation of China General Program, No. 82570660; Fujian Provincial Natural Science Foundation of China, No. 2026J010043; Fujian Provincial Natural Science Foundation of China, No. 2025J01116; Fujian Natural Science Foundation, No. 2023J01651; Young and Middle-Aged Talents Training Project of Fujian Provincial Health Commission, No. 2023GGA018; and National Key Clinical Specialty Construction Project of Fujian Province, China, No. 2023-1594.
Institutional review board statement: The study was reviewed and approved by the Institutional Ethics Committee of Fujian Medical University Union Hospital, No. 2022(85).
Institutional animal care and use committee statement: All animal experiments were reviewed and approved by the Institutional Animal Care and Use Committee of Fujian Medical University, No. 2022-NSFC-0403.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Data sharing statement: Bulk RNA-Seq data are available on reasonable request. All other data relevant to the study are included in the article or uploaded as online supplemental information.
Corresponding author: Bi-Yun Zheng, MD, PhD, Associate Chief Physician, Associate Professor, Department of Gastroenterology, Fujian Medical University Union Hospital, No. 29 Xinquan Road, Fuzhou 350001, Fujian Province, China.
drzhengby@163.com
Received: April 7, 2026
Revised: June 30, 2026
Accepted: July 20, 2026
Published online: November 7, 2026
Processing time: 164 Days and 1.3 Hours
BACKGROUND
Esophageal squamous cell carcinoma (ESCC) remains a highly lethal malignancy with limited therapeutic options. Cyclooxygenase-2 (COX-2) is frequently overexpressed in ESCC, yet the mechanisms leading to its dysregulation remain poorly understood. Heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2B1), an oncogenic N6-methyladenosine (m6A) reader, has been implicated in various cancers, but its role in regulating COX-2 expression and promoting ESCC progression has not been defined.
AIM
To investigate how hnRNPA2B1 promotes ESCC progression through COX-2 regulation.
METHODS
Expression of hnRNPA2B1 and COX-2 was analyzed in ESCC tissues and cell lines by reverse transcription-quantitative polymerase chain reaction (qPCR), western blotting, and immunohistochemistry. Stable hnRNPA2B1 knockdown and overexpression models were established to assess cellular proliferation, migration, invasion, and xenograft tumor growth. Bulk RNA-seq, m6A RNA immunoprecipitation-qPCR and RNA immunoprecipitation-qPCR, and actinomycin D assays were used to delineate post-transcriptional regulation of COX-2. Functional and therapeutic relevance of the hnRNPA2B1-COX-2/prostaglandin E2 (PGE2) axis was evaluated using PGE2 supplementation and celecoxib treatment in vitro and in vivo.
RESULTS
HnRNPA2B1 was significantly upregulated in ESCC and early intraepithelial neoplasia, correlating with advanced stage and poor survival. Functionally, hnRNPA2B1 promoted proliferation, colony formation, migration, invasion, and xenograft growth, whereas its silencing had opposite effects. Transcriptomic and mechanistic analyses identified COX-2 as a downstream effector. HnRNPA2B1 bound to m6A-modified COX-2 transcripts, stabilized its mRNA, and enhanced COX-2/PGE2 axis. Exogenous PGE2 supplementation rescued the inhibitory effects of hnRNPA2B1 knockdown, while celecoxib treatment suppressed hnRNPA2B1-driven malignant phenotypes both in vitro and in vivo.
CONCLUSION
HnRNPA2B1 drives ESCC initiation and progression by epitranscriptomically activating the COX-2/PGE2 axis. Targeting COX-2 or hnRNPA2B1-mediated m6A stabilization may offer a therapeutic strategy for ESCC.
Core Tip: Heterogeneous nuclear ribonucleoprotein A2/B1 (HnRNPA2B1) is upregulated in esophageal squamous cell carcinoma and early intraepithelial neoplasia and promotes tumor progression. Mechanistically, hnRNPA2B1 stabilizes cyclooxygenase-2 mRNA in an m6A-related manner, leading to activation of the cyclooxygenase-2/prostaglandin E2 axis. Prostaglandin E2 supplementation rescues the inhibitory effects of hnRNPA2B1 silencing, whereas celecoxib suppresses hnRNPA2B1-driven malignant phenotypes. These findings reveal a novel epitranscriptomic mechanism of esophageal squamous cell carcinoma progression and highlight hnRNPA2B1 as a potential therapeutic target.
