Published online Nov 7, 2026. doi: 10.3748/wjg.121890
Revised: June 30, 2026
Accepted: July 20, 2026
Published online: November 7, 2026
Processing time: 167 Days and 15.7 Hours
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.
To investigate how hnRNPA2B1 promotes ESCC progression through COX-2 regulation.
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.
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.
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.
- Citation: Lu JQ, Fang XF, Guo XX, Liu M, Lin JH, Zheng HL, Zhong CM, Lin QY, Huang XY, Wang XZ, Tian H, Que JW, Chen FL, Zheng BY. Epitranscriptomic regulation of the COX-2/PGE2 axis by hnRNPA2B1 promotes esophageal squamous cell carcinoma progression. World J Gastroenterol 2026; 32(41): 121890
- URL: https://www.wjgnet.com/1007-9327/full/v32/i41/121890.htm
- DOI: https://dx.doi.org/10.3748/wjg.121890
Esophageal squamous cell carcinoma (ESCC) is one of the most prevalent and lethal malignancies worldwide, particularly in East Asia. Despite advances in surgery, radiotherapy, chemotherapy, and immunotherapy, the overall survival of patients with ESCC remains dismal, primarily due to late diagnosis, high recurrence rates, and resistance to therapy[1,2]. A deeper understanding of the molecular mechanisms driving ESCC progression is therefore essential to identify eff
N6-methyladenosine (m6A) is the most abundant internal modification of eukaryotic mRNA, influencing RNA splicing, stability, translation, and degradation[3,4]. Dysregulation of m6A regulators has been increasingly linked to the initiation and progression of various cancers[5]. m6A modification is dynamically regulated by methyltransferase “writers” (METTL3/METTL14), demethylase “erasers” (FTO, ALKBH5), and binding “readers”, including YTHDF proteins, IGF2BPs, and heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2B1)[6,7].
HnRNPA2B1, originally identified as an RNA-binding protein involved in alternative splicing and microRNA processing, has recently been recognized as an m6A reader that modulates transcript stability and oncogenic signaling[8,9]. Increasing evidence indicates that hnRNPA2B1 plays a pivotal role in multiple tumor types[10-12]. Pan-cancer analyses have reported elevated hnRNPA2B1 expression in ESCC, correlating with advanced stage and poor prognosis[13,14]. Functional studies suggest that hnRNPA2B1 promotes malignant progression by regulating lipid metabolism and the miR-17-92 cluster[15,16]. However, the downstream effectors and pathways through which hnRNPA2B1 drives ESCC progression remain largely unclear.
In this study, we found that the levels of hnRNPA2B1 were increased in ESCC. We further demonstrated that hnRNPA2B1 regulated the mRNA stability of cyclooxygenase-2 (COX-2), a rate-limiting enzyme in prostaglandin biosynthesis[17] in an m6A-related manner. Prostaglandin E2 (PGE2) is one of the major downstream prostaglandins produced through COX-2 activity and has been implicated in tumor cell proliferation, invasion, inflammation, and immune modu
ESCC tissues, matched adjacent tissues, and distal normal tissues were obtained from patients undergoing surgical resection at Fujian Medical University Union Hospital. High-grade intraepithelial neoplasia (HGIN) and low-grade intraepithelial neoplasia (LGIN) samples were collected from patients who underwent endoscopic submucosal dissection (ESD). None of the patients had received preoperative chemotherapy or radiotherapy. All tissue samples were reviewed and confirmed by two experienced pathologists. A tissue microarray containing 30 ESCC cases with matched adjacent and distant normal tissues was purchased from Outdo Biotech Co., Ltd. (Shanghai, China). Written informed consent was obtained from all patients, and the study protocol was reviewed and approved by the Institutional Ethics Committee of Fujian Medical University Union Hospital, No. 2022(85). All procedures were conducted in accordance with the Dec
RNA-seq data and clinical information for esophageal carcinoma (ESCA) patients were obtained from The Cancer Genome Atlas (TCGA, https://portal.gdc.cancer.gov/projects/TCGA) and Gene Expression Omnibus (https://www.ncbi.nlm.nih.gov/geo/) databases. Expression differences of hnRNPA2B1 and prostaglandin-endoperoxide synthase 2 (PTGS2) between tumor and normal tissues, correlations with clinicopathological parameters, and associations with overall survival were analyzed using Gene Expression Profiling Interactive Analysis (http://gepia.cancer-pku.cn/) and Kaplan-Meier Plotter (http://kmplot.com).
Total RNA was isolated from Eca109 cells with stable hnRNPA2B1 knockdown and corresponding control cells using TRIzol reagent (Invitrogen, Thermo Fisher Scientific, Waltham, MA, United States). RNA purity and integrity were assessed using a NanoDrop spectrophotometer and an Agilent 2100 Bioanalyzer, and samples with RNA integrity number ≥ 7.0 were selected for library construction. Polyadenylated mRNA was enriched from 1 μg of total RNA, fragmented, and used for strand-specific complementary DNA library preparation with the TruSeq Stranded mRNA Library Prep Kit (Illumina, San Diego, CA, United States) according to the manufacturer’s instructions. Indexed libraries were quantified, pooled, and sequenced on an Illumina NovaSeq 6000 platform to generate 150-bp paired-end reads.
Adaptor sequences, low-quality reads, and reads containing more than 10% ambiguous bases were removed during quality control. Clean reads were aligned to the human reference genome (GRCh38) using HISAT2, and gene-level read counts were generated with featureCounts. Differential expression analysis between knockdown and control groups was performed using DESeq2 with default normalization settings, and genes with an adjusted P value < 0.05 were defined as differentially expressed. Hierarchical clustering and volcano plots were generated based on normalized gene expression values. Functional annotation of differentially expressed genes was performed using clusterProfiler, including Gene Ontology enrichment analysis for biological processes.
Human ESCC cell lines (Eca109 and KYSE150) and the immortalized esophageal epithelial cell line Het-1A were cultured in RPMI-1640 medium (Gibco, Thermo Fisher Scientific, Waltham, MA, United States) supplemented with 10% fetal bovine serum (Gibco, Thermo Fisher Scientific, Waltham, MA, United States), 100 U/mL penicillin, and 100 μg/mL streptomycin at 37 °C in a humidified incubator with 50 mL/L CO2. All cell lines were routinely tested and confirmed to be free of mycoplasma contamination. Cell identities were verified by short tandem repeat profiling. Cells were used at low passage numbers for all experiments.
Lentiviruses carrying hnRNPA2B1 short hairpin RNAs (sh-hnRNPA2B1-56-1, sh-hnRNPA2B1-57-12, and sh-hnRNPA2B1-58-1; for clarity, these are referred to as sh56-1, sh57-12, and sh58-1 throughout the manuscript) and the corresponding control (shCON), as well as lentiviruses for hnRNPA2B1 overexpression (OE) and its negative control (NC), were purchased from GeneChem Co., Ltd. (Shanghai, China). Cells were transduced at a multiplicity of infection of 20 and selected with puromycin (2 μg/mL) for 7 days. Infection efficiency was assessed by fluorescence microscopy, and knockdown or overexpression efficiency was validated by western blotting and reverse transcription-quantitative polymerase chain reaction (RT-qPCR).
Total protein was extracted using RIPA lysis buffer (Beyotime Biotechnology, Shanghai, China) containing protease and phosphatase inhibitors. Protein concentration was determined by bicinchoninic acid assay, and equal amounts were separated by sodium-dodecyl sulfate gel electrophoresis and transferred to polyvinylidene fluoride membranes. Membranes were blocked with 5% nonfat milk and incubated overnight at 4 °C with the following primary antibodies: Anti-hnRNPA2B1 (1:1000; Abcam, Cambridge, United Kingdom; Cat# ab259894), anti-COX-2 (1:1000; Cell Signaling Technology, Danvers, MA, United States; Cat# 12282S), anti-GAPDH (1:5000; Proteintech, Wuhan, China; Cat# 10494-1-AP), and anti-β-actin (1:5000; Proteintech, Wuhan, China; Cat# 20536-1-AP). After washing, membranes were incubated with HRP-conjugated secondary antibodies and visualized using enhanced chemiluminescence substrate (Clarity™ Western ECL Substrate; Bio-Rad, Cat#1705061). Band intensity was quantified by ImageJ software (version 1.53, National Institutes of Health, Bethesda, MD, United States). The full-length western blots are provided in Supplementary Figure 1.
Total RNA was extracted using TRIzol reagent, reverse-transcribed with PrimeScript RT kit (Takara Bio Inc., Shiga, Japan), and amplified with SYBR Green Master Mix (Takara Bio Inc., Shiga, Japan). Relative expression was calculated by the 2-ΔΔCt method using GAPDH as the internal control. Primer sequences are listed in Supplementary Table 1.
Cell proliferation was assessed using the cell counting kit-8 (Biosharp, Hefei, China). Briefly, 2 × 103 cells were seeded in 96-well plates and incubated for up to 5 days. Absorbance at 450 nm was measured daily. For colony formation assays, 1000 cells were seeded in 6-well plates and cultured for 14 days. Colonies were fixed with methanol, stained with 0.1% crystal violet, photographed, and counted.
For all in vitro functional assays, cells were treated with PGE2 (1 μmol/L; Selleck Chemicals, Houston, TX, United States; Cat# S3003)[18,19] or celecoxib (10 μmol/L; Selleck Chemicals, Houston, TX, United States; Cat# S1261)[20,21] as indicated, with 0.1% dimethyl sulfoxide (DMSO) serving as the vehicle control. Drug treatments were initiated 12 hours after cell seeding to allow cell attachment and were maintained throughout the experimental period unless otherwise specified.
For wound-healing assays, confluent cells were scratched with a sterile pipette tip, washed to remove debris, and incubated in serum-free medium. Wound closure was imaged at 0, 12, and 24 hours under a microscope to assess wound closure. Cells were treated with PGE2 (1 μM) or celecoxib (10 μM) as indicated, with 0.1% DMSO serving as the vehicle control.
For Transwell migration and invasion assays, 5 × 104 cells were seeded in the upper chambers of Transwell inserts (8 μm pore size; Labselect, Beijing, China; Cat# 14347) with or without Matrigel coating (for invasion). Medium containing 10% fetal bovine serum was added to the lower chamber as chemoattractant. After 24 hours, migrated or invaded cells were fixed, stained with crystal violet, and counted in five random fields. Cells were treated with PGE2 (1 μM) or celecoxib (10 μM) as indicated, and 0.1% DMSO served as the vehicle control.
PGE2 concentrations in culture supernatants were measured using an ELISA kit (Upingbio, Shanghai, China; Cat# YPJ1896) according to the manufacturer’s instructions. Absorbance was recorded at 450 nm and normalized to cell number.
For m6A RNA immunoprecipitation (MeRIP)-qPCR, total RNA was extracted, fragmented to approximately 100 nt, and incubated with an anti-m6A antibody (BersinBio, Guangzhou, China; Cat# Bes5203) or control IgG for immunoprecipitation. A portion of fragmented RNA was reserved as input. The immunoprecipitated RNA was then purified and subjected to RT-qPCR analysis using COX-2-specific primers.
For RIP-qPCR, cell lysates were prepared and incubated with magnetic beads conjugated with an anti-hnRNPA2B1 antibody or control IgG using the Magna RIP Kit (MilliporeSigma, St. Louis, MO, United States; Cat# 17-700) according to the manufacturer’s instructions. A portion of the lysate was saved as input. The co-immunoprecipitated RNAs were purified and analyzed by RT-qPCR to determine the enrichment of COX-2 mRNA.
Eca109 cells were treated with actinomycin D (5 μg/mL; Selleck Chemicals, Houston, TX, United States; Cat# S8964) to inhibit transcription. Total RNA was extracted at the indicated time points (0, 2, 4, and 6 hours) using TRIzol reagent (Invitrogen, United States). COX-2 mRNA levels were measured by RT-qPCR and normalized to GAPDH. Relative COX-2 mRNA abundance at each time point was calculated relative to that at 0 hour to assess mRNA decay.
Male BALB/c nude mice (6 weeks old) were obtained from Guangdong Yaokang Biotechnology Co., Ltd. (Foshan, Guangdong, China). Six mice were included in each group. The sample size was determined based on previous xenograft studies, experimental feasibility, and ethical considerations to minimize animal use. All animal procedures were designed to minimize pain and discomfort. Mice were housed under specific pathogen-free conditions at 22 ± 2 °C with 50% ± 10% humidity under a 12 hours light/dark cycle, with ad libitum access to food and water, and were acclimatized to the animal facility for 1 week before experimentation. A total of 5 × 106 Eca109 cells stably transduced with shCON, sh-hnRNPA2B1-56-1, NC, or OE were injected subcutaneously. Tumor volumes were measured with calipers (V = 0.5 × L × W2). At the endpoint, mice were euthanized by CO2 inhalation, and tumors were excised, weighed, and processed for hematoxylin and eosin and immunohistochemistry (IHC) staining. Tumor inhibition rate was calculated based on endpoint tumor weight using the following formula: Tumor inhibition rate (%) = (1 - mean tumor weight of treatment group/mean tumor weight of corresponding control group) × 100.
For pharmacological studies, tumor-bearing mice were monitored for 21 days in total. Treatment with celecoxib (20 mg/kg, intraperitoneally every other day) or vehicle control began 7 days after tumor formation and continued for 14 days[22,23]. Tumor size and weight were recorded. All animal experiments were reviewed and approved by the Institutional Animal Care and Use Committee of Fujian Medical University, No. 2022-NSFC-0403 and were performed in accordance with institutional guidelines.
Paraffin-embedded tissue sections were deparaffinized in xylene and rehydrated through graded ethanol solutions (100%, 95%, 80%, and 70%). Antigen retrieval was performed by heating sections in citrate buffer (pH 6.0; Servicebio, Wuhan, China; Cat# G1202) for 15 minutes. Endogenous peroxidase activity was blocked using 3% hydrogen peroxide (Servicebio, Wuhan, China; Cat# G0115) for 10 minutes, followed by blocking with 5% goat serum (Servicebio, Wuhan, China; Cat# G5001) for 30 minutes at room temperature.
Sections were incubated overnight at 4 °C with the following primary antibodies: Anti-hnRNPA2B1 (1:250; Abcam, Cambridge, United Kingdom; Cat# ab259894), anti-COX-2 (1:250; Cell Signaling Technology, Danvers, MA, United States; Cat# 12282S), and anti-Ki-67 (1:250; Abcam, Cambridge, United Kingdom; Cat# ab16667). After washing with phosphate-buffered saline, sections were incubated with an HRP-conjugated secondary antibody (Servicebio, Wuhan, China; Cat# G1215) for 50 minutes at room temperature. Signal was developed using a DAB substrate kit (ZSGB-Bio, Beijing, China; Cat# ZLI-9018), and nuclei were counterstained with hematoxylin (Servicebio, Wuhan, China; Cat# G1004). Finally, sections were dehydrated, cleared, and mounted with neutral resin (Servicebio, Wuhan, China; Cat# G8590) for mic
All in vitro experiments were independently performed at least three times as biological replicates, with technical replicates included where applicable. Data are presented as the mean ± SD. Comparisons between two groups were analyzed using the Student’s t-test. For comparisons among more than two groups, one-way ANOVA followed by appropriate post hoc tests was performed. When experiments involved two independent factors, two-way ANOVA was applied. Categorical variables were evaluated using the χ2 test or Fisher’s precision probability test. Correlations between continuous variables were assessed using Pearson’s correlation analysis. Overall survival was analyzed using the Kaplan-Meier method and compared with the log-rank test. A two-sided P < 0.05 was considered statistically significant. All statistical analyses were conducted using GraphPad Prism 10.0 (GraphPad Software, La Jolla, CA, United States) and SPSS Statistics 27.0 (IBM, Armonk, NY, United States).
To investigate the clinical significance of hnRNPA2B1 in ESCC, we first analyzed transcriptomic data from TCGA and Gene Expression Omnibus cohorts. HnRNPA2B1 was markedly upregulated in ESCA tissues compared with normal counterparts (Figure 1A and B). Expression levels increased with advancing clinical stage, with higher HnRNPA2B1 expression observed in more advanced tumors (Figure 1C). Kaplan-Meier survival analysis further demonstrated that patients with high hnRNPA2B1 expression had significantly worse overall survival than those with low expression (Figure 1D).
To assess hnRNPA2B1 expression in early lesions, we performed IHC staining on samples from ESD. HnRNPA2B1 expression was elevated in LGIN and further increased in HGIN (Figure 1E and F). These findings are consistent with recent single-cell spatial atlases revealing early molecular alterations during esophageal carcinogenesis[24]. In line with these observations, tissue microarray analysis revealed stronger hnRNPA2B1 staining in ESCC compared with adjacent and distant normal tissues (Figure 1G and H). Elevated hnRNPA2B1 expression correlated positively with pathological grade (Table 1). In matched ESCC patient samples, both hnRNPA2B1 protein and mRNA levels were significantly higher in tumors than in adjacent normal tissues (Figure 1I and J). Moreover, elevated hnRNPA2B1 expression was also detected in ESCC cell lines (Eca109, KYSE150) compared with the normal esophageal epithelial cell line Het-1A (Figure 1K and L). Collectively, these results demonstrate that hnRNPA2B1 is aberrantly upregulated in ESCC, detectable even at the stage of LGIN, and positively associated with tumor stage, grade, and poor prognosis, suggesting a role in early malignant transformation.
| Variables | HnRNPA2B1 expression | P1 value | |
| High | Low | ||
| Age (years) | |||
| < 60 | 11 | 7 | 1.000 |
| ≥ 60 | 8 | 4 | |
| Gender | |||
| Female | 4 | 3 | 1.000 |
| Male | 15 | 8 | |
| Grade | |||
| I | 6 | 9 | 0.021 |
| II-III | 13 | 2 | |
| Tumor size (cm) | |||
| < 5 | 16 | 6 | 0.104 |
| ≥ 5 | 3 | 5 | |
| Lymph node metastasis | |||
| N0 | 11 | 5 | 0.412 |
| N+ | 4 | 4 | |
| COX-2 expression | |||
| High | 18 | 5 | 0.004 |
| Low | 1 | 6 | |
To investigate the functional role of hnRNPA2B1, we established stable knockdown in Eca109 and KYSE150 cells using three independent short hairpin RNA plasmids (sh56-1, sh57-12, and sh58-1) (Supplementary Figure 2A and B). Knockdown efficiency was confirmed by green fluorescent protein fluorescence imaging, western blotting, and RT-qPCR (Supplementary Figure 2C; Figure 2A and B). Among them, sh56-1 achieved the most robust suppression and was selected for subsequent experiments. In parallel, stable hnRNPA2B1 overexpression was generated in Eca109, KYSE150, and the non-malignant esophageal epithelial cell line Het-1A (Supplementary Figure 2D), with overexpression validated by green fluorescent protein fluorescence, protein and mRNA analysis (Supplementary Figure 2E; Figure 2C and D). These models provided a reliable system for functional characterization of hnRNPA2B1.
Using these models, we next evaluated the impact of hnRNPA2B1 on cell growth. Cell counting kit-8 assays showed that hnRNPA2B1 knockdown markedly inhibited proliferation of Eca109 and KYSE150 cells. By contrast, hnRNPA2B1 overexpression enhanced proliferation in both ESCC cells and Het-1A cells (Figure 2E). Consistently, colony formation assays in Eca109 cells showed that hnRNPA2B1 knockdown reduced clonogenic capacity, whereas hnRNPA2B1 overexpression promoted colony formation (Figure 2F and G).
We further assessed the effects of hnRNPA2B1 on cell motility. Transwell assays demonstrated that hnRNPA2B1 silencing significantly suppressed both migration and invasion of Eca109 cells, whereas hnRNPA2B1 overexpression markedly promoted these phenotypes (Figure 2H and I). Wound-healing assays confirmed that hnRNPA2B1 knockdown impaired, while overexpression accelerated migratory capacity (Figure 2J and K). These findings demonstrate that hnRNPA2B1 enhances ESCC cell proliferation, migration, and invasion in vitro.
To identify potential downstream effectors of hnRNPA2B1, we performed bulk RNA-seq in Eca109 cells with or without hnRNPA2B1 knockdown. PTGS2, which encodes COX-2, was among the significantly downregulated genes after hnRNPA2B1 silencing (Figure 3A and B). Gene Ontology enrichment analysis revealed that hnRNPA2B1-regulated genes were mainly enriched in metabolic and redox-related pathways, including oxidation-reduction processes, organic acid metabolism, and oxidoreductase activity (Figure 3C). These findings suggest that hnRNPA2B1 may regulate multiple biological processes in ESCC.
To further support the association between hnRNPA2B1 and COX-2 in patient datasets, TCGA pan-cancer profiling showed that PTGS2 expression was elevated across multiple tumor types, including ESCA (Figure 3D). Comparative analysis of normal, primary, and metastatic tissues demonstrated increased expression of both hnRNPA2B1 and PTGS2 during tumor progression (Figure 3E). Correlation analysis in ESCA samples further confirmed a positive association between hnRNPA2B1 and PTGS2 expression (Figure 3F).
To further validate the association between hnRNPA2B1 and COX-2, we first examined COX-2 expression in ESCC cell lines. Western blotting and RT-qPCR revealed that COX-2 levels were markedly higher in tumor tissues and ESCC cell lines compared with normal controls (Figure 4A-D), consistent with previous findings that COX-2 is significantly overexpressed in ESCC or hepatocellular carcinoma compared with adjacent non-tumorous tissues[25,26]. Silencing hnRNPA2B1 decreased COX-2 expression. In contrast, hnRNPA2B1 overexpression led to increased levels of COX-2 (Figure 4E-H). Similar to hnRNPA2B1 expression, immunohistochemical analysis of ESD specimens revealed that COX-2 expression was elevated in LGIN and further upregulated in HGIN (Figure 4I and J). Consistently, COX-2 staining was markedly stronger in ESCC tissues compared with adjacent or distant normal tissue (Figure 4K and L).
We then performed MeRIP-qPCR to determine whether COX-2 mRNA harbors m6A modification, and observed significant enrichment in the m6A immunoprecipitated fraction (Figure 4M). RIP-qPCR further confirmed the association between hnRNPA2B1 and COX-2 transcripts, which was reduced by hnRNPA2B1 knockdown and enhanced by hnRNPA2B1 overexpression (Figure 4N). Actinomycin D assays showed that hnRNPA2B1 knockdown accelerated, whereas hnRNPA2B1 overexpression delayed, COX-2 mRNA decay (Figure 4O). Collectively, these data indicate that hnRNPA2B1 promotes COX-2 expression by stabilizing its mRNA through an m6A-related mechanism, and that COX-2 expression follows a pattern similar to that of hnRNPA2B1 during ESCC progression.
To determine the functional significance of the hnRNPA2B1-COX-2/PGE2 axis, we first measured PGE2 production. ELISA revealed that PGE2 secretion was reduced after hnRNPA2B1 knockdown and elevated upon hnRNPA2B1 overexpression (Figure 5A). We next investigated whether PGE2 supplementation or COX-2 inhibition modulates hnRNPA2B1-driven phenotypes. Exogenous PGE2 partially rescued the proliferation defects induced by hnRNPA2B1 silencing, while celecoxib treatment markedly suppressed proliferation and colony formation in hnRNPA2B1-overexpressing cells (Figure 5B-D). Consistently, functional assays showed that PGE2 supplementation restored, whereas celecoxib signi
To assess whether the in vitro observations translated into tumorigenic potential in vivo, we established xenograft models using Eca109 cells with stable hnRNPA2B1 knockdown or overexpression. Tumors derived from hnRNPA2B1-knockdown cells exhibited markedly slower growth and reduced final volume and weight, whereas hnRNPA2B1 overexpression significantly accelerated tumor growth (Figure 6A and B). Based on endpoint tumor weight, the tumor inhibition rate of hnRNPA2B1 knockdown was 43.94% compared with the shCON group. Histological examination confirmed tumor formation, and IHC demonstrated decreased hnRNPA2B1, COX-2 and Ki-67 staining in knockdown tumors, with the opposite pattern observed in hnRNPA2B1-overexpressing xenografts (Figure 6C and D). These results indicate that hnRNPA2B1 promotes ESCC tumor growth in vivo.
To further evaluate the therapeutic relevance of the hnRNPA2B1-COX-2/PGE2 axis, we administered celecoxib in xenograft-bearing mice (Figure 6E). Celecoxib treatment significantly suppressed tumor growth, as evidenced by reduced tumor volume and weight (Figure 6F and G). Based on endpoint tumor weight, the tumor inhibition rates were 67.31% for celecoxib treatment in hnRNPA2B1-overexpressing xenografts compared with the OE + vehicle group and 60.50% for celecoxib treatment in Eca109 xenografts compared with the Eca109 + vehicle group. IHC analysis further revealed decreased COX-2 and Ki-67 expression in treated tumors (Figure 6H and I). Together, these findings validate that the oncogenic effects of hnRNPA2B1 in ESCC are mediated, at least in part, by the COX-2/PGE2 axis, and that pharmacological inhibition of COX-2 attenuates hnRNPA2B1-driven tumor growth in vivo.
In this study, we identified hnRNPA2B1 as an oncogenic m6A reader that promotes the progression of ESCC through stabilization of COX-2 mRNA and activation of the COX-2/PGE2 axis. HnRNPA2B1 was markedly upregulated in ESCC and early intraepithelial neoplasia, correlating with pathological grade and poor survival. Functional experiments demonstrated that hnRNPA2B1 enhances tumor cell proliferation, migration, invasion, and xenograft growth. Mechanistically, hnRNPA2B1 was associated with m6A -modified COX-2 transcripts, stabilized their mRNA, and augmented COX-2/PGE2 axis (Figure 7). Importantly, exogenous PGE2 supplementation restored the suppressed phenotypes caused by hnRNPA2B1 silencing, whereas celecoxib treatment abrogated hnRNPA2B1-induced tumorigenic effects both in vitro and in vivo.
Previous studies have demonstrated diverse oncogenic roles of hnRNPA2B1 across multiple tumor types, including lung, breast, and liver cancers[27,28]. In ESCC, Guo et al[29] reported that hnRNPA2B1 upregulates ACLY and ACC1 to enhance de novo fatty acid synthesis, while Li et al[16] demonstrated that hnRNPA2B1 modulates the oncogenic miR-17-92 cluster to influence tumor progression. HnRNPA2B1 has been reported to dynamically shuttle between the nucleus and cytoplasm, where it participates in mRNA export and stability[27-30]. This dynamic localization may partly explain its potential dual function in transcriptional and post-transcriptional regulation of COX-2, as suggested in previous studies. Unlike these metabolic or microRNA-mediated mechanisms, our findings identify a distinct m6A-related post-transcriptional mechanism by which hnRNPA2B1 stabilizes COX-2 mRNA, thereby contributing to inflammation-associated tumor progression.
COX-2, a rate-limiting enzyme in prostaglandin biosynthesis[17], is frequently overexpressed in ESCC and contributes to proliferation, invasion, angiogenesis, and immune evasion[31,32]. COX-2 regulation by hnRNPA2B1 appears to be multilayered. Xuan et al[33] reported transcriptional activation of COX-2 via hnRNPA2B1-p300 interaction in lung cancer, whereas our work demonstrates post-transcriptional mRNA stabilization in ESCC. Beyond RNA methylation, broader epigenetic alterations also contribute to ESCC initiation; for example, CBX family upregulation correlates with TP53 mutations and immune infiltration[34]. Consistent with this epigenetic landscape, another study recently established a genetically engineered esophageal organoid model showing that Trp53 knockout or KrasG12D expression is sufficient to induce squamous neoplastic transformation, recapitulating early transcriptional and chromatin alterations characteristic of ESCC initiation[35]. Together, these findings suggest that early genetic alterations, particularly TP53 loss, create an epigenetically permissive environment that cooperates with inflammation-associated pathways such as hnRNPA2B1-mediated COX-2 activation to drive ESCC development. The identification of an hnRNPA2B1-COX-2/PGE2 axis carries important translational implications. COX-2/PGE2 axis is a well-established driver of tumorigenesis[36,37], and our data provide a mechanistic rationale for therapeutic targeting of this pathway in ESCC. In this study, PGE2 was selected as the major functional downstream readout of COX-2 activity, whereas other COX-2-derived prostanoids were not examined and may be worthy of further investigation in future studies. Although our study did not directly assess immune modulation, the known role of COX-2/PGE2 axis in recruiting myeloid-derived suppressor cells and regulatory T cells and suppressing cytotoxic T-cell responses[38,39] suggests that hnRNPA2B1-driven activation of this pathway may also contribute to an immunosuppressive tumor microenvironment in ESCC. While the clinical benefit of celecoxib mono
Despite these advances, several limitations should be acknowledged. Although our findings were validated in cell lines, tissue microarrays, and xenograft models, larger clinical cohorts with complete follow-up and clinicopathological information are needed to confirm the prognostic value of hnRNPA2B1 and its correlation with COX-2 in ESCC. In addition, our survival analysis was based primarily on public TCGA-ESCA data; although this dataset provides useful exploratory evidence, the number of available cases and clinicopathological variables suitable for comprehensive Cox regression analysis were limited. Moreover, while COX-2 was identified as a key downstream effector, hnRNPA2B1 may also regulate additional oncogenic transcripts and pathways, including metabolic and redox-related processes suggested by our RNA-seq analysis, which warrant further exploration[41-43]. Although our in vivo experiments using subcu
In conclusion, our study identifies hnRNPA2B1 as an oncogenic m6A reader that stabilizes COX-2 mRNA and promotes ESCC progression through the COX-2/PGE2 axis. These findings provide new mechanistic insight into COX-2 dysregulation and highlight hnRNPA2B1 as a potential therapeutic target and biomarker for precision treatment of ESCC.
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