Published online Jul 15, 2026. doi: 10.4251/wjgo.119282
Revised: February 28, 2026
Accepted: April 14, 2026
Published online: July 15, 2026
Processing time: 157 Days and 20.6 Hours
Gastric cancer (GC) remains one of the leading causes of cancer-related mortality globally and is associated with poor patient prognosis, which highlights an urgent need to identify effective biomarkers and therapeutic targets. N6-methylade
To investigate the role of IGF2BP1 in the progression of GC.
The IGF2BP1 expression in GC tissues was assessed via immunohistochemistry and correlated with clinicopathological characteristics. Gain-of-function and loss-of-function experiments were performed to explore the functional roles of IGF2BP1 and its potential downstream target in GC cells and a nude mouse xenograft model. Cell proliferation, migration, and invasion were assessed using cell counting kit-8, wound-healing, and Transwell assays. RNA sequencing, methylated RNA immunoprecipitation quantitative polymerase chain reaction, and dual-luciferase reporter assays were conducted to elucidate the molecular mechanisms involved.
The IGF2BP1 was significantly upregulated in GC tissues and was positively associated with lymph node metastasis and poor overall survival. Functionally, IGF2BP1 knockdown inhibited GC cell proliferation, migration, and invasion in vitro and attenuated tumor growth in vivo. Integrated multi-omics analysis identified heparan sulfate 6-O-sulfotransferase 2 (HS6ST2) as a key downstream target of IGF2BP1. IGF2BP1 recognized and bound to m6A-modified sites within HS6ST2 mRNA, thereby enhancing its stability in an m6A-dependent manner. Rescue experiments confirmed that HS6ST2 mediated the oncogenic effects of IGF2BP1. Additionally, HS6ST2 knockdown inhibited the malignant characteristics of GC cells and triggered apoptosis, which was associated with inactivation of the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin signaling pathway.
These findings demonstrated that IGF2BP1 drives GC progression by stabilizing HS6ST2 mRNA via m6A modification. The IGF2BP1/HS6ST2 axis may serve as a potential prognostic biomarker and therapeutic inter
Core Tip: Insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) is an N6-methyladenosine reader that is highly expressed in gastric cancer (GC) and is associated with lymph node metastasis and poor prognosis. This study elucidates the oncogenic mechanism of IGF2BP1 via its downstream target, heparan sulfate 6-O-sulfotransferase 2 (HS6ST2). Both in vitro and in vivo analyses demonstrate that IGF2BP1 stabilizes HS6ST2 mRNA in an N6-methyladenosine-dependent manner, which, in turn, activates the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin signaling pathway, thereby driving GC cell proliferation, invasion, and metastasis. Taken together, these results may identify the IGF2BP1/HS6ST2 axis as a potential prognostic biomarker and therapeutic target in GC.
- Citation: Liu L, Zhou YJ, Xu Y, Yin QQ, Wang JJ, Xu SJ, Yan LL, Wang ZZ, Li SW, Mao XL, Zhang Y. IGF2BP1 promotes gastric cancer progression by stabilizing HS6ST2 mRNA in an N6-methyladenosine-dependent manner. World J Gastrointest Oncol 2026; 18(7): 119282
- URL: https://www.wjgnet.com/1948-5204/full/v18/i7/119282.htm
- DOI: https://dx.doi.org/10.4251/wjgo.119282
Gastric cancer (GC) remains a major cause of cancer-related mortality and morbidity worldwide[1]. Despite advances in early detection and radical surgical resection, the prognosis of GC remains unfavorable, particularly for patients with metastatic disease[2]. Recent advances in immunotherapy and biomarker-guided therapy have provided new therapeutic opportunities[3]. However, the identification of more effective biomarkers and therapeutic targets is still urgently needed.
N6-methyladenosine (m6A) is the most abundant internal chemical modification of eukaryotic mRNA and non-coding RNA and plays an important role in regulating multiple processes in the RNA life cycle[4]. This reversible process involves the methylation of adenine at the nitrogen-6 position[5] and is dynamically regulated by three classes of proteins: Methyltransferases (writers), demethylases (erasers), and binding proteins (readers)[6]. Writer complexes, such as methyltransferase-like (METTL) 3 and METTL14, rapidly increase the methylation of adenosine[7]. Next, erasers such as fat mass and obesity-associated protein[8] and alkB homolog 5[9] remove these modifications, ensuring their reversibility. Reader proteins, such as members of the YTH domain family[10] and the insulin-like growth factor 2 mRNA-binding protein (IGF2BP) family[11], selectively recognize m6A-modified sites and fine-tune gene expression post-transcriptionally by influencing RNA stability, translation, and degradation.
The coordinated actions of these proteins make m6A modification a part of important biological processes such as cell differentiation[12], embryonic development[13], immune responses[14], and circadian rhythm control[15]. Dysregulation of m6A methylation can disrupt the balanced expression of proto-oncogenes and tumor suppressor genes, thereby promoting tumorigenesis, cancer progression, and therapeutic resistance[16]. Consequently, m6A modification has emerged as a growing frontier in cancer research and a promising avenue for the development of novel diagnostic and therapeutic strategies.
IGF2BP1 is a highly conserved RNA-binding protein that recognizes m6A modifications and enhances the stability of its target mRNAs, thereby regulating gene expression and tumor-related signaling pathways[17,18]. IGF2BP1 is an oncofetal protein that is highly expressed during embryogenesis, suppressed in most adult tissues, and frequently re-expressed in various cancers[19]. Its overexpression is associated with poor prognosis in multiple cancer types, including colorectal cancer[20,21], hepatocellular carcinoma[22,23], and lung cancer[24,25].
Our preliminary immunohistochemical (IHC) analysis demonstrated that IGF2BP1 expression was significantly upregulated in GC tissues with lymph node metastasis and during metastatic progression. However, the precise mechanism through which IGF2BP1 facilitates lymph node metastasis in GC remains unclear. This study seeks to examine the influence of IGF2BP1 on the malignant phenotypes of GC cells and to clarify the underlying molecular mechanisms, thereby providing experimental evidence to assess its viability as a diagnostic biomarker and therapeutic target in GC.
Human GC tissues and paired adjacent non-tumor tissues were collected from Taizhou Hospital Affiliated with Wenzhou Medical University in China. All patients were diagnosed based on postoperative pathological examination. GC cell lines were purchased from FuHeng Biology (Shanghai, China). Cell line authentication was performed using short tandem repeat profiling, and all cell lines were confirmed to be free of mycoplasma contamination. Cells were cultured in the appropriate medium supplemented with 10% fetal bovine serum and 1% penicillin-streptomycin (YEASEN, Shanghai, China) and maintained at 37 °C in a humidified room with 5% CO2.
IHC staining was performed following a standard protocol as previously described[26]. Briefly, tissue samples were fixed in 4% paraformaldehyde for 24-48 hours, then dehydrated, embedded in paraffin, and cut into sections. After deparaffinization, rehydration, and antigen retrieval, 3% H2O2 was used to block endogenous peroxidase activity. The sections were then incubated overnight at 4 °C with primary antibodies against m6A, IGF2BP1, and heparan sulfate 6-O-sulfotransferase 2 (HS6ST2; all from Abcam, Cambridge, United Kingdom), CD33 (Biodragon, Jiangsu Province, China), and periostin (POSTN; Immunoway, San Jose, CA, United States). Following this, sections were treated with corresponding secondary antibodies for 1 hour at room temperature, followed by chromogenic detection with 3,3′-diaminobenzidine.
For quantitative analysis, three representative high-power fields (× 100 magnification) were randomly selected per section. All images were acquired under identical lighting conditions. The mean optical density and percentage of positively stained area (brown) were quantified using Fiji software to assess target protein expression.
Lentiviral vectors for the overexpression or knockdown of IGF2BP1/HS6ST2, along with their control vectors, were purchased from GeneChem (Shanghai, China). GC cell lines were transduced with an appropriate volume of lentiviral supernatant according to the respective viral titers provided by the manufacturer. Stable transduced cell lines were selected using culture medium containing 2 μg/mL of puromycin or neomycin for 48-72 hours. Quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and western blotting confirmed the effectiveness of gene overexpression or knockdown.
Total RNA was extracted from cells using Trizol reagent (Ambion, Austin, TX, United States), according to the manufacturer’s instructions. Complementary DNA was synthesized using the PrimeScript™ RT Reagent Kit (Cat#RR037A; Takara, Tokyo, Japan). qRT-PCR was performed using TB Green™ Premix Ex Taq™ (Cat. No. RR820A; Takara, Tokyo, Japan) on a QuantStudio™ 3 real-time qRT-PCR system (Thermo Fisher Scientific, MA, United States). Relative gene expression levels were calculated using the 2-ΔΔCt, with gyceraldehyde-3-phosphate dehydrogenase (GAPDH) serving as the internal control. Primer sequences used for qRT-PCR were synthesized by RiboBio (Guangzhou, Guangdong Province, China).
Total cellular protein was extracted using radioimmunoprecipitation assay lysis buffer supplemented with protease and a phosphatase inhibitor cocktail (Beyotime, Shanghai, China). Protein bands were visualized using an enhanced chemiluminescence detection kit (Millipore, Billerica, MA, United States). The details of the primary antibodies are shown in the Supplementary material.
Cell proliferation was assessed using the cell counting kit-8 (CCK-8) assay. 1 × 103 cells per well were seeded in 96-well plates and cultured for 24 hours, 48 hours, 72 hours, and 96 hours. For measurement, 10 μL of CCK-8 reagent was added to each well containing 90 μL of fresh Roswell Park Memorial Institute 1640 medium. After incubation at 37 °C for 2 hours (protected from light), the absorbance at 450 nm was determined with a microplate reader (Thermo Fisher Scientific, MA, United States).
Cell migration was evaluated using a wound-healing assay. Briefly, transfected GC cells were seeded into 6-well plates and grown until they reached 80%-90% confluence. A sterile 200-μL pipette tip was used to draw a straight line across the cell monolayer. After washing with phosphate-buffered saline to remove detached cells, the cultures were maintained in a medium with 1% fetal bovine serum. Wound closure was observed and photographed at 0 hour, 24 hours, and 48 hours using an inverted microscope (× 40 magnification; Thermo Fisher Scientific, MA, United States). The wound-healing rate was calculated using the formula: Wound healing rate = 100% × [(wound width at 0 hour - wound width at 24/48 hours)/wound width at 0 hour].
Cell migration and invasion assays were performed using 24-well Transwell chambers (8.0-μm pore size, 6.5-mm diameter; Corning, NY, United States). For invasion assays, the upper chambers were precoated with Matrigel (BD Biosciences, NJ, United States). Briefly, 100 μL of cell suspension [(2-5) × 104 cells/mL] in serum-free medium was seeded into the upper chamber. The lower chamber was filled with culture medium containing 10% fetal bovine serum as a chemoattractant. After incubation for 24 hours, the cells on the upper surface of the membrane were carefully removed using a cotton swab. Then treat the cells with 4% paraformaldehyde and 0.1% crystal violet. Stained cells were visualized under a light microscope, and the number of cells was quantified in three randomly chosen fields per chamber using ImageJ software (version 1.6.0).
Six-week-old BALB/c nude mice were obtained from Hangzhou Paisio Biotechnology Co., Ltd. (Hangzhou, Zhejiang Province, China). The animals were acclimatized for 2 weeks under standard laboratory conditions (23 °C, 12 hours/12 hours light/dark, 50% humidity) with ad libitum access to food and water before experimentation. Stable GC cells (1 × 106 cells per mouse) were resuspended in sterile phosphate-buffered saline and subcutaneously injected into the flank of each mouse. Tumor length (R) and width (r) were measured weekly using digital calipers starting 1 week after inoculation. Tumor volume was calculated using the formula V = R × r2/2. At the end of the experiment, all animals were euthanized by overdose of pentobarbital sodium (intravenous injection, 150 mg/kg) for tissue collection.
Methylated RNA immunoprecipitation (MeRIP) experiments were performed using protein A/G Magnetic Beads (Cat. No. Bes5203-1; BersinBio, Guangzhou, Guangdong Province, China), according to the manufacturer’s instructions.
RNA immunoprecipitation (RIP) experiments were performed using protein A/G Magnetic Beads (Cat. No. Bes5101; BersinBio, Guangzhou, Guangdong Province, China), according to the manufacturer’s instructions.
SGC7901 and MGC803 cells were inoculated in six-well plates. After 24 hours, the cells were treated with actinomycin D (5 μg/mL, GC16866, GLPBIO, USA). Subsequently, total RNA was extracted at 0 hour, 3 hours, and 6 hours and then analyzed by qRT-PCR.
Wild-type and mutant reporter plasmids were constructed by Ruipute Biotechnology (Hangzhou, Zhejiang Province, China). Briefly, fragments of the HS6ST2 mRNA 3’ untranslated region containing the predicted m6A consensus motifs were cloned into the pcDNA3.1-LUC luciferase reporter vector to create the wild-type reporter. Mutant reporter constructs deficient in m6A modification were generated by site-directed mutagenesis, in which adenine residues within the core m6A motifs were substituted with cytosine. For the assay, GC cells were co-transfected with the reporter constructs along with either an IGF2BP1 overexpression plasmid or its corresponding empty vector control. Luciferase activity was measured using a dual-luciferase reporter assay system, and firefly luciferase activity was normalized to Renilla luciferase activity for each sample.
When cells reached 70%-80% confluence, they were harvested by trypsinization. Apoptosis was assessed using the Apoptosis and Necrosis Assay Kit (Cat. No. C1056; Beyotime, Shanghai, China) in strict accordance with the manu
Statistical analyses were conducted using GraphPad Prism software (version 9.0) and R software (version 4. 4. 3). The sample size for IHC analysis was determined a using a power analysis conducted with G*Power software (version 3.1.9.7). The analysis was configured for a two-tailed Wilcoxon signed-rank test (matched pairs), with an anticipated effect size (Cohen’s d), a significance level (α), and a target statistical power. The statistical power for all analyses was well above the conventional threshold of 80%, indicating that the sample size was sufficient to reliably detect the observed intergroup differences. The normality of data distribution was assessed using the Shapiro-Wilk test, and the equality of variances was evaluated with Levene‘s test. For comparisons between two groups, if the data met the assumptions of normality and homogeneity of variances, an unpaired two-tailed Student’s t-test was applied; otherwise, the non-parametric Mann-Whitney U test was used.
The Wilcoxon signed-rank test was used to assess the disparities in IHC scores between GC tissues and paired adjacent non-tumor tissues. The Pearson χ² test was used to analyze correlations between protein expression levels and clinicopathological parameters. The correlation coefficient (R-value) and P-values between two genes were calculated using Pearson correlation analysis. Comparisons between two groups were conducted using an unpaired two-tailed Student’s t-test. For comparisons involving more than two groups, one-way or two-way analysis of variance (ANOVA) was employed, followed by appropriate post hoc tests. Data are presented as the mean ± SD. All experiments were independently repeated at least three times. A P-value of less than 0.05 was considered statistically significant.
To elucidate the potential role of m6A modification in GC progression, we initially assessed m6A levels via IHC in 36 human GC tissue samples with or without lymph node metastasis. The findings indicated that m6A expression was markedly elevated in GC tissues exhibiting lymph node metastasis compared with those without metastasis (Figure 1A). Analysis of the Gene Expression Omnibus dataset GSE17187 indicated that IGF2BP1 and IGF2BP3 were markedly upregulated in GC tissues exhibiting lymph node metastasis (Figure 1B). To further assess the clinical prognostic value of IGF2BP1 and IGF2BP3, we performed Kaplan-Meier survival analysis using stomach adenocarcinoma (STAD) data. Investigations indicated that elevated expression of IGF2BP1 was significantly associated with reduced overall survival (Figure 1C), whereas IGF2BP3 expression showed no significant correlation with patient prognosis (Supplementary Figure 1A). Consequently, IGF2BP1 was selected for subsequent investigations. Consistently, STAD data corroborated that patients with GC with lymph node metastasis exhibited a markedly inferior overall survival compared with those without metastasis, in accordance with established clinical consensus (Figure 1D and Supplementary Figure 1B). Compared to normal gastric tissues, IGF2BP1 expression was significantly upregulated in GC tissues of stage II, stage III, and stage IV, suggesting its high expression is associated with tumor progression (Supplementary Figure 1C). Furthermore, we found that IGF2BP1 was strongest in the intestinal type, particularly the tubular adenocarcinoma subtype. In contrast, we observed no significant upregulation in diffuse-type carcinomas, including signet-ring cell carcinoma and papillary adenocarcinoma (Supplementary Figure 1D). Kruskal-Wallis test revealed highly significant differences in IGF2BP1 expression among the four major molecular subtypes (chromosomal instability, Epstein-Barr virus, genomic stability, microsatellite instability). Notably, the most significant finding was that IGF2BP1 expression levels were significantly higher in the EBV-positive subtype compared to others (Supplementary Figure 1E).
Based on these findings, IHC was performed on a tissue microarray comprising 76 GC tissues and their paired adjacent non-tumor counterparts. IHC analysis showed that IGF2BP1 was much more active in GC tissues than in the adjacent controls (Figure 1E). Patients were subsequently categorized into low- and high-expression groups according to the mean IGF2BP1 expression level. Further examination of the relationship between IGF2BP1 expression and the clinical attributes of patients with GC revealed no significant correlation with age or pathological stage. In contrast, IGF2BP1 expression was significantly associated with sex and the status of lymph node metastasis (Table 1). Furthermore, lymph node status (N stage) exhibited a strong inverse correlation with patient survival, where overall survival rates declined significantly with advancing N stage (Supplementary Figure 1F).
| Variables | Cases (n) | IGF2BP1 expression | P value | |
| Low | High | |||
| Age in years | 0.303 | |||
| ≥ 60 | 37 | 5 (13.5) | 32 (86.5) | |
| < 60 | 35 | 8 (22.9) | 27 (77.1) | |
| Sex | 0.017a | |||
| Male | 48 | 5 (10.4) | 43 (89.6) | |
| Female | 24 | 8 (33.3) | 16 (66.7) | |
| Pathological stage | 0.759 | |||
| I/II | 36 | 7 (19.4) | 29 (80.6) | |
| III/IV | 36 | 6 (16.7) | 30 (83.3) | |
| Lymph node metastasis | 0.013a | |||
| No | 19 | 7 (36.8) | 12 (63.2) | |
| Yes | 53 | 6 (11.3) | 47 (88.7) | |
To further elucidate the role of IGF2BP1 in metastatic GC, we initially examined its mRNA expression profile across GC cell lines using the Dependency Map database. IGF2BP1 expression demonstrated considerable heterogeneity among different GC cell lines and molecular subtypes (Figure 1F). To validate these findings at the protein level, we selected four GC cell lines for western blot analysis. Consistent with the mRNA expression data, the protein levels of IGF2BP1 were notably higher in SGC-7901 and MGC803 cells (Figure 1G). Subsequently, stable IGF2BP1 knockdown cell lines were generated using short hairpin-RNA in MGC803 and SGC-7901 cells. The knockdown efficiency was verified at the mRNA (Figure 2A and B) and protein (Figure 2C and D) levels. These two cell lines were therefore chosen for subsequent fun
To further investigate the biological significance of IGF2BP1 in GC progression, we assessed its impact on tumor cell behaviors in vitro. Transwell migration and invasion assays (Figure 2E) and wound healing assays (Figure 2F) demon
To evaluate the oncogenic function of IGF2BP1 in vivo, we developed a xenograft tumor model by subcutaneously injecting nude mice with GC cells. Consistent with the in vitro findings, tumors derived from IGF2BP1-knockdown cells exhibited significantly reduced average tumor volume and weight, as well as slower kinetics of tumor growth, compared to the control group (Figure 3A and B).
IGF2BP1 is an m6A reader protein that selectively recognizes and binds certain m6A-modified transcripts to exert its regulatory effects. To identify key oncogenic targets of IGF2BP1 in metastatic GC, we integrated our internal functional genomics data with public database resources. A multi-tiered integrative analysis was performed by combining RNA sequencing data from IGF2BP1-knockdown MGC803 cells, public GC datasets (MeRIP-seq: GSE163310; IGF2BP1 RIP-seq: GSE90639), and gene sets significantly associated with poor prognosis in the STAD cohort. This comprehensive approach identified HS6ST2 and SH3-domain binding protein 1 (SH3BP1) at the core intersection of these gene sets (Figure 3C).
Validation with the STAD cohort demonstrated a significant positive relationship between IGF2BP1 expression and HS6ST2 (Figure 3D) as well as SH3BP1 expression (Supplementary Figure 2A), suggesting potential co-regulation. However, Kaplan-Meier survival analysis revealed their distinctly different clinical significance. High HS6ST2 expression was linked to shorter overall survival (Figure 3E), whereas SH3BP1 expression showed no significant prognostic value (Supplementary Figure 2B). Consistently, IHC analysis of our tissue microarray (76 GC/adjacent non-tumor tissue pairs) further confirmed that HS6ST2 protein expression was markedly increased in GC tissues compared with adjacent non-tumor tissues (Figure 3F). Pearson correlation analysis revealed a highly significant positive correlation between the protein expression levels of IGF2BP1 and HS6ST2 in clinical GC samples (Supplementary Figure 2C). As IGF2BP1 stabilizes target mRNAs and facilitates their translation in an m6A-dependent manner, we hypothesized that it upregulates HS6ST2 through this mechanism. Analysis using the sequence-based RNA adenosine methylation site predictor prediction tool identified multiple high-confidence m6A modification sites within the HS6ST2 mRNA (Figure 3G). An MeRIP-quantitative polymerase chain reaction assay confirmed significant enrichment of HS6ST2 mRNA in both SGC-7901 and MGC803 cells compared with the Input control (Figure 3H) and the GAPDH negative control (Supplementary Figure 2D). RIP-quantitative polymerase chain reaction assays were performed in SGC7901 and MGC803 cells using an IGF2BP1-specific antibody with the Input control. Compared to the IgG control group and the GAPDH negative control, the IGF2BP1 antibody group exhibited significant enrichment of HS6ST2 mRNA (Supplementary Figure 2E). Furthermore, gain-and loss-of-function experiments revealed that IGF2BP1 directly modulates the m6A modification status of HS6ST2. Specifically, knockdown of IGF2BP1 in SGC-7901 cells significantly decreased m6A enrichment on HS6ST2 mRNA (Figure 3I), whereas its overexpression in MGC803 cells resulted in a marked increase in HS6ST2 m6A modification levels (Figure 3J). To demonstrate that IGF2BP1 regulates HS6ST2 in an m6A-dependent manner, we conducted a dual luciferase reporter assay. The results showed that overexpression of IGF2BP1 significantly enhanced the reporter gene activity containing the 3’UTR of wild-type HS6ST2 (Figure 3K). In contrast, this activating effect was completely abolished when the predicted m6A site was mutated (Figure 3L). In addition, silencing of IGF2BP1 reduced the stability of HS6ST2 mRNA after actinomycin D treatment, whereas IGF2BP1 overexpression produced the opposite effect (Supplementary Figure 2F and G).
HS6ST2, a key sulfotransferase involved in heparan sulfate modification, regulates multiple signaling pathways and has been associated with cancer progression[27]. To investigate the functional role of HS6ST2 in GC, we assessed its effects on GC cell behaviors in vitro. Stable HS6ST2-knockdown SGC-7901 cells and HS6ST2-overexpressing MGC803 cells were established, with transfection efficiency validated via qRT-PCR and western blot analysis (Figure 4A-D). Functional assays showed that HS6ST2 knockdown significantly inhibited the invasion and migration of SGC-7901 cells (Figure 4E and F), whereas its overexpression enhanced these capabilities in MGC803 cells (Figure 4G and H). Consistently, the CCK-8 assay demonstrated that HS6ST2 knockdown suppressed, while its overexpression promoted, GC cell proliferation (Figure 4I and J). Collectively, these findings indicate that HS6ST2 drastically improves the proliferation, invasion, and migration of GC cells in vitro.
Based on our earlier observations that IGF2BP1 directly interacts with and enhances HS6ST2 in an m6A-dependent manner, we postulated that IGF2BP1 facilitates GC malignancy predominantly through HS6ST2. To test this hypothesis, we examined whether the oncogenic functions of IGF2BP1 are facilitated by HS6ST2. In SGC-7901 cells, IGF2BP1 overexpression elevated the expression of both IGF2BP1 and HS6ST2, an effect that was mitigated by simultaneous HS6ST2 knockdown (Figure 5A and B). Functionally, the enhanced invasion, migration (Figure 5C and D), and proliferation (Figure 5E) abilities induced by IGF2BP1 overexpression were significantly attenuated upon HS6ST2 knockdown. Conversely, in MGC803 cells, IGF2BP1 knockdown did not markedly alter the basal expression level of HS6ST2 (Figure 5F and G), suggesting that IGF2BP1 may not be essential for its baseline maintenance but could be critical for its inducible expression in oncogenic contexts. Nevertheless, exogenous HS6ST2 overexpression effectively restored HS6ST2 levels. Consequently, the impaired invasion, migration (Figure 5H and I), and proliferation (Figure 5J) caused by IGF2BP1 knockdown were substantially rescued by HS6ST2 overexpression. Taken together, these rescue experiments demonstrate that HS6ST2 is a critical functional downstream effector through which IGF2BP1 drives the aggressive behaviors of GC cells.
To elucidate the downstream mechanisms through which HS6ST2 enhances the malignant phenotype of GC, we performed transcriptome sequencing on control and HS6ST2-knockdown GC cells. We identified a total of 437 significantly differentially expressed genes, comprising 291 upregulated and 146 downregulated genes (Figure 6A). Hierarchical clustering heatmap analysis confirmed distinct expression profiles between the control and knockdown groups, with high reproducibility among biological replicates (Figure 6B).
Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis revealed that the differentially expressed genes were predominantly enriched in the mitogen-activated protein kinases and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling pathways (Figure 6C). Concurrently, Gene Ontology analysis indicated their involvement in key biological processes related to cell growth and regulation of cell growth (Supplementary Figure 3). Collectively, these results indicate that the depletion of HS6ST2 disturbs pro-survival signaling pathways, which may potentially lead to apoptosis. Based on this assumption, we further analyzed apoptosis by flow cytometry. The results showed that the proportion of apoptotic cells was markedly increased in the HS6ST2-knockdown group compared with the control group (Figure 6D). To further explore the underlying molecular mechanisms, we examined the activity of the PI3K/Akt/mammalian target of rapamycin (mTOR) pathway by western blotting. HS6ST2 knockdown markedly reduced the levels of phosphorylated PI3K, Akt, and mTOR, without significantly affecting the total protein levels, indicating inhibition of this key pro-survival signaling pathway (Figure 6E).
Our transcriptome data also suggested that HS6ST2 knockdown affected pathways related to the immune microenvironment and extracellular matrix (ECM) in Figure 6C, hinting at its potential role in remodeling the tumor micro-environment (TME). Therefore, we selected two key protein markers for further investigation: CD33, representing an immunosuppressive TME, and POSTN, a pro-tumorigenic matricellular protein. IHC analysis was performed to evaluate their expression in human GC tissues with or without lymph node metastasis. The results demonstrated that the levels of both CD33 and POSTN were higher in GC tissues exhibiting lymph node metastasis compared with those without metastasis (Figure 6F). This clinical observation suggests that an immunosuppressive and ECM-remodeled TME, characterized by high CD33 and POSTN, is associated with lymph node metastasis in GC.
m6A, the most prevalent internal mRNA modification in eukaryotes, plays fundamental roles in regulating RNA metabolism, including transcription, splicing, translation, and decay[28]. Its aberrant methylation status is intricately linked to tumor progression and is frequently dysregulated across diverse cancer types[29,30]. This modification critically influences tumor biology by promoting cancer cell invasion and migration[31,32], enhancing the immunosuppressive capacity of the TME[33], and mediating chemoresistance[34].
An increasing number of studies link aberrant m6A modification to the onset and development of GC. For instance, the m6A demethylase alkB homolog 5 impedes GC invasion by regulating m6A modification of protein kinase, membrane associated tyrosine/threonine 1 RNA[35], while METTL3 enhances the migration and proliferation of GC cells by stabilizing DEK mRNA[36].
As an m6A reader protein, IGF2BP1 promotes tumor malignancy by recognizing m6A modifications on target mRNAs and modulating their stability and translation efficiency[37]. In this study, we found that IGF2BP1 is significantly overexpressed in GC tissues. Moreover, elevated IGF2BP1 expression was strongly associated with lymph node metastasis and poor patient prognosis. Our results are consistent with the reported oncogenic roles of IGF2BP1 in other gastrointestinal malignancies, such as hepatocellular carcinoma[38] and colorectal cancer[39], suggesting a conserved pro-tumorigenic function across cancer types. Functional validation confirmed that IGF2BP1 knockdown significantly reduced GC cell growth, migration, and invasion in vitro and markedly suppressed tumor growth in vivo. Collectively, these findings establish IGF2BP1 as a key driver of malignant progression in GC. Collectively, these findings establish IGF2BP1 as a key driver of malignant progression in GC.
Through integrated bioinformatics and multi-omics analysis, we identified HS6ST2 as a critical downstream target of IGF2BP1 in GC. HS6ST2 encodes a heparan sulfate 6-O-sulfotransferase that catalyzes the sulfation modification of heparan sulfate, playing an important function in regulating cell growth, differentiation, adhesion, and migration[40]. HS6ST2 is significantly expressed in various cancers and, owing to its involvement in tumorigenesis and immune regulation, may serve as a potential pan-cancer prognostic marker[41]. For example, high HS6ST2 expression is associated with poor clinical outcomes in GC, highlighting its therapeutic potential[42,43]. However, the specific mechanism underlying HS6ST2 upregulation and its contribution to lymph node metastasis in GC remained unclear.
Here, we provide compelling evidence for an m6A-dependent regulatory axis wherein IGF2BP1 directly binds to specific m6A sites within the HS6ST2 3’UTR to enhance its mRNA stability. Rescue experiments confirmed HS6ST2 as a primary functional effector mediating the oncogenic effects of IGF2BP1, as HS6ST2 knockdown effectively reversed the protumorigenic phenotypes induced by IGF2BP1 overexpression. Interestingly, basal expression of HS6ST2 was unaltered after IGF2BP1 knockdown in MGC803 cells, whereas ectopic overexpression of HS6ST2 rescued the loss-of-function phenotypes. These findings indicate that IGF2BP1 may not be essential for maintaining basal HS6ST2 expression. Instead, it acts as an important enhancer that promotes its inducible expression under cancerous conditions, thereby activating downstream malignant signaling pathways. While the present findings are supported by orthogonal approaches, definitive validation using an additional independent shRNA or CRISPR-Cas9 knockout would further strengthen the conclusions.
The PI3K/Akt/mTOR signaling pathway, commonly dysregulated in human cancers, profoundly affects tumor initiation, progression, and therapy response by regulating cell growth, survival, and metastasis[44]. In the present study, transcriptome sequencing revealed that knockdown of HS6ST2 significantly affected signaling pathways such as PI3K/Akt and mitogen-activated protein kinases and induced apoptosis. Consistently, western blot showed that HS6ST2 deficiency markedly reduced the phosphorylation levels of key components of the PI3K/Akt/mTOR pathway, which is associated with the inhibition of this critical survival signaling axis.
With respect to its biochemical function, HS6ST2 is a sulfotransferase that modifies heparan sulfate chains on heparan sulfate proteoglycans (HSPGs). It is well established that HSPGs serve as co-receptors or reservoirs for numerous growth factors, and their sulfation patterns, determined by enzymes including HS6ST2, critically modulate growth factor-receptor binding and signaling activation[45,46]. Therefore, we hypothesize that in our model, HS6ST2 may promote tumor progression by shaping the heparan sulfate sulfation landscape, which could enhance the recruitment and activation of specific receptor tyrosine kinases, ultimately leading to the observed activation of the downstream PI3K/Akt/mTOR pathway. Future studies aimed at identifying the specific growth factor-receptor pairs whose signaling is potentiated by HS6ST2-mediated heparan sulfate modifications will be crucial to fully elucidate this upstream mechanism.
Moreover, in this study, we extended our investigation to the potential TME alterations linked to metastasis. Transcriptome analysis indicated that HS6ST2 knockdown influences ECM-related pathways. Given the well-established role of HS6ST2 in modifying HSPGs, which are integral components of the ECM and key regulators of growth factor and cytokine bioavailability[47,48], it is plausible that the IGF2BP1/HS6ST2 axis contributes to TME remodeling. This remodeling could, in turn, foster a pro-metastatic niche. In line with this notion, we observed a significant increase in the immunosuppressive marker CD33 and the pro-tumorigenic matricellular protein POSTN in GC tissues with lymph node metastasis. This clinical correlation, while not proving direct causality, aligns with the critical roles of ECM repro
This study has several limitations. Firstly, the exact molecular partners involved in IGF2BP1-mediated regulation of HS6ST2 m6A modification remain to be fully characterized. Secondly, the spatial expression and activation patterns of IGF2BP1, HS6ST2, and the key phospho-proteins within the in vivo xenograft model have not been validated by IHC. Finally, the functional dependency of HS6ST2 on IGF2BP1 demonstrated in this study is primarily at the cellular level. Future studies, including in vivo rescue experiments in xenograft models, will be essential to confirm the significance of this regulatory axis in a more complex pathophysiological context.
In this study, we demonstrated that high expression of IGF2BP1 in GC is associated with poor prognosis. Mechanistically, IGF2BP1 was shown to regulate HS6ST2 expression in an m6A-dependent manner, and HS6ST2 was confirmed to promote GC cell proliferation, migration, and invasion. Furthermore, knockdown of HS6ST2 was shown to inhibit GC progression and invasiveness by inactivating the PI3K/AKT/mTOR signaling pathway. The IGF2BP1/HS6ST2 axis may serve as a potential prognostic biomarker and therapeutic intervention for GC.
We sincerely thank the Public Laboratory of Taizhou Hospital Affiliated with Wenzhou Medical University, for providing the essential equipment for this study.
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