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. 2026 Jun 4;70:102844. doi: 10.1016/j.tranon.2026.102844

Super-enhancer-driven ITGB2-AS1 promotes ovarian cancer progression by binding to IQGAP1

Yuhan Wang 1, Peiling Li 1,⁎
PMCID: PMC13254713  PMID: 42241993

Highlights

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    Abnormal expression of long non-coding RNA ITGB2-AS1 was studied in ovarian cancer.

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    Ovarian cancer metastasis was regulated by lncRNA.

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    ITGB2-AS1 was driven by super-enhancer.

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    ITGB2-AS1 bound to IQGAP1 protein and activated the Wnt/β-catenin signaling pathway.

Keywords: Ovarian cancer, Long non-coding RNA, ITGB2-AS1, Super-enhancer

Abstract

Long non-coding RNAs (lncRNAs) are involved in the development and progression of ovarian cancer (OC). Super-enhancers play vital roles in epigenomic regulation. We investigated the functions and mechanisms of the super-enhancer-driven OC-specific lncRNA ITGB2-AS1. In this study, we revealed that the lncRNA ITGB2-AS1 was abnormally expressed in OC tissues and cells and was associated with poor prognosis. In vitro, ITGB2-AS1 silencing attenuated the proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) of SKOV3 and A2780 cells, whereas ITGB2-AS1 overexpression showed the opposite effect. ITGB2-AS1 inhibition in SKOV3 cells reduced tumor growth and EMT progression in vivo. Further analysis revealed that the transcription factor TFAP2C acts on a specific super-enhancer and drives ITGB2-AS1 to activate transcription. `ITGB2-AS1 directly binds to IQGAP1 protein, positively regulates its expression, and activates the canonical Wnt/β-catenin signaling pathway. The TFAP2C / ITGB2-AS1 / IQGAP1 / β-catenin axis may be a potential target for OC treatment.

Introduction

Ovarian cancer is one of the most common cancers affecting the female reproductive system [1]. Owing to its aggressive tumor growth and high metastatic activity, the 5-year survival rate of patients with OC is only 30–50% [2]. Therefore, understanding the molecular mechanism of OC metastasis and developing treatment strategies are important for improving the prognosis and treatment strategies [[3], [4], [5]].

Enhancers are cis-acting DNA sequences that promote the transcriptional activity of target genes by specifically recruiting transcription factors and their cofactors, thereby enhancing promoter transcriptional activity and target gene expression [[6], [7], [8]]. Super-enhancers are clusters of enhancers that strongly activate transcription [9,10]. Compared with enhancers, super-enhancers have a larger size (8–20 kb), bind a larger number of transcription factors and their cofactors, have higher histone modifications related to transcriptional activation, such as H3K27ac and H3K4me1 modifications, and promote increased gene expression [11,12]. Super-enhancers have powerful regulatory functions. Functionally, super-enhancers drive the expression of genes that control cellular identity, particularly by inducing the transcription of key oncogenes [13]. An increasing number of recent studies have suggested that during tumor pathogenesis, cancer cells regulate protein-coding genes and long non-coding RNAs (lncRNAs) driven by super-enhancers [[14], [15], [16]].

In ovarian cancer, the functional role of super-enhancers is gradually being recognized, although it remains less well characterized compared with other tumor types. Emerging evidence suggests that SEs may contribute to ovarian tumor progression by regulating key oncogenic transcriptional programs and non-coding RNAs. In particular, SE-associated regulatory networks have been implicated in controlling gene expression patterns related to cell proliferation, invasion, and therapeutic resistance [17,18]. However, the involvement of SE-driven lncRNAs in ovarian cancer is still poorly understood, and the underlying molecular mechanisms remain largely unclear.

LncRNAs are transcripts that are >200 nucleotides long and do not encode proteins [17]. Recent studies have revealed that approximately 98% of the human transcriptome RNAs are non-coding [18]. Furthermore, lncRNAs may be involved in various pathophysiological processes, and abnormally expressed lncRNAs can function as oncogenes or tumor suppressor genes and impact tumor progression and metastasis [[19], [20], [21]]. Although some lncRNAs were confirmed to play important roles in OC cell growth, apoptosis, invasion, chemotherapy resistance, and epithelial-mesenchymal transition (EMT) progression [[22], [23], [24]], the roles of most lncRNAs in OC remain unclear. Therefore, further studies are needed to identify potential lncRNAs involved in OC metastasis. For example, the lncRNA ITGB2-AS1 is upregulated in some malignant tumors, including renal, breast, and pancreatic cancers, and plays a role in tumorigenesis and cancer development [[25], [26], [27], [28]]. However, the role of ITGB2-AS1 in OC occurrence and progression is unclear.

Therefore, this study aimed to investigate the role of lncRNA ITGB2-AS1 in OC progression. In this study, we found that lncRNA ITGB2-AS1 was significantly upregulated in both serous epithelial OC tissues and cell lines and was associated with poor OC prognosis. Functional analysis showed that ITGB2-AS1 promoted the proliferation, migration, invasion, and EMT of tumorous OC cells. Therefore, ITGB2-AS1 may play an oncogenic role in OC progression. Mechanistic studies have shown that ITGB2-AS1 is driven by specific super-enhancers. We also revealed that ITGB2-AS1 mediated the proliferation and metastasis-related phenotypes of OC by regulating the Wnt/β-catenin pathway through binding with IQ motif-containing GTPase-activating protein 1 (IQGAP1). Thus, the super-enhancer-driven lncRNA ITGB2-AS1 has potential as a prognostic biomarker and therapeutic target in OC.

Materials and methods

Patient and clinical information

Thirty OC and 30 normal ovarian epithelial tissue specimens were obtained from patients undergoing gynecological surgery at the Second Affiliated Hospital of Harbin Medical University. The tissue samples were snap-frozen in liquid nitrogen and stored at −80 °C. All patients provided written informed consent before participating in the study. This study was approved by the Ethics Committee of the Second Affiliated Hospital of Harbin Medical University (KY2020–060). The clinicopathological characteristics of patients are presented in Table S1.

Cell culture

The normal ovarian cell line IOSE-80 and the epithelial OC cell lines A2780, OVCA-3, and SKOV3 (Shanghai, China) were cultured in RPMI 1640 medium (Gibco, Grand Island, NY, USA) containing 10% fetal bovine serum (FBS; Clark Bioscience, Richmond, VA, USA) and 100 U/mL penicillin-streptomycin (Beyotime, Shanghai, China). SKOV3 cells were maintained in McCoy’s 5A medium (Merck Millipore, Billerica, MA, USA) containing 10% FBS and 100 U/mL penicillin-streptomycin. All cells were cultured at 37 °C in an incubator with 5% CO2.

Fluorescence in situ hybridization

In situ hybridization was performed using a fluorescence in situ hybridization (FISH) kit (GeneChem, Shanghai, China). GeneChem synthesized a Cy3-labeled ITGB2-AS1 RNA-FISH probe mix, fixed cultured SKOV3 and A2780 cells in 4% paraformaldehyde, and conducted the analysis according to the manufacturer's instructions. Finally, images were obtained using a confocal microscope and analyzed using an LAS AF Lite (Leica, Wetzlar, Germany). An 18S FISH probe was used for cytoplasmic imaging. A negative control probe was used as a control, and 4′,6-diamidino-2-phenylindole (DAPI) was used to stain the nuclei.

RNA extraction and reverse transcription-quantitative PCR

Ovarian cancer and normal ovarian tissues were removed using TRIzol reagent (Invitrogen, Carlsbad, CA, USA), and RNA was extracted from the cells according to the manufacturer’s instructions. The isolated RNA was reverse transcribed into cDNA using a reverse transcription kit (Takara Bio, Shiga, Japan). Reverse transcription quantitative polymerase chain reaction (RT-qPCR) was performed using SYBR Green PCR Master Mix (Takara Bio) with the following thermal cycler steps: amplification at 95 °C for 1 min, 95 °C for 15 min, and 95 °C for 40 min cycles for 15 s at 52 °C for 15 s. All RT-qPCR analyses were performed in duplicate. The PCR sequences are listed in Table S2. Expression data were analyzed using the relative quantification method and calculated using the 2-ΔΔCT method [29].

Cell transfection

Small interfering RNAs (siRNAs) were purchased from GenePharma (Shanghai, China), and transfected into OC cells using the X-tremeGene siRNA Transfection Reagent (Roche Applied Science, Mannheim, Germany) according to the manufacturer’s instructions. RNA interference sequences are listed in Table S3. Full-length cDNA sequences of ITGB2-AS1 or IQGAP1 were inserted into the pcDNA3.1 vector (GenePharma) for overexpression and then transfected into cancer cells using Lipofectamine 2000 (Thermo Fisher Scientific, Waltham, MA, USA). RNA was collected after 48 h, and protein was collected after 72 h for comparison with the corresponding negative controls.

Cell counting kit-8 assay

Transfected SKOV3 or A2780 cells (approximately 2 × 103 per well) were seeded into 96-well plates; each well contained 100 µL of RPMI-1640 medium and 10% FBS. At four time points (0, 24, 48, and 72 h), 10 µL of Cell Counting Kit-8 (CCK-8) solution (Biosharp, Beijing, China) was added to each well of 96-well plates and incubated at 37 °C for 1 h, after which the absorbance (OD value) was measured at 450 nm.

EdU assay

Transfected SKOV3 or A2780 cells were seeded into 24-well plates, stained with 5-ethynyl-2′-deoxyuridine (EdU) using an EdU Cell Proliferation Assay Kit (Invitrogen), washed with phosphate-buffered saline, double-stained with DAPI solution, and evaluated using fluorescence microscopy.

Transwell assay

Cell migration was assessed using Transwell chambers (Corning Costar; Corning Life Sciences, Corning, NY, USA) coated with Matrigel (BD Biosciences, Franklin Lakes, NJ, USA). A total of 5 × 104 OC cells was suspended in 200 μL of serum-free medium and seeded into the upper chamber; 600 μL of culture medium containing 10% FBS was added to the lower chamber. After 24 h, the cells remaining on the membrane surface were removed using a wet cotton swab, and the cells that had migrated to the bottom of the membrane were fixed in 4% paraformaldehyde, stained with 0.4% crystal violet solution, photographed, and counted under an inverted microscope (Nikon, Tokyo, Japan).

Wound healing assay

Transfected SKOV3 and A2780 cells were seeded into six-well plates and cultured to 90% confluence. A sterile pipette tip was used to scratch the cell surface, and the cells were observed at 0 and 24 h to determine their migration distance. This experiment was repeated thrice.

Western blotting

The cells were lysed in pre-chilled lysis buffer containing protease inhibitors to extract proteins. Protein samples were separated using sodium dodecyl sulfate-polyacrylamide gel electrophoresis (8–12% polyacrylamide gel), transferred to nitrocellulose membranes, blocked with 10% nonfat milk, and incubated with primary antibodies at 4 °C. The following primary antibodies were used: anti-E-cadherin (Proteintech, Rosemont, IL, USA), anti-vimentin (Proteintech), anti-Snail (Cell Signaling Technology, Danvers, MA, USA), anti-IQGAP1 (Proteintech), anti-TFAP2C (Abcam, Cambridge, UK), anti-H3K27ac (Abcam), anti-β-catenin (Proteintech), anti-c-Myc (Proteintech), anti-cyclinD1 (Proteintech), and anti-β-actin (Abcam). After four washes with Tris-buffered saline containing Tween 20 (0.05%), incubation with appropriate horseradish peroxidase-conjugated secondary antibodies was conducted for 1 h at 37 °C, after which the protein bands were visualized using enhanced chemiluminescence reagent (Beyotime).

RNA pull-down assay

An RNA pull-down assay was performed using an RNA pull-down kit (BersinBio, Guangzhou, China) according to the manufacturer’s instructions. Briefly, ITGB2-AS1 or a negative control probe was labeled with biotin and mixed with the cell lysates. Streptavidin-agarose beads were added, and the samples were further incubated. RNA-binding proteins were collected from the eluate and subjected to sodium dodecyl sulfate-polyacrylamide gel electrophoresis and silver staining, and differential protein bands were extracted and identified using mass spectrometry.

RNA immunoprecipitation assay

RNA immunoprecipitation (RIP) assay was performed using an RNA immunoprecipitation kit (BersinBio) according to the manufacturer’s instructions. Briefly, SKOV3 cells were digested and washed using phosphate-buffered saline. The cells were lysed in RIP buffer, and the cell extracts were conjugated to control immunoglobulin or anti-IQGAP1 antibodies (Proteintech) and incubated with protein A/G magnetic beads. After RNA extraction, ITGB2-AS1 levels were analyzed using RT-qPCR.

Chromatin immunoprecipitation assay

A Chromatin Immunoprecipitation (ChIP) Assay Kit (Beyotime) was used to perform the assay. Briefly, formaldehyde was added to the OC cell culture medium at a concentration of 1% to cross-link the protein of interest and genomic DNA. The cells were lysed and sonicated to shear the genomic DNA into 200–1000-bp fragments. Protein A/G Plus Agarose was conjugated to TAPF2C and H3K27ac antibodies (Abcam) for ChIP. RT-qPCR was performed on the eluted DNA pellets, and normal immunoglobulin G (IgG) was used as the negative control.

Tumor xenograft model

All animal experiments complied with the requirements of the Ethics Review Committee of Harbin Medical University. Four-week-old female BALB/c nude mice were purchased from Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd. (Beijing, China) and housed under pathogen-free conditions at the Animal Center of the Second Affiliated Hospital of Harbin Medical University. To establish a subcutaneous tumor model, SKOV3 cells (5 × 106 cells) were subcutaneously injected into the left axilla of nude mice, and 10 nmol cholesterol-modified ITGB2-AS1 siRNA or control siRNA (RiboBio, Guangzhou, China) was injected into each tumor. Intratumoral injections were administered once every four days, and the tumor volume was measured using a vernier caliper every four days. After 24 d, mice were sacrificed, tumor tissues were collected, and tumor weights were measured.

CRISPRi-mediated repression of the candidate super-enhancer

To repress the candidate super-enhancer (SE) region, a CRISPR interference (CRISPRi) system based on dCas9-KRAB was used. Two sgRNAs targeting the H3K27ac-enriched core region of the predicted SE were designed and transfected into SKOV3 and A2780 cells together with dCas9-KRAB plasmids. A non-targeting sgRNA was used as the negative control. After 72 h, ITGB2-AS1 expression was analyzed by RT-qPCR.The sgRNA targeting sites within the candidate super-enhancer region are shown in Fig. 5A.

Fig. 5.

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Specific super-enhancer drives lncRNA ITGB2-AS1. (A–B) H3K27ac microarray data of ITGB2-AS1 in normal human tissue and transcription factors acting at the site. (C) Q-PCR analysis of TFAP2C expression in ovarian cancer and normal ovarian cells. (D) ChIP-PCR data shows that the ITGB2-AS1 super-enhancer regions can enrich H3K27ac and TFAP2C in ovarian cancer cells (SKOV3). (E) ChIP-PCR products were visualized using agarose gel electrophoresis. (F) Co-immunoprecipitation assay to determine the interaction between H3K27AC and TFPA2C in SKOV3 ovarian cancer cells. (G) After silencing TFAP2C, the expression of ITGB2-AS1 was determined using RT-qPCR. Data are presented as the mean ± standard deviation. (H) CRISPRi-mediated repression of the ITGB2-AS1 super-enhancer significantly reduces ITGB2-AS1 expression.*P  < 0.05; **P  < 0.01; ***P  < 0.001.

Statistical analysis

Patients were stratified into high- and low-expression groups based on the median value of ITGB2-AS1 expression in the clinical cohort. This approach was chosen to minimize bias and ensure balanced group sizes given the relatively small sample size.

All experiments were performed at least thrice. All data were analyzed using the SPSS software (version 22.0; SPSS, Inc., Chicago, IL, USA) and expressed as the mean ± standard deviation. Charts were constructed using the GraphPad Prism 8.0 software (GraphPad Inc., San Diego, CA, USA). An independent sample t-test was used to compare two groups, and one-way analysis of variance and Bonferroni’s test [30] were used for multiple comparisons. Kaplan–Meier curve analysis and log-rank test were used to analyze overall survival (OS) and progression-free survival. Pearson’s correlation coefficient was used to evaluate the correlation between gene expression levels. Statistical significance was set at P < 0.05.

Results

ITGB2-AS1 is upregulated in ovarian cancer tissues and is associated with poor prognosis

To identify dysregulated lncRNAs in OC, we first analyzed the sequencing data from the TCGA database. ITGB2-AS1 was significantly upregulated in OC tissues compared with normal ovarian tissues (Fig. 1A), and thus it was further analyzed. Additionally, RT-qPCR analysis of 30 specimens each of OC and normal ovarian tissues revealed that ITGB2-AS1 expression was higher in OC tissues than in normal tissues (Fig. 1B). We also measured the expression of ITGB2-AS1 in normal ovarian IOSE-80 cells and OC cell lines (OVCA-3, SKOV3, and A2780) using RT-qPCR, which revealed a consistently high expression in OC cell lines (Figure S1). Patients with OC were divided into two subgroups (low and high ITGB2-AS1 groups) based on the median ITGB2-AS1 expression in OC tissues. As shown in Table S1, high ITGB2-AS1 expression was significantly associated with tumor size, lymph nodes, and metastatic stage. Kaplan–Meier survival analysis showed that patients with OC and high ITGB2-AS1 expression had shorter OS (Fig. 1C). TCGA data from GEPIA2 confirmed that patients with higher levels of ITGB2-AS1 had shorter OS than those with lower expression levels (Fig. 1D). This demonstrated that ITGB2-AS1 was overexpressed in OC and was associated with poor prognosis. According to IncLocator, ITGB2-AS1 was mainly expressed in the cytosol (score = 0.445) and cytoplasm (score = 0.213) (Fig. 1E). RNA-FISH confirmed the subcellular localization of ITGB2-AS1 in OC cell lines (A2780 and SKOV3) (Fig. 1F). Collectively, ITGB2-AS1 is upregulated in OC, mainly expressed in the cytosol of OC cells, and associated with poor prognosis

Fig. 1.

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ITGB2-AS1 is upregulated in ovarian cancer tissues and is associated with a poor prognosis. (A) Comparison of ITGB2-AS1 expression in ovarian cancer and normal ovarian tissues according to TCGA data. (B) RT-qPCR analysis of ITGB2-AS1 expression in ovarian cancer and normal ovarian tissues. (C) Kaplan-Meier analysis showing overall survival with high or low ITGB2-AS1 expression. (D) Overall survival of patients with ovarian cancer based on high or low ITGB2-AS1 expression in the TCGA database. The data are presented as the mean ± standard deviation (n = 3). (E) Bioinformatics prediction of subcellular localization of ITGB2-AS1. (F) RNA-FISH detection of ITGB2-AS1 (red) expression in ovarian cancer cell lines (SKOV3 and A2780). Nuclei were counterstained with DAPI (blue).

ITGB2-AS1 promotes proliferation, migration, invasion, and EMT of OC cells in vitro

To determine the biological importance of ITGB2-AS1 in OC, we transfected ITGB2-AS1 siRNA into A2780 and SKOV3 cells to suppress endogenous ITGB2-AS1 expression. We also used an overexpression plasmid to upregulate endogenous ITGB2-AS1 expression in A2780 and SKOV3 cells (Figure S2A–B). CCK-8 and EdU analyses showed that the upregulation of ITGB2-AS1 significantly enhanced OC cell proliferation (Fig. 2A–B), whereas the knockdown of ITGB2-AS1 notably inhibited OC cell proliferation (Fig. 3A–B). Furthermore, overexpression of ITGB2-AS1 significantly increased the invasive and migratory abilities of cells compared with those in the control group (Fig. 2C–D), whereas ITGB2-AS1 downregulation showed the opposite effects (Fig. 3C–D). Notably, we detected EMT markers in OC cells. Western blotting showed that the knockout of ITGB2-AS1 led to increased levels of E-cadherin in OC cells, whereas the levels of Snail and vimentin decreased (Fig. 2E). Overexpression of ITGB2-AS1 led to the opposite trend (Fig. 3E), indicating that ITGB2-AS1 promotes EMT progression in OC cells.

Fig. 2.

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ITGB2-AS1 knockdown suppresses cell growth, invasion, migration, and EMT progress. (A) CCK-8 assay was conducted to assess the proliferative ability of A2780 and SKOV3 cells with ITGB2-AS1 knockdown. (B) EdU was used to determine the proliferative ability of OC cells with ITGB2-AS1 knockdown. (C) Wound healing analysis was performed on SKOV3 and A2780 cells transfected with ITGB2-AS1 siRNA or siNC to explore the cell migration and invasion abilities. (D) Transwell analysis was performed on SKOV3 and A2780 cells transfected with ITGB2-AS1 siRNA or siNC to investigate their cell migration and invasion abilities. (E) Knocking down ITGB2-AS1 attenuated EMT progression in SKOV3 and A2780 cells. Data are presented as the mean ± standard deviation. *P  < 0.05; **P  < 0.01; ***P  < 0.001.

Fig. 3.

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Overexpression of ITGB2-AS1 promotes cell growth, invasion, migration, and EMT progress. (A) CCK-8 was used to determine the proliferative ability of A2780 and SKOV3 cells overexpressing ITGB2-AS1. (B) EdU was used to determine the proliferative ability of ovarian cancer cells overexpressing ITGB2-AS1. (C) Transwell analysis was performed on SKOV3 and A2780 cells transfected with lncRNA ITGB2-AS1-dt or vector to determine the cell migration and invasion abilities. (D) Wound healing analysis was performed on SKOV3 and A2780 cells transfected with ITGB2-AS1-dt or vector to explore the cell migration and invasion abilities. (E) ITGB2-AS1 upregulation enhanced EMT progression in SKOV3 and A2780 cells. The data are presented as the mean ± standard deviation. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.

Knockdown of lncRNA ITGB2-AS1 inhibits OC cell tumorigenesis in vivo

SKOV3 cells were subcutaneously injected into BALB/c nude mice for 12 d to generate tumor xenografts and further examine the role of lncRNA ITGB2-AS1 in OC tumorigenesis. After 12 d, we started subcutaneous injections of 10 nmol cholesterol-modified ITGB2-AS1 siRNA or negative control siRNA at the tumor site every four days for 24 d (Fig. 4A–B). After 32 d, the tumor volume and weight of mice treated with ITGB2-AS1 siRNA were significantly lower than those of mice treated with control siRNA (Fig. 4C–D), indicating that ITGB2-AS1 promoted OC cell growth in vivo. These results support the role of ITGB2-AS1 in OC tumorigenesis and progression. We also evaluated the expression of the EMT-related proteins E-cadherin, Snail, and vimentin in the tumor tissues of mice treated with ITGB2-AS1 siRNA and control siRNA. E-cadherin expression in the ITGB2-AS1 knockdown group was higher than that in the control group, and expression levels of both Snail and vimentin were significantly lower than those in the control group (Fig. 4E). These results confirm that the knockdown of ITGB2-AS1 inhibits OC growth in vivo.

Fig. 4.

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Knockdown of ITGB2-AS1 inhibits tumor growth in vivo. (A–B) Representative images of BALB/c nude mice bearing ovarian cancer tumors. (C) Tumor volume was measured every 4 days. (D) Relative tumor weight. (E) Western blot detection of E-cadherin, Snail, and vimentin expression in tumor xenograft biopsies. The data are presented as the mean ± standard deviation (n = 3).*P  < 0.05; **P  < 0.01; ***P  < 0.001.

lncRNA ITGB2-AS1 is driven by a super-enhancer

Given that ITGB2-AS1 is upregulated in OC tissues and associated with poor prognosis, we explored the transcriptional regulatory mechanism of ITGB2-AS1. Using ChIP-seq data from the SEA database and with the histone modification marker H3K27ac as a recognition factor, we identified a 346-kb super-enhancer downstream of ITGB2-AS1 in various cell types. Additionally, we identified a transcription factor, TFAP2C, which interacts with this super-enhancer (Fig. 5A–B). The increased expression of the super-enhancer in OC cells was confirmed by RT-qPCR (Fig. 5C). The ChIP-qPCR results showed that the ITGB2-AS1 super-enhancer was specifically bound to TFAP2C and H3K27ac, validating the ChIP-seq data (Fig. 5D–E). Co-immunoprecipitation analysis revealed a binding interaction between H3K27ac and TFAP2C in OC cells (Fig. 5F). Importantly, silencing TFAP2C significantly reduced the expression of ITGB2-AS1 (Fig. 5G). Collectively, these results suggest that TFAP2C interacts with the super-enhancer to promote the transcriptional activity of ITGB2-AS1.To functionally validate the role of this super-enhancer, CRISPRi was used to repress the ITGB2-AS1 super-enhancer core region. RT-qPCR analysis showed that both independent sgRNAs significantly reduced ITGB2-AS1 expression (Fig. 5H).

ITGB2-AS1 directly binds to IQGAP1

To further investigate the pathways involved in the ITGB2-AS1 regulatory network, we performed RNA pull-down and mass spectrometry analyses. ITGB2-AS1 binds to several proteins (Fig. 6A), and IQGAP1 is one of the major proteins that interact with ITGB2-AS1 (Fig. 5B). In addition, RIP-PCR analysis of the immunoprecipitated RNA samples confirmed the interaction between ITGB2-AS1 and IQGAP1 (Fig. 6C). We also conducted co-localization analysis using fluorescence and protein immunostaining, which confirmed the interaction between ITGB2-AS1 and IQGAP1 (Fig. 6F). To investigate the regulatory role of ITGB2-AS1 in IQGAP1 expression, the mRNA and protein levels of IQGAP1 were determined using RT-qPCR and western blotting, respectively, which were found to be significantly decreased in ITGB2-AS1-knockdown OC cells (Fig. 6D–E).

Fig. 6.

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IQGAP1 directly binds to ITGB2-AS1 and regulates its expression. (A) RNA pull-down and silver staining experiments to identify ITGB2-AS1-protein complexes. (B) Secondary mass spectrogram of IQGAP1. (C) The RNA immunoprecipitation assay showed that the IQGAP1 protein was enriched in the lncRNA ITGB2-AS1. (D) Q-PCR determination of IQGPA1 mRNA expression levels in ITGB2-AS1 knockdown SKOV3 and A2780 cells. (E) Western blotting was performed to determine the expression level of the IQGPA1 protein in SKOV3 and A2780 cells with ITGB2-AS1 knockdown and overexpression. (F) Relative expression levels of ITGB2-AS1 and IQGAP1 were determined in FISH and protein immunostaining experiments. The data are presented as the mean ± standard deviation (n = 3).*P  < 0.05; **P  < 0.01; ***P  < 0.001.

ITGB2-AS1 promotes OC progression by binding and positively regulating the expression of IQGAP1

To investigate the role of IQGAP1 in ITGB2-AS1-mediated OC oncogenesis, IQGAP1-overexpressing plasmids were co-transfected into cells with downregulated expression of ITGB2-AS1. The CCK-8 (Fig. 7A) and EdU (Fig. 7B) assays showed that the decrease in OC cell proliferation caused by the decreased ITGB2-AS1 expression was reversed by an increase in IQGAP1 expression. Furthermore, wound healing and Transwell assays showed that increased IQGAP1 significantly reduced ITGB2-AS1 knockout-induced suppression of cell invasion and migration (Fig. 7C–D). IQGAP1 overexpression partially reversed the effects of ITGB2-AS1 knockdown on EMT-related proteins, leading to decreased E-cadherin expression and increased Snail and vimentin expression (Fig. 7E), suggesting that IQGAP1 inhibits EMT. These results suggest that ITGB2-AS1 plays a role in OC progression by binding to IQGAP1.

Fig. 7.

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IQGAP1 overexpression partially rescues the inhibitory effects of ITGB2-AS1 knockdown in ovarian cancer cells. (A) Cell activity was determined using a CCK-8 assay. (B) The EdU assay was used to evaluate cell proliferation ability. (C–D) Wound healing and Transwell assays were used to evaluate cell migration and invasion. (E) Western blot detection of EMT-related protein expression.The data are presented as the mean ± standard deviation (n = 3). *P < 0.05, **P < 0.01, ***P < 0.001.

ITGB2-AS1 activates the Wnt/β-catenin signaling pathway by binding to IQGAP1

Previous studies have demonstrated that IQGAP1 can regulate the Wnt/β-catenin signaling pathway, thereby promoting cancer cell proliferation and EMT progression. The STRING database (https://www.string-db.org/) analysis suggests a potential regulatory relationship between IQGAP1 and the Wnt/β-catenin signaling pathways (Fig. 8A). Based on the Spearman correlation test on TCGA-OVCA data, IQGAP1 was positively correlated with the transcriptional expression of β-catenin, c-MYC, and cyclin D1 (Fig. 8B). Experiments based on IQGAP1 knockdown and overexpression showed that IQGAP1 knockdown led to downregulation of β-catenin and its downstream targets c-MYC and cyclin D1, while the overexpression showed the opposite results (Fig. 8C). Activation of the Wnt/β-catenin pathway by Si-ITGB2-AS1 was reversed following co-transfection with IQGAP1 overexpression plasmid (Fig. 8D). Therefore, ITGB2-AS1 activates the Wnt/β-catenin pathway in an IQGAP1-dependent manner.

Fig. 8.

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ITGB2-AS1 regulates the Wnt/β-catenin signaling pathway through IQGAP1. (A-B) The STRING and TCGA-OVCA databases showed that IQGAP1 could interact with the Wnt/β-catenin signaling pathway. (C) Western blotting was used to measure the protein expression of the Wnt/β-catenin pathway following IQGAP1 knockdown. (D) The protein expression of β-catenin, c-Myc, and cyclin D1 was assessed using western blotting after co-transfecting ITGB2-AS1 siRNA into the IQGAP1-upregulated cells.

Discussion

Ovarian cancer is highly aggressive and has a high recurrence rate, which leads to poor prognosis [[31], [32], [33]]. Therefore, identifying the target genes that regulate OC progression and developing new therapeutic approaches are important [[34], [35], [36]]. lncRNAs are key regulators of multiple cellular processes, including tumorigenesis and development [37,38]. However, the molecular mechanisms mediating the malignant behavior of OC are not well understood. In this study, we analyzed the expression profiles of lncRNAs in OC and selected abnormally expressed ITGB2-AS1 for further investigation. We examined the expression of ITGB2-AS1 in tissues and cells and analyzed the correlation between its expression and clinical features. We confirmed that TFAP2C binds to the super-enhancer region of ITGB2-AS1, enhances its activation, and upregulates the expression of ITGB2-AS1. ITGB2-AS1 overexpression promoted OC cell growth, migration, invasion, and EMT progression in vitro and in vivo. ITGB2-AS1 plays a tumor-promoting role by interacting with IQGAP1 and positively regulating its expression, thereby promoting Wnt/β-catenin signaling. These findings suggest that ITGB2-AS1 plays a significant role in the development of OC.

Super-enhancers are clusters of transcriptionally active enhancers that drive the expression of key genes involved in defining cell identity [9,10]. Several oncogenic enhancers have been identified in various types of cancer, and the role of super-enhancers in tumorigenesis and the development of cancer has attracted attention [[39], [40], [41]]. Some super-enhancers regulate lncRNA expression and thus play a role in cancer development. For example, Myc binds to the promoter and super-enhancer of TMEM44-AS1 in gliomas to regulate the expression of this gene [42]. Additionally, lncRNA-DAW is driven by super-enhancers, and its activation stimulates the proliferation of hepatoma cells [43]. However, super-enhancer-driven lncRNAs have not been reported in OC. We identified the H3K27ac signal and super-enhancers that function in ITGB2-AS1 as well as the transcription factor TFAP2C, which binds to the super-enhancer. Furthermore, we demonstrated that the combination of TFAP2C and super-enhancer played a role in activating transcription in OC and promoting ITGB2-AS1 expression.

Abnormal lncRNA expression is closely associated with tumor progression. Therefore, we examined the role of ITGB2-AS1 in the development of OC. ITGB2-AS1 knockdown strongly inhibited the proliferation, migration, invasion, and EMT progression of OC cells in vivo and in vitro. In contrast, ITGB2-AS1 overexpression promoted the biological functions of OC cells. These results suggest that ITGB2-AS1 plays a role in OC tumorigenesis. lncRNAs participate in cancer development through various regulatory mechanisms, such as competing with miRNAs and regulating mRNA stability [44,45]. However, a recent study has shown that lncRNAs bind to proteins and play important roles in regulatory processes [46]. Although ITGB2-AS1 has been shown to promote the progression of renal cell carcinoma and pancreatic ductal carcinoma through a "miRNA-adsorbing sponge" mechanism [27,28], the mechanism of ITGB2-AS1 in OC remains unclear. The localization of lncRNAs in cells provides insights into their functional mechanisms [19]. We found that ITGB2-AS1 was mainly localized in the cytosol and cytoplasm and identified its potential binding proteins. ITGB2-AS1 targets IQGAP1, a multi-domain scaffold protein found in the human body. IQGAP1 regulates a range of cancer-related cellular activities, including proliferation, apoptosis, migration, invasion, and metastasis, by promoting signal transduction in cells [47]. A previous study confirmed the effect of IQGAP on the invasion of OC cells [48]. Our results demonstrate that IQGAP1 is a downstream effector of ITGB2-AS1 and that its binding to ITGB2-AS1 is important for the proliferation, invasion, and EMT progression of OC cells.

Dysregulation of the Wnt/β-catenin signaling pathway in cancer and the carcinogenic effects associated with lncRNAs have been widely reported. For example, Min Zhou [49] found that the lncRNA FAM83H-AS1 promoted malignant progression of pancreatic ductal adenocarcinoma by activating the Wnt/β-catenin signaling pathway. Xinping Li [50] reported that hypoxia-induced lncRNA RBM5-AS1 promoted tumorigenesis in breast cancer by activating the Wnt/β-catenin signaling pathway. In this study, we found that IQGAP1 overexpression drives activation of the typical Wnt/β-catenin pathway. More importantly, we demonstrated that the suppression of the Wnt/β-catenin signaling pathway caused by ITGB2-AS1 knockdown is reversed by IQGAP1 overexpression. These results support the conclusion that ITGB2-AS1 promotes OC progression by upregulating the IQGAP1/WNT/β-catenin signaling pathway.

This study has several limitations. First, the clinical validation cohort included only 30 paired ovarian cancer samples, which may limit the statistical power for survival analysis and restrict the robustness of prognostic conclusions. Although the association between ITGB2-AS1 expression and patient prognosis was supported by TCGA data, the findings from our clinical cohort should be interpreted with caution. Second, this was a single-center study, which may introduce potential selection bias. Therefore, future studies based on larger, independent, and multicenter cohorts are required to further validate the clinical and prognostic significance of ITGB2-AS1. In addition, no multiple-testing correction was applied, which may increase the risk of type I error.

Conclusions

We identified ITGB2-AS1 as an OC-related lncRNA. Functionally, ITGB2-AS1 promotes cell proliferation, invasion, migration, and EMT progression in vitro and promotes tumorigenesis and development in vivo. Mechanistically, the transcription factor TFAP2C directly binds to the ITGB2-AS1 super-enhancer and activates transcription in OC cells. Furthermore, the increase in ITGB2-AS1 allows it to bind to RNP IQGAP1 and enhance its expression, thereby activating the Wnt/β-catenin signaling pathway and mediating the tumor-promoting effect of ITGB2-AS1. ITGB2-AS1 shows potential as a therapeutic target and biomarker for predicting the prognosis of OC, which may be useful for developing molecular therapies for OC.

Funding

This study was funded by The National Natural Science Foundation of China (No. 82072864).

Ethics approval and bioethics statement

This study was approved by the Ethics Committee of the Second Affiliated Hospital of Harbin Medical University, and performed in accordance with the Declaration of Helsinki. All patients provided informed consent.

Consent for publication

The manuscript is approved by all authors for publication.

Availability of data and materials

The datasets used and analyzed during the current study are available from the corresponding author upon reasonable request.

CRediT authorship contribution statement

Yuhan Wang: Writing – original draft, Validation, Project administration, Methodology, Investigation, Conceptualization. Peiling Li: Writing – review & editing, Supervision, Funding acquisition.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

Not applicable.

Footnotes

Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.tranon.2026.102844.

Appendix. Supplementary materials

mmc1.pdf (5.1MB, pdf)
mmc2.pdf (190.4KB, pdf)
mmc3.pdf (520.3KB, pdf)

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

mmc1.pdf (5.1MB, pdf)
mmc2.pdf (190.4KB, pdf)
mmc3.pdf (520.3KB, pdf)

Data Availability Statement

The datasets used and analyzed during the current study are available from the corresponding author upon reasonable request.

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