Downregulation of F11R in Colorectal Cancer and Tumour Progression

By Fengjiao Wang¹, Xiumin Bao^1,2, Qingchun Lei³, Xiao Yuan¹, Xiaodan Tang¹, Pengli Zhang¹

Affiliations

1. Department of Gastroenterology, Affiliated Hospital of Kunming University of Science and Technology, the First People’s Hospital of Yunnan Province, Kunming, China
2. Department of Gastroenterology, School of Medicine, Kunming University of Science and Technology, Kunming, China
3. Department of Neurosurgery, Puer People’s Hospital, Yunnan, China

doi: 10.29271/jcpsp.2025.10.1269

ABSTRACT
Objective: To evaluate the prognostic value and expression profile of F11R (junctional adhesion molecule-A, JAM-A) in colorectal cancer (CRC) and to elucidate its functional role, particularly in epithelial–mesenchymal transition (EMT) and Rap1 signalling.
Study Design: Integrated bioinformatic and experimental study.
Place and Duration of the Study: Department of Gastroenterology, Affiliated Hospital of Kunming University of Science and Technology, the First People’s Hospital of Yunnan Province, Kunming, China, from 1^st August 2021 to 30^th June 2023.
Methodology: F11R-associated genes were analysed using The Cancer Genome Atlas (TCGA) and the Human Protein Atlas (HPA). Protein expression was assessed by immunohistochemistry, and cell-type localisation was determined by single-cell RNA-seq. Functional enrichment was performed to explore related pathways. CRC cell proliferation, migration, invasion, and apoptosis were examined with CCK-8, Transwell, scratch, and flow cytometry assays, while EMT-related proteins were evaluated by western blotting.
Results: F11R expression was significantly reduced in CRC compared with normal tissues. IHC revealed cytoplasmic and membranous localisation, and single-cell data showed enrichment in endothelial and epithelial cells. Enrichment analysis implicated F11R in T-cell receptor signalling, cadherin binding, and tight-junction pathways. Expression correlated with CD4⁺ Th1-like cells, effector and resting Tregs, and effector-memory T cells. Silencing F11R enhanced proliferation, migration, and invasion; reduced apoptosis; and promoted EMT, evidenced by decreased ZO-1 and E-cadherin, increased N-cadherin and vimentin, and Rap1 activation.
Conclusion: F11R regulates EMT and Rap1 signalling, thereby influencing CRC metastasis. Its reduced expression is associated with unfavourable outcomes and tumour progression. Cell type–specific enrichment in endothelial and epithelial cells, along with links to immune subsets, highlights F11R as a potential prognostic biomarker in CRC.

Key Words: Colorectal cancer, F11R, Tumour progression, Prognostic potential, Immune infiltration.

INTRODUCTION

Colorectal cancer (CRC) is among the most commonly diagnosed malignancies worldwide and remains a major contributor to cancer-related mortality, ranking fourth in global cancer deaths.¹ In China, CRC accounts for approximately 517,000 new cases annually,^1,2 making it one of the most common malignancies. Its pathogenesis involves the accumulation of genetic alterations in oncogenes, tumour suppressor genes, and DNA repair pathways,³ leading to a prolonged preclinical phase.
 

This relatively slow disease evolution offers a crucial window for early screening and timely therapeutic intervention. Since prognosis is closely tied to the stage at detection, identifying molecular markers that reflect tumour progression and patient outcomes is of paramount importance.⁴ However, prognosis remains highly dependent on the stage at detection, and the persistence of late-stage diagnoses highlights the need for additional strategies beyond conventional screening methods. Therefore, identifying reliable prognostic biomarkers that could complement existing programmes is crucial for improving early detection, guiding treatment decisions, and ultimately reducing the disease burden in clinical practice. This provides the rationale for investigating novel molecular determinants in CRC.²

  The F11 receptor (F11R), also known as junctional adhesion molecule-A (JAM-A), is a membrane-spanning protein primarily localised in epithelial and endothelial cells. It is integral to the formation and stability of tight junctions, thereby preserving the selective barrier function and structural cohesion of cellular monolayers.⁵ Moreover, F11R has been shown to facilitate leucocyte transmigration across endothelial barriers, underscoring its involvement in immune surveillance and inflammation.⁶

The clinical significance of F11R varies across tumour types. For instance, elevated F11R expression has been correlated with poor overall survival in triple-negative breast cancer, where it contributes not only to cell motility but also to the regulation of proliferation and apoptosis.⁷ In lung adenocarcinoma, F11R upregulation appears to support tumourigenesis, while its suppression impairs the growth and invasiveness of gastric cancer cells in vitro.⁸ Mechanistically, increased F11R may activate pro-migratory signalling pathways, whereas reduced expression has been associated with compromised cell polarity and tight junction disassembly.⁹ Since tight junction dysfunction is a hallmark of both inflammatory and neoplastic processes, F11R’s multifaceted roles across malignancies have positioned it as a promising candidate for antibody-based therapy and molecular targeting.

Previous studies have reported an association between the F11R rs790056 polymorphism and increased susceptibility to CRC.¹⁰ Nonetheless, investigations into the corresponding expression levels of F11R at the mRNA and protein levels remain limited. Therefore, this research aimed to evaluate the impact of F11R dysregulation on CRC progression and metastatic behaviour.

METHODOLOGY

The research was carried out, from 1^st August 2021 to 30^th June 2023, at the Department of Gastroenterology, Affiliated Hospital of Kunming University of Science and Technology, the First People’s Hospital of Yunnan Province, Kunming, China. Transcriptomic profiles from The Cancer Genome Atlas (TCGA) Pan-Cancer cohort (PANCAN; N = 10,535; G =  60,499) were accessed via the UCSC Xena platform. F11R (ENSG00000 158769) expression data were extracted from both primary tumour and solid normal tissue samples. Cases with expression values of zero were excluded, and the remaining data were normalised using a log2 (x + 0.001) transformation. Subsequent analyses focused on Colon Adenocarcinoma (COAD) and combined Colon/Rectum Adenocarcinoma (COADREAD) datasets. Protein expression and immunohistochemical (IHC) images for F11R were retrieved from the Human Protein Atlas (HPA), while single-cell transcriptomic expression data were sourced from GTEx (httpss://www.gtexportal.org).

To explore F11R-related gene networks, the top 100 co-expressed genes in CRC were identified using GEPIA2.0. These candidates underwent Pearson’s correlation analysis, followed by functional annotation through Gene Ontology (GO) and Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway analyses, with a threshold of p <0.05 for statistical significance. For immune landscape assessment, F11R expression in COADREAD and rectum adenocarcinoma (READ) datasets was log2 (x+1) transformed. Immune, stromal, and ESTIMATE scores were retrieved from the SangerBox platform, and CIBERSORT was applied to deconvolute the proportions of 22 immune cell types within the tumour microenvironment (TME) using normalised data. Cellular heterogeneity and immune checkpoint associations were visualised based on single-cell RNA-seq data.

Colorectal tumour and adjacent non-tumorous tissues were obtained from patients with pathologically confirmed CRC. Individuals who had received any form of neoadjuvant therapy, including chemotherapy, radiotherapy, or chemoradiotherapy, undergone prior surgical procedures, or failed follow-up were excluded. Inclusion criteria required participants to be adults aged 18 years or older with a pathologically confirmed diagnosis of CRC evaluation. Additionally, participants were required to provide colorectal tumour and adjacent non-tumorous tissue samples, along with written informed consent to participate in the study. Clinical variables collected included age, gender, tumour location, and tumour, node and metastasis (TNM) classification following the American Joint Committee on Cancer Staging Manual, 8^th edition.¹¹ Although all patients included had colorectal adenocarcinoma, histological subtypes and stages were recorded because different stages and subtypes could influence prognosis. Ethical approval was granted by the Research Ethics Committee of the First People’s Hospital of Yunnan Province, Kunming, China (Approval No. #KHLL2021-KY130). The collected samples were stored at −80℃.

For immunohistochemistry (IHC), commercially sourced CRC and adjacent non-cancerous tissue sections (4 μm thickness) were deparaffinized in xylene, rehydrated via graded ethanol, and subjected to microwave-mediated antigen retrieval using Tris-EDTA buffer. Sections were blocked and incubated over- night at 4°C with anti-F11R/JAM-A antibody (1:100), followed by Horseradish Peroxidase (HRP)-conjugated secondary antibody and diaminobenzidine/Haematoxylin staining. Two independent observers evaluated staining intensity (scored 0-3) and the percentage of positive cells (0-4), generating a composite IHC score (range 0-12) for stratification into high or low expression groups.

SW480 and HCT116 CRC cell lines were maintained in Dulbecco’s Modified Eagle Medium (DMEM; Gibco, Thermo Fisher Scientific, USA) supplemented with 10% foetal bovine serum and antibiotics under standard culture conditions (37°C, 5% CO₂). Gene overexpression and silencing of F11R were achieved using pBabe-puro and pLKO.1-puro lentiviral vectors, respectively. Viral particles were generated in 293T cells and transduced into target cells with Polybrene enhancement. Following puromycin selection, successful transfection was confirmed via fluorescence microscopy and Western blot.

Cellular proliferation was measured using the CCK-8 assay at multiple time points (0, 24, 48, 72, and 96 hours), with absorbance read at 450 nm post-incubation with reagent. Migration and invasion assays were conducted in Transwell chambers, where serum-starved cells migrated toward FBS-containing media for 48 hours prior to fixation, staining, and microscopic counting. Scratch wound healing assays were performed to evaluate 2D migration, and closure areas were quantified using imaging software.

Figure 1: Expression of F11R in human cancer and normal tissues. (A) F11R expression levels in CRC from TCGA. (B) Representative IHC images of F11R expression levels in CRC tissue showing strong positive (High) and weak positive (Low) staining. (C) F11R expression in endothelial cells. (D) Global t-SNE visualisation of F11R across all cell types. (E) Transcript per million expressions of F11R across different tissues. (F) Top ten KEGG pathways enrichment analysis F11R-correlated genes. (G) Top ten GO terms enrichment analysis of F11R-correlated gene. Figure 2: ESTIMATE scores distribution and tumour-infiltrating immune cell (TIIC) analysis by CIBERSORT. (A) ESTIMATE scores of COAD, COADREAD and READ samples from TCGA. (B) Histogram showing the differences in the proportions of 22 TIIC subsets in the CRC TME. (C) Correlation analysis of F11R to the immune checkpoint.
Figure 3: Expression patterns and functional characterisation of F11R in CRC. (A) Representative images of haematoxylin and eosin (H&E) staining and IHC analysis of F11R expression in CRC and adjacent normal colon/rectal tissues. Left: H&E staining of transverse colon (20×); Middle: IHC staining of rectum (20×); Right: transverse colon (40×). (B) Quantification of F11R-positive cells at 20× magnification using ImageJ software. (C) Cell proliferation assay using CCK-8; absorbance at 450 nm measured at various time points. Data were shown as mean ± SD from three independent experiments, each with technical triplicates. (D) Transwell assay evaluating the invasive capacity of CRC cells. (E) Wound-healing assay assessing cellular migratory ability. (F) Western blot analysis of F11R protein levels in tumour versus adjacent tissues. (G) Densitometric analysis of F11R protein bands showing a statistically significant difference between CRC tissues and peritumoural tissues, with a p-value of 0.002. Statistical significance was determined using the Mann-Whitney U test, which is appropriate for comparing non-normally distributed data between the two independent groups. *p <0.05 confirmed that the differences in F11R protein expression were highly statistically significant.
Figure 4: Functional impact of F11R modulation in CRC cell lines. (A) Apoptosis in HCT116 and SW480 cells with altered F11R expression, evaluated by flow cytometry following dual staining (PI) and Annexin V-FITC. (B) Quantitative analysis of apoptotic cells based on flow cytometry data. (C) Western blot analysis of EMT markers (ZO-1, E-cadherin, N-cadherin, and vimentin) in HCT116 (left panel) and SW480 (right panel) cells, showing consistent results across three independent experiments. (D) Measurement of Rap1 activity using a G-LISA small GTPase activity assay in HCT116 and SW480 cells following F11R KD or OE. The x-axis indicates different treatment groups (F11R KD vs. control, F11R OE vs. control), and the y-axis shows Rap1 activity levels (ng/ml). 
Statistical significance was determined using the Mann-Whitney U test. *p <0.05 was considered statistically significant.

Apoptotic rates were determined using Annexin V-PE/PI double staining and flow cytometry, with analysis performed in triplicate using CytExpert software. Western blotting was conducted to assess expression levels of F11R, β-actin, and epithelial-mesenchymal transition (EMT) markers, including zonula occludens-1(ZO-1), epithelial cadherin (E-cadherin, CDH1), neural cadherin (N-cadherin, CDH2), and vimentin. Protein lysates were prepared using standard kits, quantified with a BCA assay, and visualised via chemiluminescence after SDS-PAGE and transfer to PVDF membrane. Densitometric analysis was performed using ImageJ software (v1.8.0, NIH, USA).

Rap1 activity was quantified using a Human Rap1 ELISA Kit (COIBO BIO, Shanghai, China). Supernatants were incubated with assay reagents, and absorbance was measured at 450 nm. Statistical evaluations were conducted using R software (v3.6). Comparisons of continuous variables (protein expression levels) between two groups were assessed with the Mann-Whitney U test. Pathway enrichment data were visualised using the ggplot2 package (v3.3.6), while immune deconvolution by CIBERSORT employed the e1071 package (v1.7.9). Differential expression was evaluated and visualised using online platforms, incorporating embedded statistical analyses. Statistical significance was defined as p <0.05.

RESULTS

A significant reduction of F11R expression was observed in tumour tissues in comparison with normal tissues (Figure 1A). IHC results showed strong positive F11R staining, mainly in the cytoplasm and the cell membrane (Figure 1B). In single-cell database analysis of CRC, F11R was primarily expressed in endothelial cells (Figure 1C). Single-cell clustering of CRC revealed high F11R expression in epithelial cells (Figure 1D). F11R exhibited substantial expression heterogeneity across different tissues (Figure 1E). The top 100 F11R co-expressed genes, based on relevant coefficients, were selected for further investigation. Subsequently, the top 10 GO functions and KEGG pathways were ranked based on false discovery rate (FDR). According to KEGG analysis, genes correlated with F11R participate in key pathways, such as T cell receptor signalling, proteoglycans in cancer, adherens junctions, and pathogenic Escherichia coli infection (Figure 1F). GO enrichment further demonstrated that the differentially expressed genes were mainly involved in biological processes such as Golgi reconstruction and enhanced translation in response to external signals. In terms of cellular components, these co-expressed genes were found to be associated with cell-cell junctions and adherens junctions. Additionally, in molecular functions, the enrichment analysis highlighted the involvement of MAP kinase activity and cell adhesion molecule binding (Figure 1G).

To explore the immunological landscape of CRC, the SangerBox platform was employed to analyse the correlation between F11R expression and immune infiltration scores. Using gene expression profiles from the TCGA database, ESTIMATE scores were computed for the COAD, COADREAD, and READ cohorts. Spearman’s correlation analysis was subsequently performed to evaluate the relationship between F11R levels and immune infiltration across the three CRC subtypes. A total of 746 tumour samples were included in this analysis: COAD (n = 282, r = 0.03, p = 0.65), COADREAD (n = 373, r = 0.04, p = 0.40), and READ (n = 91, r = 0.10, p = 0.35) (Figure 2A). Additionally, to further characterise the TME, the CIBERSORT algorithm was applied to estimate the proportions of 22 different immune cell subsets present within the CRC TME (Figure 2B).

The relationship between F11R expression and immune checkpoint molecules was further explored using the GEPIA platform. The results demonstrated significant positive associations between F11R and multiple immune cell-related genes. Specifically, F11R expression was strongly correlated with markers of Th1-like cells (CXCL13, HAVCR2, IFNG, CXCR3, BHLHE40, CD4; r = 0.6; p <0.05), effector regulatory T-cells (FOXP3, CTLA4, CCR8, TNFRSF9; r = 0.68; p <0.05), effector memory T-cells (PDCD1, DUSP4, GZMK, GZMA, IFNG; r = 0.64; p <0.05), and resting Tregs (FOXP3, IL2RA; r = 0.62; p <0.05). These associations suggested that F11R may contribute to immune regulation within the CRC microenvironment (Figure 2C).

IHC images in Figure 3A demonstrated that F11R, predo-minantly located in the cytoplasm and membrane with stronger staining in normal tissue, is significantly more expressed in normal cells compared to CRC cells, as confirmed by quantifying F11R-positive cells at higher magnification, with normal tissues exhibiting a notably higher proportion (p <0.05, Figure 3B). To understand F11R's role in CRC, F11R expression was knocked down using siRNA in HCT116 cells, and overexpression was induced through a pLKO.1-puro vector. The CCK-8 assay revealed no difference in cell viability among groups at 24 hours. By 72 hours, the F11R knockdown (F11R KD) group showed the highest cell proliferation, while the F11R overexpression (F11R OE) group had reduced proliferation (Figure 3C). Functional tests indicated that, in HCT116 and SW480 cells, F11R KD resulted in increased cell proliferation and invasiveness (Figure 3D), as well as enhanced migratory capabilities (Figure 3E), while F11R OE suppressed cell proliferation and migration, corroborating bioinformatics predictions. Tumour and peritumoural tissue samples were collected from 4 male and 4 female patients with CRC, with the peritumoural tissues typically harvested within a range of 2 to 5 centimetres from the primary tumour margin. Of these, 5 cases were staged as III and 3 as IV. The median age was 62.5 years (Table I), with 5 cases located in the transverse colon and 3 in the rectum. Following tissue acquisition, F11R protein expression was assessed, revealing significantly higher levels of F11R protein in the peritumoural tissues of CRC patients compared to the tumour tissues (Figure 3F, G).

The potential role of F11R in apoptosis regulation in CRC cell lines (HCT116 and SW480) was further investigated. As shown in Figure 4A and 4B, F11R KD resulted in decreased apoptosis in CRC cell lines, while F11R OE significantly increased apoptosis. EMT plays a key role in early CRC development and dissemination, marked by shifts in proteins such as ZO-1, E-cadherin, N-cadherin, and Vimentin. It was observed that F11R KD in HCT116 and SW480 cells led to decreased ZO-1 and E-cadherin expression, along with elevated N-cadherin and Vimentin levels (Figure 4C). Conversely, F11R OE levels had the opposite effect. Using a G-LISA assay, downregulation of F11R was observed to boost Rap1 activity, whereas F11R OE suppressed it, indicating regulatory role of F11R in the Rap1 pathway (Figure 4D).

DISCUSSION

The exact contribution of F11R to CRC development has yet to be fully elucidated. In this study, the expression characteristics and functional significance of F11R in CRC were investigated. The results demonstrated that F11R is mainly distributed in the cytoplasm and the cell membrane. Moreover, consistent with earlier studies, F11R appears to hold potential as a prognostic indicator across multiple tumour types.^8,12-14

GO and KEGG pathway analyses indicated that F11R-related genes are significantly involved in multiple signalling cascades, such as the T-cell receptor pathway, as well as adherens and tight junction signalling. GO results further suggested that F11R may play a role in functions including protein binding, cadherin binding, and mediating cell-cell adhesion. Importantly, previous studies have linked disruptions in cadherin interactions with increased risk of distant metastasis and unfavourable clinical outcomes in CRC, potentially due to decreased expression of cadherin family members, especially E-cadherin. The downregulation or mutation of E-cadherin could disrupt cadherin binding, thereby fostering the invasion and metastasis of tumour cells.¹⁵ Additionally, the dysregulation of tight junction proteins may contribute to the development of inflammation-related CRC.¹⁶ Consequently, F11R is likely integral to CRC pathogenesis, with possible roles in regulating tumour cell attachment, invasive capacity, and metastatic spread.

A notable association between F11R expression and immune checkpoint-related genes was revealed through investigation of the immune microenvironment, including those linked to Th1, such as cells, effector regulatory T-cells, effector memory T-cells, and resting regulatory T-cells. In the context of CRC metastasis, the immune microenvironment is characterised by increased levels of CD4+T cells, Th1-like T-cells, and elevated expression of inhibitory receptors such as PDCD1. These findings suggest that the abundance of T-cell subsets may contribute to CRC metastasis.¹⁷ Thus, F11R may represent a valuable factor for predicting immunotherapeutic outcomes in patients with CRC.

Following experimental validation, F11R KD significantly promoted the proliferation, migration, and invasion of the tumour cell lines HCT116 and SW480, while reducing apoptosis. This indicates that F11R serves as a negative regulator of cell proliferation, migration, and invasion in CRC. EMT is a process in which cells lose their epithelial characteristics, such as cell polarity and cell-cell adhesion, and acquire mesenchymal properties. In CRC, EMT is associated with invasive or metastatic phenotypes. Upregulation of certain inducers can promote EMT, leading to increased invasiveness and metastasis in CRC. These inducers can downregulate E-cadherin and upregulate N-cadherin by modulating EMT-related signalling pathways and transcription factors.¹⁸ The F11R OE led to increased expression of ZO-1 and E-cadherin, while reducing the levels of N-cadherin and Vimentin in both HCT116 and SW480 cell lines. This indicates a potential role of F11R in regulating EMT markers in CRC cells. Downregulation of ZO-1 expression may lead to weakened intercellular connections and alterations in the extracellular matrix.¹⁹ Downregulation of E-cadherin reduces intercellular adhesion, making cancer cells more likely to detach from the primary tumour and invade surrounding tissues. Elevated levels of N-cadherin could enhance the migratory and invasive capabilities of cancer cells.²⁰ Vimentin is an intermediate filament protein, and its increased expression is typically associated with mesenchymal transition and enhanced migratory ability of cells.²¹ Therefore, F11R may act as an upstream regulator of EMT and influence the progression of CRC.

Rap1 is a small GTPase and is essential for cell-matrix adhesion.²² Rap1 signalling regulates cell invasion and metastasis by interacting with other proteins, modulating integrin and cadherin expression, controlling Rho GTPase, and regulating matrix metalloproteinase expression.²³ Rap1-GTP activates leucocyte function-associated antigen 1 (LFA-1) to induce cell stasis, whereas Rap1-GDP hinders T cell lineage formation and rolling behaviour.²⁴ In oesopha-geal squamous cell carcinoma (ESCC), Rap1B promotes cell growth, migration, and metastasis by activating the β-catenin/TCF signalling pathway.²⁵ F11R KD significantly upregulated Rap1 in tumour cells. Therefore, these findings suggest that F11R may contribute to CRC.

There were several limitations to this study. Firstly, validation of the TCGA data was not supported by large-sample prospective cohorts. Secondly, the relatively small sample size precluded detailed analysis of outcomes across different TNM stages and histological subtypes of adeno-carcinoma, each of which may carry distinct prognostic implications. Future research should clarify the role of F11R in CRC migration and cytoskeleton regulation, particularly through its interaction with Rap1.

CONCLUSION

Downregulation of F11R in CRC tissues, compared to non-tumour tissues, was associated with poor prognosis, although prognosis is also influenced by multiple clinicopathological and molecular factors. Functional experiments showed that reduced F11R expression promoted proliferation, migration, and invasion, while inhibited apoptosis in HCT116 and SW480 cell lines. Moreover, F11R expression was linked to immune checkpoint regulation. In vitro, F11R downregulation induced EMT and activated Rap1 signalling. Collectively, these findings suggest that F11R may serve as a potential prognostic biomarker and therapeutic target in CRC, warranting further investigation in larger, well-designed studies.

ETHICAL APPROVAL:
Ethical approval was obtained from the Research Ethics Committee of the First People’s Hospital of Yunnan Province, Kunming, China (Approval No. #KHLL2021-KY130).

PATIENTS’ CONSENT:
Informed consent was obtained from all individual participants included in the study.

COMPETING INTEREST:
The authors declared no conflict of interest.

AUTHORS’ CONTRIBUTION:
FW: Validation.
FW, XB, QL: Data curation.
XY: Methodology.
XT, PZ: Funding acquisition.
XT, FW: Conception of the study.
PZ: Writing of the original draft.
All authors approved the final version of the manuscript to be published.

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