CNTN1 promotes cell proliferation and metastasis in ovarian cancer through PSEN1

Introduction

Background

Ovarian cancer (OC) ranks as the eighth most common malignancy among females globally, accounting for approximately 320,000 new cases and 210,000 deaths annually (1). The majority of diagnoses occur at advanced stages, contributing to unfavorable survival outcomes (2). Advancements in diagnostic and therapeutic strategies remain imperative to improve early detection and clinical management of OC.

Rationale and knowledge gap

Contactin-1 (CNTN1), a glycosylphosphatidylinositol-anchored neuronal membrane protein of the immunoglobulin superfamily, functions as a neuronal cell adhesion molecule (3). While initially characterized within the human nervous system, recent studies illustrated its involvement in oncogenic signaling pathways. Aberrant CNTN1 activation correlates with pathological processes including uncontrolled proliferation, enhanced invasion, metastasis, and poor clinical outcomes (4,5). First identified in lung cancer by Su et al. (6), subsequent research has examined CNTN1’s oncogenic potential across diverse malignancies by mapping its regulatory interactions within multiple signaling cascades. Elevated CNTN1 expression is consistently linked to aggressive phenotypes and adverse prognosis in cancers of the lung, stomach, prostate, oral squamous epithelium, and breast. Nevertheless, its functional significance in OC remains poorly understood.

Presenilin-1 (PSEN1), the catalytic subunit of the γ-secretase complex, mediates transmembrane protein cleavage and serves as a central regulator of tumor initiation and progression. PSEN1 contributes to diverse oncogenic mechanisms, including cell proliferation, apoptosis, and chemoresistance (7,8). Evidence demonstrates its involvement in promoting gastric cancer invasion and metastasis in vitro and in vivo (9). In contrast, PSEN1 exhibits tumor-suppressive functions in breast cancer (10) and skin cancer (11). Despite these findings, its function in OC remains unclear.

Objective

This study aimed to examine CNTN1 overexpression in human OC tissues and cell lines, focusing on its regulatory role in OC cell proliferation, migration, and invasion via interaction with PSEN1. The findings offer mechanistic insight into OC carcinogenesis and highlight CNTN1 signaling as a potential regulatory axis in tumor progression. We present this article in accordance with the MDAR and ARRIVE reporting checklists (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2024-2234/rc).

Methods

Patients

Tissue specimens for reverse transcription quantitative polymerase chain reaction (RT-qPCR) analysis were obtained from 40 female patients who underwent surgical resection for OC at the Second Hospital of Tianjin Medical University between January 2015 and December 2016. CNTN1 expression levels were stratified as high (≥3) or low (<3), using the mean CNTN1 expression in normal tissues as the reference. The cohort’s median age was 47.4 years (range, 25–70 years). Among them, 21 patients presented with metastasis involving lymph nodes or distant organs, while 19 exhibited no metastatic spread. Pathological diagnoses were independently verified by two senior pathologists. The median follow-up duration was 39.1 months (range, 8–81 months). Overall survival was calculated from the date of surgery to either death or the last follow-up using Kaplan-Meier analysis, with censoring applied to surviving patients or those lost to follow-up. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethical Committee of the Second Hospital of Tianjin Medical University (No. KY2021K035) and informed consent was taken from all the patients.

Immunohistochemistry

Formalin-fixed, paraffin-embedded OC tissues underwent deparaffinization, rehydration, and immunohistochemical staining. Endogenous peroxidase activity was quenched with 3% H₂O₂, followed by heat-induced antigen retrieval. Primary antibodies targeting CNTN1 (ab223217, Abcam, 1:1,000) and PSEN1 (sc-365495, Santa Cruz Biotechnology, 1:500) were applied in accordance with the manufacturers’ protocols. CNTN1 expression appeared as a brown nuclear signal, whereas PSEN1 localized predominantly in the cytoplasm.

Cell culture

A2780 (1101HUM-PUMC001020) and SKOV3 (4201PAT-CCTCC01017) cell lines were obtained from the Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, while HO8910 (YS142C) and HOSEpiC (YS2089C) were sourced from YaJi Biological. All cell lines were maintained in RPMI 1640 medium supplemented with 10% fetal bovine serum under standard culture conditions.

Vector construction and transfection

CNTN1-siRNAs (5'-CCGGGCCGTGTTTCAGACACATACTCGAGTATGATTGTGACACCCTGACCACGGCTTTTTG-3', 5'-CCGGCCAAGGATCATCAGTTCTACTCGAGTACTGAACTGATGATCCTTGGTTTTTG-3') and PSEN1 (5'-UGAGGCAGCACAAUAUGGCCUG-3') were obtained from GeneCopoeia (GeneCopoeia, CA, USA). All transfections were conducted using LipofectAmine 2000 Transfection reagent (Invitrogen, No. 11668019, Carlsbad, CA, USA) according to the manufacturer’s protocol.

RT-qPCR

Total RNA was extracted with TRIzol reagent (Sigma-Aldrich) and reverse transcribed into cDNA using specific primers. CNTN1 mRNA expression levels were quantified relative to GAPDH as an internal control. Primer sequences were designed as follows:

• CNTN1: forward, 5'-TTGGGAAGATGGTAGCTTGG-3'; reverse, 5'-TAGTAACAAGGGTTCCAGTGC-3';
• CNTNAP1: forward, 5'-GTCCCCTGTATGCACGCTC-3'; reverse, 5'-CCGTAGAGTAGCATGTAACGTGT-3';
• PTPRZ1: forward, 5'-TGCAGAGCTGTGTGTGTGTGTGTGTGTGTGACTT-3'; reverse, 5'-TGCCATCCTTTTCAGC-3';
• NOTCH1: forward, 5'-GCAGTTGTGCTCCTGAAGAA-3'; reverse, 5'-CGGGCGGCCAGAAAC-3'
• PSEN1: forward, 5'-TATGGCAGAACGAGACCCG-3'; reverse, 5'-CCATTCCTCACTGAACCCG-3';
• PSEN2: forward, 5'-GGAAGAGCTGACCCTCAAATAC-3'; reverse, 5'-GTGTAGAAGCGCACAGACTT-3';
• GAPDH: forward, 5'-GCATCTTCTTGTGCAGTGCC-3'; reverse, 5'- TACGGCCAAATCCGTTCACA-3'.

Dual-luciferase reporter assay

To assess the direct interaction between CNTN1 and the PSEN1 mRNA 3'-UTR, mutated and wild-type 3'-UTR sequences were cloned into the pmirGLO luciferase reporter vector. Cancer cells were co-transfected with the CNTN1 mimic alongside either the wild-type or mutant PSEN1 3'-UTR constructs. Firefly luciferase activity, normalized to Renilla luciferase, was quantified using the dual-luciferase reporter assay system. All assays were independently performed in triplicate.

Plate clonogenic assay

For the plate clonogenic assay, cells (1×10⁴/well) were seeded into 6-well plates and cultured until visible colonies, defined as clusters of at least 50 cells, were established. Colonies were subsequently fixed with methanol and stained using 0.5% crystal violet. Each assay was independently repeated three times.

Invasion and migration assays

Transwell 24-well plates equipped with 8 µm pore polyethylene terephthalate membrane inserts (Corning, NY, USA) were employed to assess cellular invasion and migration. For invasion assays, 20 µL of cell suspension (5×10⁴ cells/mL) in serum-free medium was seeded into the upper chamber pre-coated with Matrigel. Migration assays were conducted under identical conditions without Matrigel coating. The lower chamber received 500 µL of complete medium as a chemoattractant, while 200 µL of serum-free cell suspension was placed in the upper chamber. Following a 48-hour incubation, cells that traversed the membrane were fixed with cold methanol and stained with crystal violet for 30 minutes. Three random microscopic fields were selected for imaging using a Nikon microscope. Each experiment was independently repeated three times.

Western blot

Proteins were extracted using RIPA buffer, quantified, and separated by SDS-polyacrylamide gel electrophoresis before transfer onto PVDF membranes (Thermo Fisher Scientific). Membranes were blocked with 5% skim milk for 2 hours and subsequently incubated overnight at 4 ℃ with primary antibodies targeting PSEN1. After three washes with 20 mL TBS for 5 minutes each, membranes were incubated with HRP-conjugated secondary antibodies at approximately 25 ℃ for 2 hours. Protein bands were visualized using ECL reagent (Amersham Biosciences, UK). All assays were performed in triplicate.

Tumor xenograft model in nude mice

The functional involvement of CNTN1 in OC was validated through a tumor xenograft model using BALB/c nude mice. Fifteen female mice (4 weeks old, Beijing HFK Bioscience Co., Ltd., Beijing, China) were randomly assigned to three groups (n=5) and maintained under SPF conditions. Subcutaneous injections of si-NC, si-CNTN1, or si-CNTN1 combined with PSEN1 overexpression cells were administered into the upper right flank. Tumor growth was assessed weekly by digital caliper measurements, and volumes were calculated using the formula: volume = [length (mm) × width² (mm)]/2. A protocol was prepared before the study with registration in the Ethical Committee of the Second Hospital of Tianjin Medical University. Experiments were performed under a project license (No. TMUaMEC201804) granted by Tianjin Medical University Institutional Animal Care and Use Committee, in compliance with Tianjin Medical University guidelines for the care and use of animals.

Statistical analyses

Data analysis was conducted using SPSS19.0 software (SPSS, Chicago, IL, USA). Comparisons between groups were assessed with two-tailed unpaired Student’s t-tests, while χ² tests evaluated parameter correlations. Graphs display mean values derived from a minimum of three independent experiments. Statistical significance was defined as P≤0.05.

Results

CNTN1 overexpression in OC tissues and cell lines

CNTN1 expression was quantified by RT-qPCR in 40 paired OC tissue samples and OC cell lines, including A2780, SKOV3, HO8910, and HOSEpiC. CNTN1 levels were markedly elevated in OC tissues relative to adjacent non-cancerous tissues (Figure 1A). Correlation analysis demonstrated that high CNTN1 expression (>3) was significantly associated with advanced FIGO stage and the presence of metastases (P=0.009 and P=0.049, respectively; Table 1). Kaplan-Meier survival analysis revealed that patients with elevated CNTN1 expression exhibited reduced overall survival (34.9±13.9 months) compared to those with low expression (50.4±15.5 months, P=0.01; Figure 1B). Immunohistochemistry (IHC) staining localized CNTN1 predominantly to the cell membrane (Figure 1C). Additionally, OC cell lines displayed significantly higher CNTN1 expression, with SKOV3 (P<0.001) and A2780 (P<0.001) showing the most pronounced upregulation (Figure 1D). CNTN1 knockdown via siRNA transfection in SKOV3 and A2780 cells effectively suppressed its expression (Figure 1E).

Figure 1 CNTN1 was highly expressed in ovarian tumor tissues and cell lines. (A) RT-qPCR analysis quantified CNTN1 mRNA levels in ovarian tumor samples. (B) Kaplan-Meier and log-rank analyses revealed significantly reduced overall survival in OC patients with high CNTN1 expression compared to those with low expression (P=0.01). (C) CNTN1 expression distribution in OC specimens (staining methods: immunohistochemistry; magnification: 20×). (D) Comparative analysis of CNTN1 expression in normal human ovarian surface epithelium cells and ovarian cancer cell lines (A2780, SKOV3, HO8910, and HOSEpiC). (E) SKOV3 and A2780 cells transfected with CNTN1-siRNA exhibited significantly reduced CNTN1 mRNA levels (P=0.001 and P=0.02, respectively), as determined by RT-qPCR, with si-NC serving as the negative control. *, P<0.05; ***, P<0.001. CNTN1, contactin-1; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; NC, negative control; OC, ovarian cancer; RT-qPCR, reverse transcription quantitative polymerase chain reaction.

Silencing CNTN1 inhibits proliferation, migration, and invasion of SKOV3 and A2780 cells

Colony formation assays demonstrated that reduced CNTN1 expression significantly impaired the proliferative capacity of SKOV3 (vs. si-NC, P<0.001) and A2780 cells (vs. si-NC, P<0.001, Figure 2A) Transwell assays further revealed that CNTN1 silencing markedly diminished both migratory and invasive potentials in si-CNTN1-transfected cells (vs. si-NC, P<0.001, Figure 2B,2C). Collectively, the data suggest that CNTN1 downregulation suppresses proliferation, migration, and invasion of OC cells.

Figure 2 CNTN1 downregulation suppressed proliferation, migration, and invasion in SKOV3 and A2780 cells. (A) Colony formation assays demonstrated that CNTN1 knockdown significantly reduced proliferative capacity, P<0.001 (staining methods: 0.5% crystal violet; magnification: 10×). (B,C) Transwell assays revealed that silencing CNTN1 inhibited both migratory and invasive abilities in SKOV3 (si-CNTN1 vs. si-NC, P<0.001) and A2780 cells (si-CNTN1 vs. si-NC, P<0.001, staining methods: 0.5% crystal violet; magnification: 20×). ***, P<0.001. CNTN1, contactin-1; NC, negative control.

CNTN1 regulates the proliferation, migration, and invasion of OC cells by regulating PSEN1

The regulatory mechanism of CNTN1 in cellular biological activity was explored through protein interaction predictions using the STRING database. Analysis identified the top 10 potential CNTN1-associated proteins (Figure 3A), among which PSEN1 exhibited the highest mRNA expression in CNTN1-overexpressing cells, as determined by qRT-PCR (Figure 3B). Luciferase reporter assays demonstrated direct binding between PSEN1 and CNTN1 (Figure 3C). Both mRNA (SKOV3 si-CNTN1 vs. si-NC, P=0.03; A2780 cells si-CNTN1 vs. si-NC, P=0.048) and protein (SKOV3 si-CNTN1 vs. si-NC, P<0.001; A2780 cells si-CNTN1 vs. si-NC, P=0.009) levels of PSEN1 were markedly reduced following si-CNTN1 transfection in SKOV3 and A2780 cells (Figure 3D,3E). To further characterize PSEN1 involvement in OC, IHC analysis revealed predominant cytoplasmic localization of PSEN1 (Figure 3F). Elevated PSEN1 expression was detected in 40 tumor specimens compared to normal tissues (Figure 3G), with a positive correlation observed between PSEN1 and CNTN1 expression (r=0.39, P=0.01, Figure 3H).

Figure 3 CNTN1 directly interacted with PSEN1 and exhibited a strong correlation with PSEN1 expression. (A) Bioinformatic analysis identified the top 10 proteins potentially interacting with CNTN1. (B) RT-qPCR analysis showed increased expression of five candidate genes in CNTN1-overexpressing cells. (C) Luciferase assays demonstrated that PSEN1 overexpression enhanced fluorescence intensity in cells transfected with pmirGLO/CNTN1-UTR, while no change was observed in pmirGLO/CNTN1-mUTR-transfected cells. (D) RT-qPCR analysis confirmed a significant reduction in PSEN1 mRNA levels following CNTN1 silencing compared to si-NC controls (SKOV3 si-CNTN1 vs. si-NC, P=0.03; A2780 cells si-CNTN1 vs.si-NC, P=0.048). (E) Western blot analysis further validated the downregulation of PSEN1 protein levels in si-CNTN1 cells (SKOV3 si-CNTN1 vs. si-NC, P<0.001; A2780 cells si-CNTN1 vs. si-NC, P=0.009). (F) Immunohistochemical analysis indicated PSEN1 expression in OC tissues (magnification: 20×). (G) PSEN1 levels were elevated in OC specimens relative to normal tissues. (H) Correlation analysis revealed a positive association between CNTN1 and PSEN1 expression in OC tissues (r=0.39, P=0.01). *, P<0.05; **, P<0.01; ***, P<0.001. CNTN1, contactin-1; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; NC, negative control; OC, ovarian cancer; OE, overexpression; PSEN1, presenilin-1; RT-qPCR, reverse transcription quantitative polymerase chain reaction.

Rescue experiments

Rescue experiments demonstrated that PSEN1 overexpression restored the diminished colony-forming capacity of si-CNTN1-transfected SKOV3 and A2780 cells, P<0.001 (Figure 4A). Consistently, PSEN1 overexpression reversed the impaired migratory and invasive capabilities induced by CNTN1 silencing, yielding levels comparable to control cells, P<0.001 (Figure 4B). Collectively, the results indicate that CNTN1 promotes OC cell progression through PSEN1-mediated mechanisms.

Figure 4 PSEN1 inhibitor restored cell proliferation, migration, and invasion ability. (A) The decreased colon formation (staining methods: 0.5% crystal violet; magnification: 10×) and (B) migration and invasion ability of SKOV3 and A2780 cells transfected with si-CNTN1 were increased when transfected with PSEN1 overexpression compared with those of control cells, P<0.001 (staining methods: 0.5% crystal violet; magnification: 20×). Data are presented as mean ± SD from three independent biological replicates. ***, P<0.001. CNTN1, contactin-1; NC, negative control; OC, ovarian cancer; OE, overexpression; PSEN1, presenilin-1; SD, standard deviation.

Decreased CNTN1 suppresses tumor growth in vivo via PSEN1

The role of CNTN1 in tumor proliferation was further validated using a nude mouse xenograft model. SKOV3 control cells (NC), si-CNTN1-transfected cells, and si-CNTN1 cells with PSEN1 overexpression were subcutaneously implanted into nude mice. Tumor volume measurements (Figure 5A,5B) demonstrated a significant reduction in the si-CNTN1 group compared to the SKOV3-NC group (P=0.01), whereas PSEN1 overexpression in si-CNTN1 cells markedly restored tumor growth (P=0.01). IHC analysis confirmed reduced PSEN1 expression in the si-CNTN1 group relative to controls (P<0.001), while PSEN1-overexpressing xenografts exhibited elevated PSEN1 levels, P<0.001 (Figure 5C). Collectively, the data indicate that CNTN1 downregulation inhibits tumor growth in vivo, potentially through modulation of PSEN1.

Figure 5 Xenograft experiments confirmed that CNTN1 knockdown inhibited tumor growth in vivo through PSEN1-dependent pathways. (A) SKOV3, si-CNTN1, and si-CNTN1 combined with PSEN1 overexpression cells were subcutaneously implanted into BALB/C mice, leading to tumor formation. (B) Tumors derived from the si-CNTN1 group exhibited significantly reduced volumes compared to the SKOV3-NC group (P=0.01), while PSEN1 overexpression partially reversed this suppression, resulting in larger tumor volumes than the si-CNTN1 group (P=0.01). (C) IHC analysis showed decreased PSEN1 expression in si-CNTN1 tumors relative to controls (P<0.001), whereas PSEN1 levels were markedly elevated in si-CNTN1 tumors with PSEN1 overexpression, P<0.001 (magnification: 20×). *, P<0.05; ***, P<0.001. CNTN1, contactin-1; IHC, immunohistochemistry; NC, negative control; OC, ovarian cancer; OE, overexpression; PSEN1, presenilin-1.

Discussion

OC remains difficult to detect at an early stage, with 70–75% of cases diagnosed at advanced stages and a 5-year survival rate ranging from 20% to 30% in most patients (12). Characterized by diverse pathological subtypes, high recurrence rates, and unfavorable clinical outcomes, OC presents greater diagnostic and therapeutic challenges compared to other gynecologic malignancies. In the recent years, it is urgent to search for effective molecular diagnostic biomarkers and drug therapy targets for OC. Several inhibitors of RAS-RAF-MEK-ERK pathway is currently being assessed in different clinical trials (13). The identification of reliable prognostic indicators and biomarkers is imperative for optimizing therapeutic strategies and improving patient survival.

This study found that CNTN1 expression was significantly elevated in OC tissues compared to adjacent non-cancerous tissues and showed a strong association with tumor stage and metastasis. In vitro experiments confirmed that CNTN1 silencing suppressed proliferation, migration, and invasion of SKOV3 and A2780 cells, indicating its oncogenic potential in OC. As a DLX4 subtype, CNTN1 plays a regulatory role in cell differentiation and early development, with aberrant expression commonly observed across various malignancies (14). Elevated CNTN1 levels have been linked to lymphatic invasion, metastasis, advanced tumor-node-metastasis (TNM) stages, and reduced overall survival in multiple cancer types, although its impact on proliferation remains controversial (15-17). Consistent with prior studies, CNTN1 was highly expressed in OC tissues and correlated with advanced FIGO stages, metastatic progression, and unfavorable prognosis (18). High CNTN1 expression emerged as a potential prognostic indicator, as patients exhibiting elevated levels experienced reduced survival. Despite these associations, the mechanistic contribution of CNTN1 to tumor aggressiveness requires further elucidation. Previous research demonstrated that CNTN1 facilitated EMT and chemoresistance through activation of the PI3K/Akt pathway in lung adenocarcinoma and prostate cancer (19,20). To elucidate the regulatory mechanism, direct interaction between CNTN1 and PSEN1 was identified through the STRING database and confirmed by luciferase reporter assays. PSEN1 exhibits context-dependent roles in tumor progression via distinct signaling pathways. For instance, miR-193a-mediated suppression of PSEN1 inhibits gastric cancer cell proliferation by modulating the PI3K/Akt pathway and promoting epithelial-to-mesenchymal transition (21). Additionally, PSEN1 is integral to Notch signaling, where its activation contributes to the differentiation and malignant potential of various cancers, including OC (22,23). In this study, PSEN1 expression showed a positive correlation with CNTN1 levels in OC tissues and cells, while PSEN1 upregulation reversed the inhibitory effects of CNTN1 silencing on cell proliferation and metastasis. These results suggest that PSEN1 functions as a malignancy-associated factor in OC. Rescue experiments further indicated that CNTN1 may enhance OC progression by activating PSEN1. However, the limited clinical sample size and the absence of mechanistic evidence explaining how CNTN1, as a non-transcription factor, regulates PSEN1 expression remain significant limitations. Moreover, downstream pathways mediating PSEN1-driven tumorigenesis require further investigation. Caution is warranted when interpreting these results.

Conclusions

Overexpression of CNTN1 drives oncogenic activity and accelerates OC progression. Silencing CNTN1 suppresses tumor growth and metastasis by modulating PSEN1 expression. Targeting the CNTN1/PSEN1 axis offers a potential therapeutic strategy for OC management.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the MDAR and ARRIVE reporting checklists. Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2024-2234/rc

Data Sharing Statement: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2024-2234/dss

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2024-2234/prf

Funding: This study was funded by the Natural Science Foundation of Tianjin (No. 21JCYBJC01670).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2024-2234/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethical Committee of the Second Hospital of Tianjin Medical University (No. KY2021K035) and informed consent was taken from all the patients. Experiments were performed under a project license (No. TMUaMEC201804) granted by Tianjin Medical University Institutional Animal Care and Use Committee, in compliance with Tianjin Medical University guidelines for the care and use of animals.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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