Folate receptor genes were up-regulated in epithelial ovarian cancer and partly associated with patients’ prognosis
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Juanli Yang
Abstract
Objective
The present work aimed to investigate folate receptor (FOLR1, FOLR2, FOLR3) expression, functional enrichment, signaling pathway and prognosis in ovarian cancer patients by integrated bioinformatics analysis.
Methods
Folate receptor (FOLR1, FOLR2, and FOLR3) mRNA expression level between epithelial ovarian cancer and corresponding normal ovarian tissue of cancer patients was compared through the TCGA database by GEPIA online analysis tool. The protein–protein interaction (PPI) network of FOLR1, FOLR2, FOLR3, and related genes were constructed through the STRING database. GO and KEGG enrichment of FOLR1, FOLR2, FOLR3, and relevant genes were analyzed. Overall survival (OS) and progression-free survival (PFS) between FOLR1, FOLR2, and FOLR3 mRNA high and low expression epithelial ovarian cancer patients were compared by log-rank test.
Results
FOLR and FOLR3 mRNA expression in epithelial ovarian cancer tissue were significantly higher than that of corresponding normal ovarian tissue of cancer patients (P < 0.05) The PPI network showed 53 nodes and 298 edges with the average node degree of 11.2. The local clustering coefficient was 0.744, which indicated that the protein–protein enrichment was statistically significant (P < 1.0 × 10−16). Folate receptor (FOLR1, FOLR2, and FOLR3) and relevant genes were mainly enriched in folic acid transport, methotrexate transmembrane transporter activity, antifolate resistance for biological process, molecular function, and KEGG pathway, respectively. The PFS of FOLR1 and FOLR3 high expression epithelial ovarian cancer patients was significantly lower compared to low-expression subjects with statistical significance [hazard ratio (HRFOLR1) = 1.26, 95% confidence interval (CI): 1.09–1.45, P < 0.05, HRFOLR3 = 1.22, 95% CI: 1.06–1.40, P < 0.05]. However, the OS was not statistically different between FOLR1, FOLR2, and FOLR3 low and high expression groups.
Conclusion
Folate receptor (FOLR1, FOLR2, and FOLR3) genes were up-regulated in epithelial ovarian cancer and partly associated with patient’s poor prognosis.
1 Introduction
Epithelial ovarian cancer is a major kind of gynecological malignant tumor with the highest mortality rate for female reproductive system [1]. Due to the lack of obvious symptom and reliable biomarkers, most of the epithelial ovarian cancer cases were at advanced stages when they were first diagnosed. At present, the morbidity of epithelial ovarian cancer in the world is increasing, and the patients tend to be younger. According to epidemiology statistics, there were more than 290,000 new epithelial ovarian cancer patients and 185,000 deaths globally in year 2018 [2]. Due to its insidious onset of epithelial ovarian cancer, more than 70% patients are accompanied by distant metastasis when they were first diagnosed s [3]. The standard treatment for advanced epithelial ovarian cancer is surgery and platinum-based chemotherapy, but the recurrence rate within 2 years is high, and there is no effective treatment after recurrence [4,5,6]. Therefore, it is of great clinical significance to identify the molecular mechanism and prognostic markers of epithelial ovarian cancer.
Folate receptor family consists of three members (FOLR1, FOLR2, and FOLR3), which are cysteine-rich cell surface glycoproteins that bind to folic acid with high affinity, thus mediating the uptake of folic acid by cells [7]. Studies have shown that FOLR1 was up-regulated in a variety of human carcinomas and was associated with patient’s prognosis [8,9,10]. FOLR1 is highly expressed in most gynecological malignant tumors and is correlated with poor long-term survival of epithelial ovarian cancer cases [9]. However, there are few studies on the expression of the three members of folate receptor in epithelial ovarian cancer and their relationship with epithelial ovarian cancer prognosis. Therefore, we performed a bioinformatics analysis of folate receptor (FOLR1, FOLR2, and FOLR3) expression, functional enrichment, signaling pathway, and association with epithelial ovarian carcinoma.
2 Material and methods
2.1 Folate receptor mRNA expression analysis
Folate receptor (FOLR1, FOLR2, and FOLR3) mRNA expression levels between ovarian carcinoma tissue and corresponding normal ovarian tissue of cancer patients were analyzed through the TCGA database by GEPIA [11]. The folate receptor (FOLR1, FOLR2, and FOLR3) mRNA expression between epithelial ovarian cancer and corresponding normal tissue of cancer patients was compared by analysis of variance and two-tailed P-value <0.05 was considered statistically differently.
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Informed consent: Informed consent has been obtained from all individuals included in this study.
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Ethical approval: The research related to human use has been complied with all the relevant national regulations, institutional policies and in accordance the tenets of the Helsinki Declaration and has been approved by the authors’ institutional review board or equivalent committee.
2.2 Protein–protein interaction (PPI) network and hub genes analysis
The PPI network of folate receptor (FOLR1, FOLR2, and FOLR3) and relevant genes was constructed through the STRING database (http://string-db.org/cgi/input.pl). The PPI network was constructed under the condition of max number of interactions no more than 50.
2.3 GO and KEGG analysis
GO and KEGG enrichment of the folate receptor (FOLR1, FOLR2, and FOLR3) and relevant genes were analyzed in the DAVID database (https://david.ncifcrf.gov/). The biological function of folate receptor (FOLR1, FOLR2, and FOLR3) and relevant genes was analyzed in the aspects of biological process (BP), cellular component (CC), and molecular function (MF) for GO.
2.4 Survival analysis
The epithelial ovarian cancer patients were divided into two groups [high expression group: folate receptor (FOLR1, FOLR2, and FOLR3) mRNA ≥ median expression; low expression: folate receptor (FOLR1, FOLR2, and FOLR3) mRNA < medial expression]. The overall survival (OS) and progression-free survival (PFS) for folate receptor (FOLR1, FOLR2, and FOLR3) high and low expression groups were compared by the survival curve through log-rank test.
3 Results
3.1 Folate receptor (FOLR1, FOLR2, and FOLR3) mRNA expression analysis
Folate receptor (FOLR1, FOLR2, and FOLR3) mRNA expression was generally elevated in most malignant carcinomas (Figures 1a, 2a and 3a). For epithelial ovarian cancer, folate receptor (FOLR1 and FOLR3) mRNA expression in cancer tissue was significantly higher than that of corresponding normal ovarian tissue (P < 0.05) of cancer patients (Figures 1b and 3b). However, FOLR2 mRNA expression between epithelial ovarian cancer and corresponding normal ovarian tissue was statistically different (P < 0.05, Figure 2b). The mRNA expression level of FOLR1, FOLR2, and FOLR3 was significantly elevated with the clinical stages increased (χ 2 = 98.5, P < 0.001) (Figures 1c, 2c and 3c).
FOLR1 mRNA expression in multiple malignant carcinoma and ovarian carcinoma. (a) FOLR1 mRNA expression in multiple malignant carcinoma and corresponding normal tissue of cancer patients (red for cancer tissue, blue for normal tissue); (b) FOLR1 mRNA expression in ovarian carcinoma and corresponding normal ovarian tissue of cancer patients (P < 0.05) (red for cancer tissue, blue for normal tissue); and (c) FOLR1 mRNA expression of different clinical stages (different colors demonstrate different stages).
FOLR2 mRNA expression in multiple malignant carcinoma and ovarian carcinoma. (a) FOLR2 mRNA expression in multiple malignant carcinoma and corresponding normal tissue of cancer patients (red for cancer tissue, blue for normal tissue); (b) FOLR2 mRNA expression in ovarian carcinoma and corresponding normal ovarian tissue of cancer patients (P < 0.05) (red for cancer tissue, blue for normal tissue); and (c) FOLR2 mRNA expression of different clinical stages (different colors demonstrate different stages).
FOLR3 mRNA expression in multiple malignant carcinoma and ovarian carcinoma. (a) FOLR3 mRNA expression in multiple malignant carcinoma and corresponding normal tissue of cancer patients (red for cancer tissue, blue for normal tissue); (b) FOLR3 mRNA expression in ovarian carcinoma and corresponding normal ovarian tissue of cancer patients (P < 0.05) (red for cancer tissue, blue for normal tissue); and (c) FOLR3 mRNA expression of different clinical stages (different colors demonstrate different stages).
3.2 PPI network enrichment and hub genes identification
The PPI network showed 53 nodes and 298 edges with the average node degree of 11.2. The local clustering coefficient was 0.744 indicating that the protein–protein enrichment was statistically significant (P < 1.0 × 10−16, Figure 4).
PPI network analysis of folate receptor (FOLR1, FOLR2, and FOLR3) and relevant genes.
3.3 GO and KEGG analysis
Folate receptor (FOLR1, FOLR2, and FOLR3) and relevant genes were mainly enriched in folate import across plasma membrane, folic acid transport, positive regulation of oligodendrocyte progenitor proliferation, and folic acid metabolic process in the aspect of biology process (Table 1). In CC, folate receptor (FOLR1, FOLR2, and FOLR3) and relevant genes were mainly enriched in complement component c1 complex, spectrin, spectrin-associated cytoskeleton, and COPII vesicle coat (Table 2). For MF, FOLR1, FOLR2, FOLR3, and relevant genes were mainly enriched in methotrexate transmembrane transporter activity, folic acid receptor activity, methotrexate binding, folic acid transmembrane transporter activity, folic acid binding, and so on (Table 3). In the aspect of KEGG pathway, FOLR1, FOLR2, FOLR3, and relevant genes were mainly enriched in antifolate resistance, endocytosis, complement and coagulation cascades, and protein processing in endoplasmic reticulum (Table 4).
Gene ontology analysis of folate receptor (FOLR1, FOLR2, and FOLR3) in the aspect of BP
| Term description | Observed gene count | Background gene count | Strength | P-Value |
|---|---|---|---|---|
| Folate import across plasma membrane | 5 | 5 | 2.57 | 1.23 × 10−8 |
| Folic acid transport | 6 | 9 | 2.39 | 7.04 × 10−10 |
| Positive regulation of oligodendrocyte progenitor proliferation | 2 | 3 | 2.39 | 0.0089 |
| Synapse pruning | 3 | 8 | 2.14 | 0.00062 |
| Folic acid metabolic process | 7 | 19 | 2.13 | 2.35 × 10−10 |
| Response to folic acid | 3 | 9 | 2.09 | 0.00081 |
| COPI coating of Golgi vesicle | 2 | 6 | 2.09 | 0.0201 |
| Pulmonary artery morphogenesis | 2 | 6 | 2.09 | 0.0201 |
| COPII-coated vesicle cargo loading | 4 | 13 | 2.06 | 3.14 × 10−5 |
| Vagina development | 3 | 10 | 2.04 | 0.00099 |
| Vesicle coating | 16 | 68 | 1.94 | 1.18 × 10−22 |
Gene ontology analysis of folate receptor (FOLR1, FOLR2, and FOLR3) in the aspect of CC
| Term description | Observed gene count | Background gene count | Strength | P-value |
|---|---|---|---|---|
| Complement component c1 complex | 2 | 2 | 2.57 | 0.002 |
| Spectrin | 4 | 9 | 2.22 | 3.15 × 10−6 |
| Spectrin-associated cytoskeleton | 4 | 9 | 2.22 | 3.15 × 10−6 |
| COPII vesicle coat | 4 | 15 | 1.99 | 1.44 × 10−5 |
| ER to Golgi transport vesicle membrane | 10 | 58 | 1.8 | 1.23 × 10−12 |
| Anchored component of external side of plasma membrane | 3 | 19 | 1.77 | 0.0013 |
| COPII-coated ER to Golgi transport vesicle | 12 | 90 | 1.69 | 7.60 × 10−14 |
| Node of ranvier | 2 | 15 | 1.69 | 0.0269 |
| Axon initial segment | 2 | 18 | 1.61 | 0.035 |
| Costamere | 2 | 19 | 1.59 | 0.038 |
Gene ontology analysis of folate receptor (FOLR1, FOLR2, and FOLR3) in the aspect of MF
| Term description | Observed gene count | Background gene count | Strength | P-value |
|---|---|---|---|---|
| Methotrexate transmembrane transporter activity | 2 | 2 | 2.57 | 0.0132 |
| Folic acid receptor activity | 2 | 2 | 2.57 | 0.0132 |
| Methotrexate binding | 2 | 3 | 2.39 | 0.0137 |
| Phosphorylation-dependent protein binding | 2 | 3 | 2.39 | 0.0137 |
| Folic acid transmembrane transporter activity | 2 | 4 | 2.27 | 0.0173 |
| Folic acid binding | 5 | 11 | 2.22 | 1.64 × 10−6 |
| Cytoskeletal anchor activity | 4 | 21 | 1.85 | 0.00047 |
| Spectrin binding | 4 | 28 | 1.72 | 0.001 |
| Modified amino acid binding | 7 | 90 | 1.46 | 1.20 × 10−5 |
| Structural constituent of cytoskeleton | 7 | 104 | 1.4 | 2.06 × 10−5 |
KEGG pathway analysis of folate receptor (FOLR1, FOLR2, and FOLR3)
| Term description | Observed gene count | Background gene count | Strength | P-value |
|---|---|---|---|---|
| Antifolate resistance | 7 | 31 | 1.92 | 2.77 × 10−9 |
| Endocytosis | 8 | 241 | 1.09 | 5.47 × 10−5 |
| Complement and coagulation cascades | 5 | 82 | 1.35 | 0.00041 |
| Protein processing in endoplasmic reticulum | 6 | 165 | 1.13 | 0.00055 |
3.4 Survival analysis
The PFS in FOLR1 and FOLR3 high expression epithelial ovarian cancer patients was significantly lower compared to low-expression subjects with statistical significance [HRFOLR1 = 1.26, 95% confidence interval (CI): 1.09–1.45, P < 0.05, HRFOLR3 = 1.22, 95% CI: 1.06–1.40, P < 0.05, Figure 5]. However, the OS was not statistically different for FOLR1, FOLR2, and FOLR3 low and high expression groups.
Overall survival and progression-free survival curve folate receptor (FOLR1, FOLR2, and FOLR3) high expression and low expression groups in ovarian carcinoma patient.
4 Discussion
Epithelial ovarian carcinoma was known as an important cause of cancer-associated death globally [12]. Both morbidity and mortality of epithelial ovarian cancer are increasing year by year, ranking seventh of all malignant tumors for female [13]. In recent years, although the comprehensive treatment of surgery combined with chemotherapy has improved the prognosis of epithelial ovarian cancer, the long-term survival of the patients was still unsatisfied due to advanced stages when they were first diagnosed [14,15,16]. Therefore, searching for key molecular targets and pathogenesis of epithelial ovarian carcinoma and regulating them effectively to improve the prognosis of patients have become a current research hotspot.
Folate receptor (FOLR1, FOLR2, and FOLR3) family was a kind of glycosylphosphatidylinositol linker proteins, which has a high affinity with folate. Folate receptor protein encoded by FOLR gene is a member of the folate receptor family. Folate receptor binds folic acid and its reduced derivatives and transports 5-methyltetrahydrofolate into cells [17,18].
In different cells of normal ovarian tissue, only primitive epithelium expressed FOLR1. The primordial epithelium of ovary can differentiate into benign mucinous epithelium or benign serous epithelium. The expression of FOLR1 decreased when the primitive epithelium transformed into mucinous cystadenocarcinoma or clear cell carcinoma. However, FOLR1 expression was elevated in almost all confirmed serous cystadenocarcinoma and correlated with tumor stages and grades, which may demonstrate tumor etiology and progression [19]. Yan Wang and Qu [20] evaluated FOLR1 protein expression in 66 epithelial ovarian cancer cases by immunohistochemistry assay and found that FOLR1 protein expression was correlated with the tumor differentiation (P < 0.05) but not correlated with the patients’ age, tumor diameter, lymph node metastasis, and FIGO stages (P > 0.05).
In our present work, we found that folate receptor (FOLR1, FOLR2, and FOLR3) gene mRNA expression levels were elevated in cancer tissue compared to normal ovarian epithelial of cancer patients. Biological function analysis indicated that folate receptor (FOLR1, FOLR2, and FOLR3) and relevant genes were mainly enriched in folic acid transport, methotrexate transmembrane transporter activity, antifolate resistance for BP, MF, and KEGG pathway, respectively. The PFS of FOLR1 and FOLR3 high expression epithelial ovarian cancer patients was significantly lower compared to low-expression subjects with statistical significance (HRFOLR1 = 1.26, 95% CI: 1.09–1.45, P < 0.05, HRFOLR3 = 1.22, 95% CI: 1.06–1.40, P < 0.05). However, there was no statistical difference between FOLR2 high and low expression cases in the aspect of PFS. The reason for lacking the statistical difference of FOLR2 high and low expression groups may due to the smaller samples size of limited statistical power. In addition, the OS was not statistically different for FOLR1, FOLR2, and FOLR3 low and high expression groups.
In conclusion, the overexpression of folate receptor (FOLR1, FOLR2, and FOLR3) may play an important role in the occurrence and development of epithelial ovarian cancer, and its expression level is closely related to patient’s prognosis. Folate receptor (FOLR1, FOLR2, and FOLR3) was expected to be a molecular marker for the prognosis of epithelial ovarian cancer. However, the exact molecular mechanism of the related signaling pathways of folate receptor in epithelial ovarian cancer remains unclear and needs further investigation.
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Conflict of interest: Authors state no conflict of interest.
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Data availability statement: The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
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© 2022 Juanli Yang et al., published by De Gruyter
This work is licensed under the Creative Commons Attribution 4.0 International License.
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Articles in the same Issue
- Research Articles
- Comparative routes to 7-carboxymethyl-pterin: A useful medicinal chemistry building block
- Immunopterin: A prospective therapy and preventative to fight COVID-19?
- MTHFR C667T polymorphism and diabetic nephropathy susceptibility in patients with type 2 diabetes mellitus: An updated meta-analysis
- Mercury exposure, neopterin profile, and tryptophan degradation in dental technicians
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- Review Articles
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- Epithelial nitric oxide synthases (eNOS) 894 G < T polymorphism and diabetic nephropathy susceptibility: A meta-analysis
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- Salivary and serum neopterin and interleukin 6 as biomarkers in patients with oral and oropharyngeal squamous cell carcinoma
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