TYMS and CENPF emerge as key oncogenes and prognostic markers in glioma

doi:10.21203/rs.3.rs-4997083/v1

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TYMS and CENPF emerge as key oncogenes and prognostic markers in glioma

https://doi.org/10.21203/rs.3.rs-4997083/v1

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Background

Glioma is a prevalent malignant tumor of central neural system. The high mortality rate among glioma patients is largely attributed to tumor metastasis and unfavorable prognosis. Diverse analysis of genomic and transcriptomic alterations is found in glioma, posing an urgent need for identifying novel therapeutic and prognostic targets with underlying molecular mechanisms.

Methods

The functional status relevant to TYMS and CENPF in pan-cancer was analyzed using CancerSEA database. We assessed the expression levels and clinical characteristics of TYMS and CENPF in TCGA-glioma data. The prognostic potential of TYMS and CENPF was assessed through Kaplan-Meier survival curve analysis and Cox proportional hazards modeling. To identify co-expressed genes, we applied a correlation analysis with a high R-value threshold, followed by PPI network construction and GSEA. Additionally, a gene-chemical interaction network was built using data from the Comparative Toxicogenomics Database (CTD), providing a framework for exploring potential therapeutic relationships. Furthermore, we collected clinical glioma tissue samples and detected mRNA and protein expression levels using qPCR and HPA analysis.

Results

We showed that TYMS and CENPF overexpression were notably higher in glioma patients, and related to histological types and glioma WHO grades. TYMS and CENPF were clinically correlated with worse prognosis in glioma and could be potential independent prognostic factors. GSEA analysis indicated that TYMS/CENPF and ten co-expressed genes regulated glioma cell motility and other cell behaviors via PI3K/AKT and MET signaling pathways.

Conclusions

Our findings suggested that aberrant TYMS/CENPF expression was significantly linked to glioma WHO grades and poor survival rates, contributing to a more comprehensive understanding of glioma therapeutic targets.

Glioma

WHO grade

therapeutic target

prognosis

drug interaction

Glioma is a common brain malignancy originating from the central nervous system, with glioblastoma (GBM) being one of the most aggressive WHO glioma grades [1]. Due to the aggressive biological characteristics of glioma, the 5-years overall survival rate for patients with GBM is 15–18 months [2]. Furthermore, the prognosis for glioma recurrence is particularly grim, with a median survival duration of only 6–9 months, underscoring the need for more effective treatment strategies [3]. Malignant cancer recurrence and metastasis after surgery resection followed by chemotherapy and/or radiation are the primary cause of mortality in glioma patients [4]. The current clinical evaluation of gene-directed therapies underscores the importance of continued research into new molecular targets, which could ultimately lead to the creation of more potent and targeted treatments.

Thymidylate synthetase (TYMS) is a cofactor which catalyzes the methylation of deoxyuridylate to deoxythymidylate in the regulation of DNA replication and repair [5]. Functionally, the polymorphism of TYMS gene is a kind of etiopathogenesis in tumorigenesis, including hepatocellular carcinoma [6] and colorectal cancer [7]. Increasing evidence suggests that TYMS improves cancer cell responsiveness to chemotherapy, such as functioning as a key target of 5-FU treatment and inhibiting tumor cell proliferation [8]. Centromere protein F (CENPF) encodes a protein that related to the centromere-kinetochore complex and maintains cell cycle in the G2 phase [9]. In cancer, it has been reported that CENPF positively regulates cell growth, inhibits cell apoptosis and tumor metastasis in papillary thyroid cancer [10]. Nevertheless, the specific function of TYMS and CENPF gene in glioma remains unknown and needs to be explored.

In this research, we aimed to investigate the function of TYMS and CENPF accompanied by the underlying regulatory mechanism in glioma. To achieve this, we performed RNA-seq analysis using TCGA-GBMLGG cohorts, allowing for a comprehensive investigation of TYMS/CENPF-regulated proteins and signaling pathways. Collectively, these results highlighted that TYMS and CENPF were related to decreased overall survival in patients with glioma, suggesting their clinical values as prognostic and therapeutic target in glioma. Mechanistically, we also investigated the co-expressed genes regulated by TYMS and CENPF and the specific regulatory signaling pathways in glioma.

Cancer cell function analysis

We employed the CancerSEA platform (http://biocc.hrbmu.edu.cn/CancerSEA/home.jsp) to conduct a comprehensive analysis of cancer cell function at the single-cell level. Subsequent correlation analysis revealed the relationships between TYMS/CENPF expression and various functional states, including angiogenic potential, metastatic capacity, cell cycle progression, and invasive behavior.

Expression levels of TYMS/CENPF and clinical significance in glioma

We analyzed individual TYMS/CENPF expression levels in normal and glioma tissue samples using TCGA clinical data and the R package. Our analysis included data from the TCGA-GBMLGG dataset for glioma samples, while normal tissue data were obtained from the Genotype-Tissue Expression (GTEx) project. The Wilcoxon test was used to compare data between normal and HCC tissue samples, and the Kruskal-Wallis test was employed to analyze the relationships between multiple clinical parameters, including age, histological types, and WHO grade, with statistical significance defined as p < 0.05.

Survival analysis of TYMS and CENPF in glioma

To assess the relationship between TYMS/CENPF expression and glioma patient survival, we created Kaplan-Meier survival curves for overall survival (OS), disease-specific survival (DSS), and progression-free interval (PFI). Patients were divided into two groups based on the median value of TYMS/CENPF mRNA transcripts. To further understand the relationship between clinical risk factors and overall survival, we conducted univariate and multivariate analysis to assess the individual and combined effects of these factors on patient survival."

PPI network analysis and gene set enrichment analysis (GSEA)

TCGA-GBMLGG cohorts were divided into two groups based on the high/low expression levels of TYMS or CENPF. The genes that coded with proteins were screened with both of Pearson and Spearman correlation R > 0.75. Then, TYMS, CENPF and other ten proteins were subjected to PPI network analysis using GeneMAINA (http://genemania.org/). In addition, gene sets or signaling pathways were considered to be significantly enriched if normalized enrichment score (NES) > 1, p.adjust < 0.05 and qvalue < 0.25.

Gene-chemicals interaction network analysis

We employed the Comparative Toxicogenomics Database (CTD, http://ctdbase.org/) to explore the interactions between TYMS/CENPF and anti-glioma chemicals. By utilizing Cytoscape software, we created a gene-chemical interaction network to visualize the relationships between TYMS/CENPF and various compounds. Our analysis aimed to identify chemicals that influence the expression of TYMS/CENPF, either by increasing or decreasing their mRNA or protein levels.

qRT-PCR analysis of TYMS/CENPF expression levels in glioma tissues

A total of 20 glioma patients who underwent surgery between 2021 and 2023 was included in this study. None of these patients had undergone preoperative radiotherapy, chemotherapy, targeted therapy, or immunotherapy, ensuring that the tissue samples were free from treatment-induced alterations. Following surgical excision, the tumor tissues and cerebral cortex tissues were rapidly frozen in liquid nitrogen to facilitate subsequent molecular analysis. The protocol was reviewed and approved by the Ethics Committee of Second hospital of Shanxi medical university. Glioma tissues and cerebral cortex were subjected to RNA extraction using TRIzol Reagent (Invitrogen), followed by reverse transcription into cDNA using the Reverse Transcription Kit (Qiagen, Hilden, Germany). The cDNA was then analyzed by qPCR using Green Premix Ex Taq II (TaKaRa, Japan) on Applied Biosystems Real-Time PCR System (Foster City, CA, USA). Gene expression levels were quantified using the 2 − ΔΔCt method, with GAPDH serving as a housekeeping gene for normalization purposes. The primers of TYMS and CNEPF are listed as following: TYMS forward primer, 5’-CTGGGGCAGATCCAACACAT-3’, TYMS reverse primer: 5’-GCCCAAGTCCCCTTCTTCTC-3’, CENPF forward primer: 5’-CTCCGAGAGGTCGTTTTCCC-3’, CENPF reverse primer: 5’-CGCAGCTTGTTGGCTTCTTT-3’.

Relevant function states of TYMS and CENPF in glioma

Given the lack of exploring function relevant to pan-cancer, our study was the first to comprehensively assess functional signatures of TYMS and CENPF at the single-cell level via CancerSEA database. The c emphasized the positive correlation between TYMS and several functional states, including cell cycle, EMT, invasion, metastasis and proliferation in glioma (Fig. 1A). Additionally, CENPF showed a strong correlation with glioma cell proliferation, cell cycle and cell invasion (Fig. 1B). The results highlighted a novel associated functional heterogeneity of glioma cells and reflected the functional states of TYMS and CENPF with tumorigenesis and progression.

TYMS and CENPF mRNA expression levels and clinical characteristics in glioma

To clarify the distinct characteristics between non-tumor tissues and glioma samples, we conducted RNA-sequencing analysis using TCGA-GBMLGG cohort. Normal GTEx sample was utilized as control for comparison. A noteworthy finding was that when focusing on gene differential expression of TYMS and CENPF, both log2(TPM + 1) of TYMS and CENPF in glioma tissues (n = 701) was substantially higher than that in non-tumor samples (n = 5) (p < 0.01, Fig. 2). Furthermore, higher TYMS and CENPF expression levels was associated with advanced clinical histological type (glioblastoma vs astrocytoma, glioblastoma vs oligodendroglioma, glioblastoma vs oligoastrocytoma) (p < 0.001, Fig. 3A-3B). For patients with glioma graded in G4/G3, TYMS and CENPF levels were upregulated in high grade glioma tissues compared to those without WHO G2 grade glioma tissues (p < 0.001, Fig. 3C-3D), suggesting that TYMS and CENPF might correlate with tumor malignant degree. Additionally, baseline information including clinical characteristics of glioma patients (699 samples) are summarized in Table 1. Clinical variable analysis showed that TYMS and CENPF expression in glioma tissues was positively associated with age, IDH status, 1p/19q codeletion and primary therapy outcome (all p < 0.001).

Table 1

Baseline clinical characteristics data of glioma patients.
		TYMS expression
Characteristics		Low expression (n = 349)	High expression (n = 350)	p value	Low expression (n = 349)	High expression (n = 350)	p value
Age n (%)	<= 60	314 (44.9%)	242 (34.6%)	8.76E-12	303 (43.3%)	253 (36.2%)	1.91E-06
Age n (%)	> 60	35 (5%)	108 (15.5%)	8.76E-12	46 (6.6%)	97 (13.9%)	1.91E-06
Gender n (%)	Female	157 (22.5%)	141 (20.2%)	0.21	149 (21.3%)	149 (21.3%)	0.97
Gender n (%)	Male	192 (27.5%)	209 (29.9%)	0.21	200 (28.6%)	201 (28.8%)	0.97
IDH status n (%)	WT	34 (4.9%)	212 (30.8%)	1.19E-45	59 (8.6%)	187 (27.1%)	1.86E-24
IDH status n (%)	Mut	311 (45.1%)	132 (19.2%)	1.19E-45	286 (41.5%)	157 (22.8%)	1.86E-24
1p/19q codeletion n (%)	Non-codel	236 (34.1%)	284 (41%)	7.24E-06	223 (32.2%)	297 (42.9%)	1.26E-11
1p/19q codeletion n (%)	Codel	112 (16.2%)	60 (8.7%)	7.24E-06	125 (18.1%)	47 (6.8%)	1.26E-11
Primary therapy outcome n (%)	PD	54 (11.6%)	58 (12.5%)	0.0006	44 (9.5%)	68 (14.6%)	9.69E-06
	SD	98 (21.1%)	50 (10.8%)		87 (18.7%)	61 (13.1%)
	PR	47 (10.1%)	18 (3.9%)		45 (9.7%)	20 (4.3%)
	CR	99 (21.3%)	41 (8.8%)		96 (20.6%)	44 (9.5%)

Prognostic values of TYMS and CENPF in glioma

To appraise the prognostic implications of TYMS and CENPF upregulation in glioma samples, we performed Kaplan-Meier analysis with glioma patients. The presence of obvious aberrant TYMS gene expression upregulation, as confirmed by gene expression grouping analysis, was related to significantly reduced survival probability, including OS, DSS and PRI, compared to those with low gene expression (p < 0.001, Fig. 4). Moreover, glioma patients with high expressing CENPF had a significant shorter survival than those with lower CENPF expression (p < 0.001, Fig. 4). Univariate (p < 0.001) and multivariate (p = 0.019) Cox regression analysis indicated that high CENPF expression was one of the independent risk factors patients with glioma (Table 2). In addition, with univariate Cox regression analysis, the expression of TYMS (p < 0.001) also did appear to be an independent prognostic factor, like IDH status and 1p/19q codeletion (p < 0.001) (Table 2). The results suggested that the identified TYMS and CENPF have high clinical values as prognostic factors for predicting worse outcomes in glioma.

Table 2

Univariate and multivariate cox regression analysis
			Univariate analysis		Multivariate analysis
Characteristics		Total(N)	HR(95% CI)	P value	HR(95% CI)	P value
TYMS	Low	349	4.798 (3.626–6.347)	< 0.001	1.177 (0.700–1.979)	0.539
TYMS	High	349	4.798 (3.626–6.347)	< 0.001	1.177 (0.700–1.979)	0.539
CENPF	Low	349	3.188 (2.439–4.168)	< 0.001	1.761 (1.097–2.826)	0.019
CENPF	High	349	3.188 (2.439–4.168)	< 0.001	1.761 (1.097–2.826)	0.019
Age	<= 60	555	4.696 (3.620–6.093)	< 0.001	3.996 (2.461–6.489)	< 0.001
Age	> 60	143	4.696 (3.620–6.093)	< 0.001	3.996 (2.461–6.489)	< 0.001
Gender	Female	297	1.250 (0.979–1.595)	0.073	1.535 (1.024–2.303)	0.038
Gender	Male	401	1.250 (0.979–1.595)	0.073	1.535 (1.024–2.303)	0.038
IDH status	WT	246	0.116 (0.089–0.151)	< 0.001	0.422 (0.253–0.705)	< 0.001
IDH status	Mut	442	0.116 (0.089–0.151)	< 0.001	0.422 (0.253–0.705)	< 0.001
1p/19q codeletion	Non-codel	520	0.225 (0.147–0.346)	< 0.001	0.821 (0.446–1.510)	0.526
1p/19q codeletion	Codel	171	0.225 (0.147–0.346)	< 0.001	0.821 (0.446–1.510)	0.526
Histological type	Astrocytoma	196	-	-	-	-
	Oligodendroglioma	199	0.578 (0.393–0.849)	0.005	0.621 (0.381–1.011)	0.056
	Oligoastrocytoma	135	0.646 (0.412–1.013)	0.057	0.933 (0.556–1.565)	0.793
	Glioblastoma	168	6.791 (4.931–9.352)	< 0.001	2.921 (0.995–8.579)	0.051
Primary therapy outcome	PD	112	-	-	-	-
	SD	148	0.440 (0.294–0.658)	< 0.001	0.502 (0.319–0.791)	0.003
	PR	65	0.167 (0.073–0.385)	< 0.001	0.217 (0.092–0.515)	< 0.001
	CR	139	0.131 (0.063–0.273)	< 0.001	0.160 (0.074–0.347)	< 0.001

PPI network analysis

To explore the downstream regulatory network of TYMS and CENPF in glioma, and to better elucidate gene interaction mechanisms, single gene differential expression analysis was performed to identify the genes that have strong correlation with TYMS/CENPF expression in glioma. Co-expressed genes were screened with the criteria of |Pearson’s R| >= 0.75, |Spearman’s R| >= 0.75 and p < 0.05. A total of top 10 co-expressed genes, including TK1, PCLAF, RRM2, CENPK, E2F7, KIF14, ASPM, BUB1B, TOP2A and TPX2, were highly correlated with TYMS/CENPF expression levels in glioma (Fig. 5A). Furthermore, in order to classify the protein alterations induced by RRAS2 overexpression, we conducted PPI analysis with the top 10 co-expressed genes. We found that 94.09% had similar co-expression network among the co-expressed 30 proteins (Fig. 5B).

GSEA analysis in glioma

To determine the underlying mechanism by which TYMS/CENPF mediates glioma, GSEA enrichment analysis was carried out in TCGA-GBMLGG datasets. The results revealed an obvious activation of PI3K-AKT signaling pathway (NES = 1.283, p = 0.025, FDR = 0.019) in the TYMS-high expression group (Fig. 6A). PI3K-AKT pathway has been identified within glioma, indicating the increased activity of GBM mutations and glioma malignancy [11]. In addition, we found a hallmark of promoting cell motility induced by MET in CENPF-expressing glioma (NES = 1.957, p < 0.001, FDR < 0.001) (Fig. 6B). The GSEA enrichment results suggested that TYMS and CENPF expression was significantly related to enhanced glioma cell motility and tumor progression.

Drug interaction network in glioma

To investigate the drug interaction targeting TYMS/CENPF in glioma, gene-drug network was constructed via the Comparative Toxicogenomics Database (CTD). As shown in Fig. 7A, a total of 18 drugs have influences on the expression of TYMS in glioma. The levels of TYMS were positively increased by 10 drugs, including camptothecin, cisplatin, fluorouracil, indomethacin and etc. The remaining 8 drugs could inhibit TYMS expression in glioma. A lower expression of CENPF expression was observed in 1,3-butadiene and quercetin-treated glioma samples (Fig. 7B). Moreover, 10 drugs have the function of promotion on CENPF levels in glioma.

TYMS and CENPF was upregulated in glioma tissues

The bioinformatics analysis of TYMS/CENPF encouraged us to further investigate the expression levels in glioma clinical specimens. When compared with cerebral cortex tissues, immunohistochemical analysis of glioma revealed the upregulation of TYMS and CENPF proteins (Fig. 8A-8B). Next, 20 clinical tissues were collected from glioma patients and their TYMS/CENPF expression was assessed using qPCR analysis. In glioma tissues, TYMS/CENPF levels were expressed 3-fold more highly than in non-tumor tissues, indicating an upregulation of TYMS/CENPF mRNA expression after tumor initiation event (p < 0.001, Fig. 8C).

Our study evaluated the potential role of TYMS and CENPF in glioma and explored the downstream mechanism regulated by TYMS and CENPF. Here, we show that patients expressing high TYMS/CENPF genes have a poor survival than those with low TYMS/CENPF expression. The analysis of TCGA data revealed that TYMS and CENPF expression levels were the highest in WHO G4 grade (GBM) tissues and lower in low-grade glioma samples. Mechanistically, TYMS/CENPF directly interacted with 10 top hub genes and are involved in cell cycle in glioma. More importantly, TYMS/CENPF-related genes activated the PI3K/AKT and MET signaling pathways in glioma, participating in glioma malignant process.

TYMS-expressing xenograft model has been identified to show genomic instability, DNA damage and tumorigenesis acceleration [5]. For example, downregulation of TYMS inhibited breast cancer cell proliferation and invasion via EMT pathways [7]. Additionally, CENPF acts as a novel regulator of tumor cell metabolism, including cell cycle and metastasis, in prostate cancer [12] and triple-negative breast cancer [13]. To elucidate the functional states regulated by TYMS/CENPF, we performed the single cells analysis based TYMS/CENPF expression levels. Our results revealed that enrichment of cell cycle, DNA damage, proliferation and EMT process are also found in TYMS/CENPF-expressed glioma, suggesting the potential functional status to be further elucidated.

IDH1/2 mutation is observed in approximately 65–90% of LGG patients, indicating a relatively favorable outcome and a low invasiveness in comparison with IDH-wild type glioma [14]. Targeted anti-IDH-mutation therapies are the key strategies for low-grade glioma (LGG), aiming to inhibit tumor procession [1, 15]. Recent studies show that IDH is a unique therapeutic target, however, selective inhibitors targeting IDH mutation is challenging as there is drug resistance to IDH inhibitors in glioma cells [16]. We demonstrate here that IDH wild type is found at a significantly higher proportion than mutated type in high TYMS/CENPF expression groups, indicating that TYMS/CENPF expression levels might be related to IDH status in glioma. Our data also show that TYMS/CENPF was overexpressed across all glioma histological types but is more highly expressed in patients with high grade glioma than in low grade ones. Given that high grade glioma overexpressing TYMS/CENPF promote tumor progression and malignancy grade, TYMS/CENPF-coexpressed genes seems to be preferentially linked to glioma developing. Therefore, our research further explored the PPI network and GSEA enrichment score of TYMS/CENPF-coexpressed genes in glioma.

PI3K/AKT has been confirmed as an essential signaling pathway in regulating glioma progression and malignant metastasis [17]. The dysregulation of PI3K/AKT pathway activates growth factors and influences glioma cell growth via promoting biosynthetic pathways [18]. Several literatures have demonstrated that therapeutic agents, targeting PI3K/AKT pathway, such as temozolomide, are currently in clinical development for improving blood-brain barrier and reducing systemic toxicity [19]. Accumulating studies indicated that MET is a pivotal oncogenic driver in cell biology and stemness of glioma [20]. MET is amplificated in transgenic mouse models and then accelerated GBM formation in vivo [21]. Copy number amplification and overexpression of MET often results in promoting glioma development and a shorter overall survival [22]. Here, we suggest, for the first time, that the 10 co-expressed genes with TYMS/CENPF participated in activating PI3K/AKT and MET signaling pathways to maintain glioma cell motility and malignance.

Collectively, the study shows that TYMS/CENPF is overexpressed in the vast majority of glioma samples regardless of WHO grade, histological type, IDH mutation and1p/19q codeletion. Moreover, the human data suggests that high TYMS/CENPF expression in glioma is associated with shorter survival and worse prognosis in glioma. Our research elucidated the intricate interplay between TYMS/CENPF and ten proteins in glioma, underscoring their significant contribution to cell cycle and motility via PI3K/AKT and MET signaling pathways. The precise mechanisms by which TYMS contributes to glioma development and progression remain unclear, with cell-based experiments providing incomplete insights that necessitate further investigation. In conclusion, we have identified TYMS and CENPF as key druggable targets that hold promise for the treatment of glioma, thereby providing insights into potential therapeutic strategies for glioma treatment and poor prognosis.

Acknowledgements

Data availability statement

The Cancer Genome Altas tumor cohorts analyzed in this research can be available at https://portal.gdc.cancer.gov/.

Ethical approval statement

The Ethics Review Committee of Second Hospital of Shanxi Medical University reviewed and approved this study. Written informed consent was obtained from all subjects before their participation in the study.

Author contributions

Conceptualization: XY and SW. Methodology: XY, QW, QL. Software: QW, QL, RD. Validation: XY, QW, QL. Formal analysis: QL, RD. Investigation: XY, LC, MJ. Resources: MJ, SW. Data Curation: XY, QW, QL. Visualization: RD, LC. Supervision: LC. Project administration: LC. Writing - Original Draft: XY, MJ, SW. Writing - Review & Editing: XY, MJ, SW. All authors read and approved the final manuscript.

Competing Interests

The authors have declared that no competing interest exists.

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No competing interests reported.

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TYMS and CENPF emerge as key oncogenes and prognostic markers in glioma

Status:

Version 1

Abstract

Background

Methods

Results

Conclusions

Figures

Introduction

Methods and materials

Cancer cell function analysis

Expression levels of TYMS/CENPF and clinical significance in glioma

Survival analysis of TYMS and CENPF in glioma

PPI network analysis and gene set enrichment analysis (GSEA)

Gene-chemicals interaction network analysis

qRT-PCR analysis of TYMS/CENPF expression levels in glioma tissues

Results

Relevant function states of TYMS and CENPF in glioma

TYMS and CENPF mRNA expression levels and clinical characteristics in glioma

Prognostic values of TYMS and CENPF in glioma

PPI network analysis

GSEA analysis in glioma

Drug interaction network in glioma

TYMS and CENPF was upregulated in glioma tissues

Discussion

Declarations

References

Additional Declarations

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