NME6 as a potential biomarker and therapeutic target involved in immune infiltration for lung adenocarcinoma

Abstract

BACKGROUND:

Lung adenocarcinoma (LUAD), a prevalent form of lung cancer, is characterized by its high global mortality rate. Previous studies have demonstrated the significance of Nucleoside diphosphate kinase (NME) in various cancers; however, the specific role of NME6 in LUAD remains inadequately understood.

OBJECTIVE:

This research aims to enhance our understanding of LUAD by investigating the expression level, epigenetic mechanism, signaling activities, and immune infiltrating characteristic immune cells of NME6 in patients.

METHODS:

The NME6 expression was explored between LUAD and normal tissue samples using GEPIA, UALCAN and HPA databases. The survival analysis was performed by Kaplan-Meier plotter. The Shiny Methylation Analysis Resource Tool was employed to examine the methylation characteristics of NME6. The Tumor Immune Single-cell Hub (TISCH) and CIBERSORT algorithm were utilized to analyze immune infiltrating characteristic immune cells between NME6 high- and low-expression group in LUAD.

RESULTS:

According to GEPIA, UALCAN, and HPA databases, NME6 is highly expressed in LUAD compared to normal tissues. At the same time, elevated levels of NME6 were found to be significantly correlated with inferior overall survival outcomes in LUAD patients. Subsequently, the top 10 genes interacted with NME6 were mainly involved in seven pathways, such as p53 signaling pathway, glutathione metabolism, thiamine metabolism, metabolic pathways, and drug metabolism. Notably, NME6 methylation in LUAD samples was lower than in normal samples. The methylation of cg04625862 has a significant impact on the regulation of NME6 expression in LUAD. Furthermore, high NME6 expression in LUAD was associated with tumor stages and relative abundance of tumor infiltrating immune cells, such as Macrophage M2, activated mast cell, and neutrophil. Moreover, NME6 regulated the expression of m6A modification of genes related to LUAD, including METTL3, WTAP, RBM15B, METTL14, RBMX, VIRMA, YTHDC1, RBM15, ZC3H13, YTHDF1, YTHDC2, IGF2BP2, YTHDF3, HNRNPA2B1, YTHDF2, HNRNPC, FTO, and ALKBH5.

CONCLUSION:

The analysis showed that NME6 is a crucial prognostic factor for LUAD patients. NME6 regulates genes related to m6A modification and immune cells infiltration. Furthermore, NME6 could sever as a potential therapeutic target for LUAD.

Keywords

Nucleoside diphosphate kinase 6 lung adenocarcinoma DNA methylation survival analysis immune infiltration m6A modification

1. Introduction

Lung cancer is responsible for the highest number of cancer cases and fatalities worldwide [1]. There are two categories of this disease: small-cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). NSCLC represents around 85% of the total occurrences of lung cancer [2]. As far as histological types of NSCLC are concerned, the majority of cases are attributed to lung adenocarcinoma (LUAD). Despite the development of multiple therapies for LUAD treatment in recent years, the mortality rate continues to remain elevated [3, 4]. For this reason, new biomarkers and novel therapeutic targets for LUAD are essential to its early diagnosis and treatment.

Nucleoside diphosphate kinase (NME) family has 10 members, and several activities have been found for members of the NME family, including nucleoside diphosphate kinase (NDPK) activity, exonuclease activity, geranyl/farnesyl pyrophosphate kinase activity [5]. NME1 plays a crucial role in various cell essential cellular processes, such as cell growth, specialization, and the formation of the nervous system. Low expression of NME1 enhanced tumor metastases in melanoma and follicular thyroid carcinoma [6]. NME2 plays a role in cell proliferation and tumor growth in both lung and cervical cancer [7]. NME4 is overexpressed in LUAD and it promotes the progression of NSCLC by stimulating cellular proliferation [8]. In addition, the upregulation of NME7 positively correlated with hepatocellular carcinoma [9]. Collectively, these studies suggest that NME has a significant impact on tumorigenesis and progression. Nevertheless, the precise function of NME6 in LUAD remains uncertain.

In this study, we examine the gene and protein expression of NME6 in patients with LUAD using multi-bioinformatics analyses. Next, we explored the DNA mutation and methylation condition, as well as the signaling pathways implicated in the overexpression of NME6. Additionally, employing machine learning techniques to identify potential diagnostic infiltrating immune cells associated with NME6 in LUAD and to predict NME6-driven m6A regulation. This research could offer valuable information on the mechanism of LUAD, and provide predictive biomarkers and immunotherapeutic molecular targets.

2. Materials and methods

2.1 Expression and survival analysis

The GEPIA (http://gepia.cancer-pku.cn/) and UALCAN (https://ualcan.path.uab.edu) databases were utilized to examine NME family gene expression levels in both LUAD and normal tissue samples obtained from TCGA, employing a significance threshold of $p\leqslant$ 0.05 and an absolute value of log2FC $\geqslant$ 2. Subsequently, the NME6 protein levels in LUAD were compared to those in normal tissue using the human protein atlas (HPA, https://www.proteinatlas.org) database. The study employed the Kaplan-Meier (K-M, https://kmplot.com) plot to assess the disparities in overall survival (OS), first progression survival (FPS), and post-progression survival (PPS) between two groups classified as high and low NME expression groups.

2.2 Interaction network and enrichment analysis of NME6

The STRING database (https://cn.string-db.org/) was utilized for the purpose of forecasting the protein-protein interaction (PPI) network of NME6, with scores greater than 0.4 indicating significant interactions. Furthermore, all genes that interact with NME6 were enriched for their KEGG pathway and GO terms using the WebGestalt (https://www.webgestalt.org) online toolkit.

2.3 DNA methylation analysis

To examine the methylation characteristics of NME6 in LUAD samples, we employed the Shiny Methylation Analysis Resource Tool (SMART, http://www.bioinfo-zs.com/smartapp). The TCGA-LUAD dataset contains 30 samples of normal tissue and 458 samples of tumor tissue, which are used for DNA methylation analysis.

2.4 Gene mutation analysis

The data pertaining to mutations were obtained from TCGA and figured out utilizing the maftools package within the R software. The resulting histogram displayed genes exhibiting a heightened incidence of mutations among patients with NSCLC.

2.5 Immune infiltration analysis

To explore the potential impact of NME6 at the single-cell level, we utilized the Tumor Immune Single-cell Hub (TISCH, http://tisch.comp-genomics.org/search-gene) database to examine the relationship between NME6 expression and immune cells. The CIBERSORT algorithm was utilized to identify the crucial immune cells among 22 immune cells in LUAD. Furthermore, the R (reshape2) packages were employed for the analysis of the genes that were differentially associated with m6A between the NME6 high- and low-expression groups.

2.6 Statistical analysis

For NME family gene expression analysis, Statistical analyses were completed using R program v4.0.3, $p$ value $<$ 0.05 was considered statistically significant. For immune infiltration analysis, the statistical difference of two groups was compared through the Wilcox test, significance difference of three groups was tested with Kruskal-Wallis test. $P<$ 0.05 was considered to indicate statistical significance for all analyses.

Figure 1.

Gene, protein expression and prognostic value of NME6 in LUAD. (A) UALCAN examination of NME6 in 24 TCAG cancers types, including LUAD. The NME6 expression level in LUAD is analyzed based on (B) Sample types, (C) Various stages of LUAD, and (D) The presence of TP53 mutations. (E) The NME6 protein expression profiles between tumor and normal tissue. NME6 overexpression is correlated to poor OS (F), FPS (G), and PPS (H) in patients with LUAD.

Figure 2.

PPI network, KEGG, and GO analyses of NME6. (A) The NME6-associated PPI network consists of the top 10 interacted genes. The top 10 KEGG and GO analyses of interacted genes of NME6 were displayed. (B) Pathway in the KEGG database. (C) CC, (D) BP, (E) MF. FDR $<$ 0.05 indicated significance.

Figure 3.

Profile of DNA methylation in LUAD for NME6. (A) The distribution and positioning of 12 methylation probes linked to NME6. (B) Methylation levels of NME6 vary among various cancer types in both tumor and normal samples. (C) Methylating each probe and aggregating the NME6 level. there is a noticeable increase in methylated probes compared to normal samples (red box). Conversely, LUAD samples exhibit a decreased level of methylation (green box). Additionally, the methylation aggregation of NME6 in LUAD patients (purple box). ns: $p>$ 0.05; ^*: $p\leqslant$ 0.05; ^**: $p\leqslant$ 0.01; ^***: $p\leqslant$ 0.001; ^****: $p\leqslant$ 0.0001.

3. Results

3.1 The expression and prognostic of NME6 in patients with LUAD

The expression of the NME6 gene was evaluated in 24 types of cancer, including LUAD. As shown in Fig. 1A, the results illustrated that NME6 was upregulated in 15 out of 24 cancer types investigated. Detailed information regarding the NME6 gene and protein can be found in Table S1. Additionally, the transcript levels of NME in LUAD and normal tissue samples were also investigated (Fig. S1A). In the LUAD tissues, the expression of NME6 mRNA was significantly upregulated in comparison to normal tissues, as indicated by a $p$ -value of less than 1.62e-12 with UALCAN analysis (Fig. 1B). More specifically, the NME6 transcript levels in LUAD samples were considerably elevated compared to normal samples across all four stages of LAUD (Fig. 1C). In Fig. 1D, individuals with TP53 mutation exhibited elevated levels of NME6 compared to those without TP53 mutation. Furthermore, the expression of NME6 protein in LUAD samples was found to be more robust compared to normal tissues using HPA insert (Fig. 1E). Take a further step, the predictive significance of NME6 was assessed by K-M. The findings suggested that the presence of NME6 was linked to the survival of individuals with LUAD (1161 samples), and an elevated NME6 mRNA level showed a significant association with OS, PPS, and FP ( $P<$ 0.05), suggesting that NME6 was connected to unfavorable prognosis of LUAD patients (Fig. 1F to H and Fig. S1B). Additionally, the prognostic significance of NME6 in conjunction with different clinicopathological factors was further investigated (Table S2). It was observed that the association between NME6 expression and the survival duration of patients with LUAD is influenced by diverse clinicopathological factors, such as the stage of cancer, the individual’s gender, and their smoking history.

Figure 4.

Somatic mutation properties of NME6. (A) Lollipop charts of the altered NME6 gene. (B) Waterfall diagram illustrating somatic mutation in NSCLC between NME6 low and high-expression group. (C) The distribution of variations based on classification, type, and SNV class.

Figure 5.

Analyzing the expression of NME6 in various immune cells of LUAD using scRNA-seq. (A) A heatmap indicating the correlation between NME6 and levels of immune cell infiltration. (B) A violin plot displaying the relationship between NME6 and the infiltration of immune cells. (C) The complete collection of cells in the GSE99254 dataset and the analysis of NME6 expression and distribution in each cell.

Figure 6.

Identification of the primary immune cells that infiltrated and are linked to NME6 in LUAD. (A) Variances in immune infiltration between NME6 high- and low-expression groups. (B) Conducting correlation analysis between the expression of NME6 and the quantities of various immune cells. ^{*p <} 0.05, ^**p< 0.01, ^***p< 0.001, ns: $p>$ 0.05.

Figure 7.

Association of NME6 with m6A-related gene. (A) Variations in the expression of genes related to m6A between groups exhibiting low and high NME6 expression. (B) The relationship between the expression of NME6 and the levels of the m6A-related gene using Spearman analysis. ^*P< 0.05; ^**P < 0.01; ^***P< 0.001; ns: $P>$ 0.05.

3.2 Functional enrichment analysis of NME6

In Fig. 2A, the PPI network revealed that NME6 interacts with neighbor genes including DUT, AK5, AK3, NUDT2, RRM2B, ITPA, DTYMK, CTPS1, CMPK1, and GUK1 (Table S3). Moreover, the results of the KEGG pathway analysis demonstrated that the NME6 and 10 adjacent genes were predominantly enriched in four pathways (Fig. 2B). In addition, CC analysis indicated that the NME6 and 10 adjacent genes were significantly enriched in the mitochondrion (Fig. 2C). The analysis of BP indicated that these genes were greatly enriched in the biosynthesis of deoxyribonucleotide, biosynthesis of pyrimidine nucleotide, and metabolic process of pyrimidine-containing compound (Fig. 2D). As shown in Fig. 2F, the analysis of MF indicated these genes were notably enriched in activities related to phosphotransferase, kinase of compounds containing nucleobase, and kinase of nucleoside monophosphates. Moreover, to further explore the role of NME6 on patients with LUAD, two distinct subgroups were formed based on the expression levels of NME6, namely the NME6 high expression group and NME6 low expression group, comprising a total of 516 LUAD patients. The DEGs, KEGG and GO analysis data were shown in Fig. S2.

3.3 DNA methylation of NME6 in patients with LUAD

In this study, a DNA methylation analysis of NME6 was conducted in LUAD patients to determine what caused this gene’s upregulation and high protein expression. As shown in Fig. 3A, the results indicated that the chromosomal arrangement of 12 NME6 methylation probes on chromosome 3, showcasing the locations of these probes on CpG island. In the island region, there are nine probes (cg04536008, cg11680236, cg18783633, cg16799988, cg11946769, cg00345094, cg18057185, cg26267791, cg20141105). Then, methylation levels of NME6 were investigated in 33 different cancers including LUAD. The results indicated that NME6 methylation in LUAD samples was lower than in normal samples (Fig. 3B). In more detail, each probe was further investigated in terms of its methylation status. As shown in Fig. 3C, the data showed that there is one probe shows significant hypo-methylation status (cg04625862) and one probe shows significant hyper-methylation status (cg11946769). Taken together, the methylation of cg04625862 has a significant impact on the regulation of NME6 expression in LUAD.

3.4 Somatic mutations of NME6 in the LUAD

The lollipop chat indicated that the mutation rate of the NME6 gene was 0.2% in patients with LUAD (Fig. 4A). Then, the horizontal histogram indicated that the genes with a higher frequency of mutation in individuals with LUAD were TP53 (47%), TTN (45%), MUC61 (39%), CSMD3 (37%), RYR2 (35%), LRP1B (32%), USH2A (31%), ZFHX4 (30%), KRAS (27%), and FLG (25%, Fig. 4B). As shown in Fig. 4C, the most frequent mutation type in patients with LUAD was missense. Single nucleotide polymorphism (SNP) had a dominant position compared to insertion (INS) and deletion (DEL). The predominant mutation type detected was C $>$ A. In addition, we conducted an examination of the frequency of mutations in each sample, as well as the categorization of mutations and the identification of the top 10 mutated genes in patients with LUAD. These results suggested that the presence and progression of LUAD are not primarily attributed to the NME6 mutation.

3.5 Correlations of NME6 expression with immune infiltration

Figure 5A indicated the connection between the distribution of immune cells and the levels of NME6 at the individual cell level. Utilizing the NSCLC_GSE99254 dataset, elevated expression of NME6 was observed in association with proliferating T cells (T prolif) (Fig. 5B). The scRNA-seq clustered plots provided valuable insights into the distribution and expression patterns of NME6 across diverse immune cell populations (Fig. 5C). These findings indicated a significant correlation between the expression levels of NME6 and the specific types of immune cells, as well as their respective proportions in LUAD.

3.6 Relationship of NME6 expression and immune cell infiltration

The CIBERSORT studies revealed that LUAD samples with elevated NME6 expression exhibited notable decreases in T cell regulatory (Tregs), memory B cell, naïve B cell, macrophage M0, plasma B cell, and monocyte. Conversely, there was a significant increase in Macrophage M2, activated mast cell, and neutrophil, respectively (Fig. 6A). Furthermore, the relationship between NME6 expression and immune cell expression was examined with Spearman correlation analysis. According to Fig. 6B, a statistically significant inverse associated was observed between NME6 expression and B cells ( $P<$ 0.05). Conversely, a statistically significant positive association was identified between NME6 expression and CD8 $+$ T cells and macrophage cells ( $P<$ 0.05). These results suggested that NME6 expression affects immune infiltration and the effectiveness of tumor therapy.

3.7 Correlation between NME6 expression and m6A-related genes

To assess the association between NME6 expression and m6A-related genes in LUAD, we initially examined the TCGA LUAD cohort’s subgroups with high- and low-NME6 expression. The results revealed a strong positive correlation between NME6 expression levels and the majority of m6A-related genes, such as METTL3, WTAP, RBM15B, METTL14, RBMX, VIRMA, YTHDC1, RBM15, ZC3H13, YTHDF1, YTHDC2, IGF2BP2, YTHDF3, HNRNPA2B1, YTHDF2, HNRNPC, FTO, and ALKBH5 (Fig. 7A). By Spearman analysis, the results were in good agreement with the previously analysis. Several genes associated with m6A exhibited elevated expression in LUAD, except for IGF2BP1 and IGF2BP3, where their expression remained unchanged (Fig. 7B). However, HNRNPC and VIRMA expression were correlated with NME6 expression still unknown in LUAD. Collectively, these findings suggest that the biological activity of NME6 significantly influences the transcriptional regulation of m6A-related genes.

4. Discussion

In most cases, Cancer detection at an early stage, particularly LUAD, improves the likelihood of successful treatment. Although treatment and diagnosis have advanced, the mortality and occurrence of LUAD remain elevated. The majority of patients receive a late-stage diagnosis due to the absence of apparent initial symptoms. Therefore, to hence the prognosis of individuals with LUAD, bioinformatics analysis was used to detect potential indicators for early screening of LUAD. In this study, we found NME6 exhibited significant overexpression in early-stage LUAD, which was associated with an unfavorable prognosis.

Previous research has demonstrated that NME6, as an oncogene, is involved in regulating the growth of cells. Additionally, its overexpression has been linked to an unfavorable prognosis in colorectal cancer [10]. Nevertheless, the role of NME6 in LUAD remains unknown, but there has been additional progress in comprehending the mechanisms of NME6. In this study, it is evident that NME6 is highly expressed in the majority of tumors, including LUAD. Furthermore, NME6 expression was significantly elevated in the early stage of LUAD. Previous study demonstrated that expression of NME6 and ASAP1 was correlated with endometrium size and lead follicle size slope [11] and correlated with unfavorable metastasis-free survival and prognosis in individuals diagnosed with colorectal cancer [12]. In the current study, we found overexpression of NME6 is responsible for poor OS, FP, and PPS in patients with LUAD.

In general, gene expression is influenced by DNA methylation or demethylation in gene promoters in most cases [13]. Moreover, the position of DNA methylation within a gene influences whether DNA methylation enhances or diminishes gene expression [14]. The aim of the present study was to examine the extent of DNA methylation level of NME6 among patients with LUAD to determine the factors contributing to the upregulation expression and elevated protein levels of NME6. In LUAD, we discovered that NME6 exhibited hyper-methylation status, with one probe showing evident hyper-methylated and another probe displaying hypo-methylation. In addition, the hypo-methylation status (cg04625862) plays a major role in regulating NME6 expression in LUAD.

To evaluate NME6 and its related genes in the LUAD pathway, STRING was used to identify the proteins that interacted with NME6, revealing a total of 10 proteins that interacted with NME6. Subsequently, the analysis of KEGG pathways unveiled that NME6 and its associated genes governed the purine metabolism, thereby influencing the progression of LUAD. The deregulation of purine metabolism has been implicated in cancer, with increased purine biosynthesis being linked to the advancement of various cancer types [15]. Moreover, in order to assess whether the DEGs in the KEGG pathway effectively classify LUAD, we obtained high- and low-expression of NME6 subgroups of LUAD. By detecting DEGs and analyzing the enrichment of gene pathways, we discovered distinct features in the two subtypes. These features include variations in the Hippo signaling pathway, ErbB signaling pathway, and primary immunodeficiency. Hence, we may conclude that NME6 regulate gene expression and signaling pathway to promote LUAD development.

The intricate biological connection between immune cells and tumor cells in the tumor microenvironment can either promote or inhibit tumor growth, leading to varied responses to immunotherapy [16, 17]. In this study, our findings indicated that NME6 predominantly localized in T proliferation cells. According to spearman analysis, the results indicated a noteworthy inverse association between the expression of NME6 and B cells, while a significant positive correlation was observed between NME6 expression and macrophage cells as well as CD8 $+$ T cells. Previous study showed that a significant infiltration of Tfh cells was linked to an unfavorable prognosis in individuals diagnosed with hepatocellular carcinoma [18]. High expression of CD4 $+$ , CD103 $+$ , CD8 $+$ T cells, as well as Treg cells was observed in patients with LUAD. Moreover, the present study has identified a correlation between NME6 and the infiltration of immune cells. Additionally, the atypical invasion of Macrophage M2, stimulated mast cells, and neutrophil cells linked to NME6 could potentially serve as a significant indicator of LUAD according to diverse database examination. Our hypothesis suggests that NME6 enhances the tumor immune response by facilitating the immunological infiltration of macrophage M2, activated mast cell, and neutrophil cells, leading to an unfavorable prognosis in individuals diagnosed with LUAD.

Regarding m6A modification, it exerts post-transcriptional influence on gene expression in eukaryotes and assumes diverse functions in various biological processes [19]. Furthermore, m6A frequently experiences dysregulation in different cancer types, resulting in the development, advancement, and metastasis of tumors [20]. Hence, comprehending the association between m6A alteration of NME6 is advantageous for comprehending the regulatory mechanism of NME6 in LUAD. Previous study have documented that the genes IGF2BP1, METTL16, IGFBP1, WTAP, and IGFBP2 potentially contribute to the advancement of severe sepsis by modulating m6A methylation alteration and facilitating infiltration of immune cells [21]. This research discovered a predominantly positive association between the expression of NME6 and the majority of m6A-associated genes. The genes include METTL3, WTAP, RBM15B, METTL14, RBMX, VIRMA, YTHDC1, RBM15, ZC3H13, YTHDF1, YTHDC2, IGF2BP2, YTHDF3, HNRNPA2B1, YTHDF2, HNRNPC, FTO, and ALKBH5. Therefore, the identification of NME6 associated with progressive LUAD offers a promising therapeutic target for the detection and management of LUAD.

Undeniably, there are some limitations of our study. (1) Although we conducted integrated bioinformatics analysis to validate NME6 as a prognostic indicator in LUAD, this approach may not be extremely precise for patients with LUAD. (2) These results showed that NME6 may be crucial regulators in the development of LUAD by influencing the immune cell infiltration, the molecular mechanisms of NME6 will be explored further.

5. Conclusions

This study investigated in depth the possible influence of NME6 on LUAD. Concurrently linked to overall survival, NME6 may possess significant prognostic importance in LUAD. The expression of NME6 mRNA is associated with the immune microenvironment of LUAD. Additionally, we documented the association between NME6 and the functions of Macrophage M2, activated mast cells, and neutrophils in the infiltration of T-cell subsets. Collectively, we presented ample evidence to endorse the clinical utilization of NME6 as a prognostic biomarker in the initial phase of LUAD. Additional examination suggested that NME6 has potential as a therapeutic target in LUAD treatment.

Author contributions

L.Y. designed the study. L.L., Y.L., and L.Z. contributed to bioinformatics analysis and wrote the manuscript. All authors read and approved the final version of the manuscript.

Funding

This research was funded by the Youth Innovation Research Project of Sichuan (grant number Q21048).

Supplementary data

The supplementary files are available to download from https://dx-doi-org.web.bisu.edu.cn/10.3233/THC-231058.

Footnotes

Conflict of interest

The authors declare no conflicts of interest.

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