Research ArticleExperimental Studies
Open Access

SLC15A2 Serves as a Novel Prognostic Biomarker and Target for Prostate Cancer

WENJUN YIN, PINGKAIQI HE, ZHIHAO ZOU, JUNDONG LIN, ZHENGUO LIANG, ZHENJIE WU, JIANHENG YE, JIANMING LU and WEIDE ZHONG
Anticancer Research January 2025, 45 (1) 153-172; DOI: https://doi.org/10.21873/anticanres.17402

Abstract

Background/Aim: Solute carrier (SLC) family 15 member 2 (SLC15A2) is an integral member of the SLC family that plays a pivotal role in numerous biological processes, including the regulation of cellular signaling pathways. However, its role in prostate cancer (PCa) remains inadequately elucidated. This study aims to investigate the prognostic significance of SLC15A2 in PCa. Materials and Methods: We evaluated the expression levels and prognostic significance of SLC15A2 in multicenter cohorts of PCa through differential expression analysis, survival analysis, and Cox regression. These findings were validated through immunohistochemistry and in vitro experiments. Gene set enrichment analysis, mutation analysis, and methylation analysis were used to investigate the potential biological functions of SLC15A2. Finally, drug target prediction analysis was conducted to identify small molecule therapeutic agents specifically targeting SLC15A2 in PCa. Results: The expression level of SLC15A2 in PCa tissues was significantly lower compared to benign tissues, and reduced expression of SLC15A2 was often associated with early biochemical recurrence (BCR) and decreased overall survival in PCa patients. Moreover, results from in vitro experiments indicated that knockdown of SLC15A2 markedly enhanced the proliferation and migratory capacity of PCa cells. Enrichment analysis indicated that SLC15A2 predominantly activates pathways related to cell proliferation, adhesion, and lipid metabolism while inhibiting pathways associated with protein synthesis, degradation, RNA metabolism, and energy metabolism. Notably, the frequency of TP53 mutations and 8q24.21 copy number variations was significantly higher in the low SLC15A2 expression group. DNA hypermethylation of SLC15A2 at gene body linked to downregulation of SLC15A2 in PCa. Finally, analysis with the Connectivity Map database identified several promising small molecule drugs for PCa treatment, including rucaparib. Conclusion: Our findings suggest that SLC15A2 serves as a promising prognostic biomarker in PCa, enabling accurate risk stratification for BCR. This insight may contribute to the advancement of personalized treatment strategies for PCa.

Key Words:

Prostate cancer (PCa) is the most prevalent malignancy among males worldwide and ranks as the second leading cause of cancer-related mortality in men (1). Recent years have witnessed a continued increase in incidence, accounting for approximately 27% of newly diagnosed cases in males (2). The primary treatment modalities for early stage localized PCa include radical prostatectomy (RP) and radiotherapy (3). Although the majority of patients are cured following these interventions, approximately 35% of those who undergo RP and 30-50% of patients receiving radiotherapy experience biochemical recurrence (BCR) within ten years. BCR is defined as an elevation in prostate specific antigen (PSA) levels to 0.2 ng/ml or greater post RP, confirmed by at least two consecutive tests indicating an upward trend. For patients treated with radiotherapy, recurrence is noted when PSA levels rise by more than 2 ng/ml from the nadir, in the absence of clinically detectable lesions (4-6). BCR represents a substantial risk factor for local recurrence, distant metastasis, and an escalation in both PCa specific and overall mortality rates (7). Studies have demonstrated that approximately 30% of patients experiencing BCR will progress to develop distant metastases. Furthermore, within ten years, 19-27% of patients may encounter PCa specific mortality if secondary treatment is not administered (8, 9). Currently, clinical evaluation of PCa aggressiveness, prognostication, and treatment guidance heavily relies on indicators, such as PSA levels and Gleason scores. However, due to the high heterogeneity of PCa and the limitations in sensitivity or specificity of these clinical indicators, clinicians often face challenges in accurately assessing patient prognosis (10). Consequently, this predicament can lead to instances of over treatment or under treatment for patients.

Solute carrier (SLC) transporters, comprising 456 members divided into 52 families, primarily reside within cell membranes and are responsible for the transport of metabolites across cellular borders, playing pivotal roles in various biological processes, including the regulation of cell signaling (11-14). Dysregulation of SLCs has been linked to numerous diseases, including cancers, neurological and metabolic diseases (15, 16). The SLC family 15 encompasses proteins encoded by the SLC15A gene (17). In mammals, the SLC15A family, also known as the peptide transporter family, comprises four gene members: SLC15A1 (PEPT1), SLC15A2 (PEPT2), SLC15A3 (PHT2), and SLC15A4 (PHT1) (18). Their topology includes 12 transmembrane domains, with both the C-terminus and N-terminus located in the cytoplasm (19). SLC15A1 is characterized as a low-affinity, high-capacity transporter predominantly expressed in the brush border membrane of intestinal epithelial cells, facilitating the transport of nutrients (dipeptides/tripeptides) and peptidomimetic drugs from the lumen into enterocytes (20). SLC15A3 is primarily expressed in the lungs, spleen, and thymus, with substantial expression noted in macrophages, dendritic cells, and monocytes. Conversely, SLC15A4 is predominantly found in brain and ocular tissues (19), while both SLC15A3 and SLC15A4 are localized on the membranes of nuclear endosomes and lysosomes, responsible for translocating histidine, dipeptides, tripeptides, and peptidomimetics from the lysosomal lumen to the cytoplasm (21).

The gene encoding SLC15A2 is located at chromosome 3q13.33 and translates into a protein consisting of 729 amino acids, with a molecular weight of approximately 82 kDa (22). SLC15A2 is a high-affinity, low-capacity transporter with a substrate profile similar to that of SLC15A1 (23), and it has been shown to play critical roles in various diseases, including hepatocellular carcinoma (24), leukemia (25), and glioma (26-28). However, the role of SLC15A2 in PCa remains inadequately elucidated. The flowchart of our study is shown in Figure 1. In this study, we systematically analyzed the role of SLC15A2 in PCa by leveraging multi-omics data obtained from public databases, such as The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), alongside clinical samples and in vitro experiments. Our findings indicated that SLC15A2 may serve as a potential prognostic biomarker, contributing to the development of personalized treatment strategies and improving prognostic assessment for PCa.

Figure 1.
Figure 1.

Schematic diagram of the study design. Expression levels and prognostic significance of SLC15A2 in PCa were initially validated using cohorts derived from publicly accessible databases, including TCGA. Subsequently, experimental methodologies were employed to confirm the tumor-suppressive effects of SLC15A2 on PCa cells. In addition, enrichment analysis, mutation analysis, and methylation analysis were conducted to explore the potential biological functions of SLC15A2. Finally, a drug-target analysis was performed to identify small molecules that specifically target SLC15A2.

Materials and Methods

Data collection and processing. We downloaded the mRNA expression profiles of normal tissues from the Genotype-Tissue Expression (GTEx, https://www.gtexportal.org/home/) database and the Human Protein Atlas (HPA, https://www.proteinatlas.org/) database. The gene expression matrix for cancer cell lines was obtained from the Cancer Cell Line Encyclopedia dataset (CCLE, https://sites.broadinstitute.org/ccle/datasets). We obtained five cohorts with PCa transcriptomic data and clinical information from the PCaDB (http://bioinfo.jialab-ucr.org/PCaDB/) website, specifically TCGA-prostate adenocarcinoma (TCGA-PRAD), GSE54460, CancerMap (GSE94767), Taylor (GSE21034), and DKFZ. Furthermore, we retrieved single nucleotide polymorphism (SNP) and copy number variation (CNV) data for TCGA-PRAD from TCGA database. The data processing workflow was consistent with our previously published work (29). Detailed baseline data for all patients are provided in Table SI.

Differential expression and prognosis analysis of SLC15A2. We analyzed the expression levels of SLC15A2 in normal tissues using data from HPA and GTEx databases. The expression levels of SLC15A2 in cancer cell lines were evaluated using data from CCLE. The R package “TCGAplot” (version 7.0.1) was employed to analyze the differential expression of SLC15A2 across pan-cancer data from TCGA (30). The R package “survminer” (version 0.4.9) (https://cran.r-project.org/web/packages/survminer/index.html) was used to determine the optimal cutoff value for SLC15A2, categorizing PCa patients in each cohort into high and low expression groups. Additionally, we utilized the R package “survival” (version 3.5-8) (https://cran.r-project.org/web/packages/survival/index.html) to perform Kaplan-Meier (KM) analysis and both univariate and multivariate Cox regression analyses to assess the impact of SLC15A2 on PCa prognosis.

Immunohistochemistry (IHC). The PCa tissue microarray (TMA) used in this study was procured from Shanghai Outdo Biotech Company (HProA120Su01, Shanghai, PR China), which obtained ethical approval from its ethics committee (Approval No. YBM-05-02). TMA cohort consists of 60 primary PCa tissue samples accompanied by prognostic information. IHC procedure followed the protocol described in our previous research (29, 31). In brief, tissue samples were first fixed with 4% paraformaldehyde and then embedded in paraffin. Next, endogenous peroxidase activity was blocked using a 1% H2O2 solution, followed by blocking the sections with non-immune goat serum (Beyotime, Shanghai, PR China). The sections were incubated overnight at 4°C with the primary antibody against SLC15A2, followed by incubation at room temperature for 30 minutes with biotinylated secondary antibody. The primary antibody used was anti-SLC15A2 antibody (Immunoway, YN5137, Suzhou, PR China).

Cell culture and transfection. The human PCa cell line 22Rv1 was purchased from the National Collection of Authenticated Cell Cultures (Shanghai, PR China). The 22Rv1 cells were cultured in RPMI-1640 medium (MA0215, Meilunbio, Dalian, PR China) supplemented with 10% fetal bovine serum (FBS, Z7187FBS-500, ZETA LIFE, Menlo Park, CA, USA) and 1% penicillin-streptomycin solution (15140–122, Gibco, Grand Island, NY, USA), maintained at 37°C in a 5% CO2 environment. According to the manufacturer’s instructions, negative control (NC) and small interfering RNAs (siRNAs) targeting SLC15A2 (Tsingke, Guangzhou, PR China) were transfected into PCa cells using siRNA-mate (Genepharma, Suzhou, PR China). The sequences of the siRNAs used are listed in Table SII.

Western blot. All protein samples were extracted from the transfected cell line using RIPA lysis buffer (Beyotime) and separated by 10% SDS-PAGE. The separated proteins were then transferred to polyvinylidene fluoride (PVDF) membranes (Millipore, Billerica, MA, USA). The membranes were blocked with 5% non-fat milk for 1 h, followed by overnight incubation with the primary antibody at 4°C and 1 h incubation with the secondary antibody at room temperature. The bands were visualized using a chemiluminescent imaging system (CLiNX ChemiScope Touch, Shanghai, PR China), and the intensity of the target protein bands was quantified by measuring their gray values using ImageJ software. The primary antibodies used were anti-SLC15A2 antibody (Immunoway, YN5137) and β-actin antibody (Proteintech, Wuhan, PR China).

Cell viability, colony formation and invasion assays. The proliferation ability of PCa cells after SLC15A2 knockdown was assessed using the Cell Counting Kit-8 (CCK-8, MA0218, Meilunbio, Dalian, PR China) and colony formation assays, while their invasion ability was evaluated using transwell assays. The detailed procedures were conducted as described previously (32).

Functional enrichment. We downloaded the gene sets ‘c2.all.v7.4. entrez.gmt’ and ‘c5.all.v7.4.entrez.gmt’ from the Molecular Signatures Database (MSigDB, https://www.gsea-msigdb.org/gsea/msigdb/index.jsp). Spearman correlation analysis was employed to evaluate the relationship between SLC15A2 and all mRNAs, with the mRNAs subsequently ranked in descending order based on their correlation coefficients. The R package ‘clusterProfiler’ (version 4.8.3) (https://bioconductor.org/packages/release/bioc/html/clusterProfiler.html) was utilized to perform Gene Set Enrichment Analysis (GSEA) on the ordered gene list to identify significantly enriched Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways (33).

The landscape of somatic mutations. We conducted online analyses using the GISTIC_2.0 module with default parameters from the GenePattern (https://cloud.genepattern.org/gp/pages/index.jsf) website to identify significantly amplified and deleted genomic regions in the SLC15A2 high expression and low expression groups. The R package ‘maftools’ (version 2.18.0) was employed to organize and analyze somatic variant data (34). Visualization was performed using the R package ‘ComplexHeatmap’ (version 2.18.0) (35). Finally, we utilized the Wilcoxon rank-sum test to compare differences in copy number variation (CNV) and mutation frequencies between the high and low expression groups of SLC15A2.

SLC15A2 DNA methylation analysis. Shiny Methylation Analysis Resource Tool (SMART; http://www.bioinfo-zs.com/smartapp/) database functions as a robust platform for analyzing DNA methylation data derived from TCGA. Employing the SMART tool, we investigated the DNA methylation levels of SLC15A2 in tumor samples.

Prediction of potential drugs. The Connectivity Map (CMap, https://www.broadinstitute.org/connectivity-map-cmap) is a public database used for studying gene interactions and drugs, containing over 7,000 transcriptomic profiles from human cells treated with 1,309 bioactive small molecules (36). To further investigate the mechanisms of action (MoA) and drug targets associated with SLC15A2, we conducted a specific analysis using the CMap tool.

Statistical analysis. Statistical analyses and visualizations were performed using R software (version 4.3.1). Spearman correlation analysis was employed to assess the relationship between two continuous variables. The experimental results are presented as mean±standard deviation (SD), and the differences between the two groups were compared using the Student’s t-test and the Wilcoxon rank-sum test. A p-value of <0.05 (two-tailed) was considered statistically significant. *p<0.05; **p<0.01; ***p<0.001; ****p<0.0001.

Results

The expression landscape of SLC15A2. Analyses of the HPA and GTEx cohorts indicated that SLC15A2 is highly expressed in normal tissues, such as the cervix, prostate and lung, while exhibiting lower expression levels in skeletal muscle and liver compared to other organs (Figure 2A). In the pan-cancer cell line cohort from CCLE, SLC15A2 exhibited moderate expression levels in PCa (Figure 2B). Furthermore, differential analysis of unpaired samples from TCGA revealed that SLC15A2 mRNA expression is significantly reduced in various cancers, including PCa, compared to normal tissues (Figure 2C). Similar expression patterns were observed in the paired sample differential analyses from TCGA database (Figure 2D). Collectively, these findings demonstrated that SLC15A2 may serve as a potential biomarker for PCa.

Figure 2.
Figure 2.
Figure 2.
Figure 2.

Expression analysis of SLC15A2 in different databases. (A) Expression levels of SLC15A2 in normal tissues (HPA and GTEx databases); (B) Expression levels of SLC15A2 in different cancer cell lines (CCLE database); (C) Expression of SLC15A2 in TCGA tumors and unmatched adjacent normal tissues; (D) Expression of SLC15A2 in TCGA tumors and matched adjacent normal tissues. Statistical significance was assessed by the Wilcoxon test. *p<0.05; **p<0.01; ***p<0.001, ****p<0.0001; not significant (ns), p≥0.05.

SLC15A2 is an independent prognostic factor for primary PCa. We subsequently evaluated the prognostic value of SLC15A2 in PCa across the TCGA-PRAD, GSE54460, DKFZ, Taylor, and CancerMap cohorts. KM survival analysis indicated that patients in the low SLC15A2 expression group had significantly earlier BCR compared to those in the high expression group across these five PCa cohorts (Figure 3A, C, E, G, and I). As shown in Figure 3B, D, F, H, and J, low expression of SLC15A2 was associated with early BCR. Additionally, univariate Cox regression analysis demonstrated that SLC15A2 is a protective factor for BCR in PCa (Figure 3K). Multivariate Cox regression analysis results indicated that SLC15A2 serves as an independent prognostic factor for BCR in PCa within the TCGA-PRAD, GSE54460, and DKFZ cohorts [TCGA-PRAD: hazard ratio (HR)=0.861, 95% confidence interval (CI)=0.747-0.992, p=0.039; GSE54460: HR=0.818, 95% CI=0.706-0.948, p=0.008; DKFZ: HR=0.642, 95% CI=0.428-0.965, p=0.033] (Figure 3L). These results suggest that SLC15A2 could serve as an independent prognostic factor for BCR in primary PCa.

Figure 3.
Figure 3.
Figure 3.

Prognostic value of SLC15A2 in PCa. (A-J) Kaplan-Meier survival analysis and BCR status scatter plot in TCGA-PRAD, GSE54460, DKFZ, Taylor, and CancerMap cohorts; (K, L) Univariate and multivariate Cox regression. PCa: Prostate cancer; BCR: biochemical recurrence; pT stage: pathological T stage; pN stage: pathological N stage; PSA: prostate specific antigen.

IHC validation of SLC15A2 using an in-house cohort. Considering that the above analyses were primarily based on PCa cohorts from European and American populations, we further validated the prognostic value of SLC15A2 in a Chinese population using clinical samples. IHC results showed that SLC15A2 is mainly localized in the nuclei of PCa glandular epithelial cells, and its expression is relatively lower in PCa compared to adjacent non-cancerous tissues (Figure 4A). Additionally, KM survival analysis indicated that patients with high expression of SLC15A2 had significantly improved overall survival (Figure 4B). These results suggest that SLC15A2 can serve as a robust prognostic biomarker for PCa at the protein level.

Figure 4.
Figure 4.

IHC validation of SLC15A2 in local cohort of primary PCa patients. (A) Representative images show SLC15A2 staining in cancerous and adjacent non-cancerous tissues. (B) Kaplan-Meier survival analysis.

SLC15A2 inhibits the proliferation and migration of PCa cells. Given that most of the results above were primarily based on in silico analysis, we further validated the role of SLC15A2 in PCa through in vitro experiments. First, we designed three different siRNAs targeting SLC15A2 and confirmed their transfection efficiency using Western blot (Figure 5A). We then selected the two siRNAs with the highest transfection efficiency for subsequent CCK-8 assays, colony formation assays, and transwell migration assays (Figure 5B-D). The results indicated that knockdown of SLC15A2 significantly enhanced the proliferation and migration abilities of PCa cells. In conclusion, these results suggest that SLC15A2 knockdown may promote PCa progression in vitro.

Figure 5.
Figure 5.

Experimental validation of SLC15A2. (A) Western blotting to detect the expression level of SLC15A2 in the 22Rv1 cell line (n=3). (B) The CCK-8 assay examined the influence of SLC15A2 silencing on cell viability in 22Rv1 (n=3). (C) Plate clone formation capability of the 22Rv1 cell line (n=3). (D) Transwell assay to detect the invasion capability of the 22Rv1 cell line (n=3). Statistical significance was assessed by unpaired Student’s T-test. *p<0.05; **p<0.01; ***p<0.001, ****p<0.0001.

Functional enrichment analysis. To explore the biological functions of SLC15A2, we utilized GSEA to analyze GO and KEGG pathways (Table SIII and Table SIV). We visualized the top 10 GO and KEGG pathways activated or inhibited by SLC15A2 based on the Normalized Enrichment Scores (NES) (Figure 6A-D). The results of the GO and KEGG analyses indicated that SLC15A2 primarily activates pathways related to cell proliferation, adhesion, and lipid metabolism, such as GOBP ‘Muscle Cell Proliferation’, GOBP ‘Vascular Transport’, KEGG ‘Adherens Junction’, and KEGG ‘Fatty Acid Metabolism’. Conversely, it inhibits pathways associated with protein synthesis, degradation, RNA metabolism, and energy metabolism, including KEGG ‘Ribosome’, KEGG ‘Spliceosome’, KEGG ‘Oxidative Phosphorylation’, and GOCC ‘Ribosomal Subunit’.

Figure 6.
Figure 6.
Figure 6.

Functional enrichment analysis of SLC15A2. (A, B) Top 10 activated and suppressed GO terms ranked by NES. (C, D) Top 10 activated and suppressed KEGG pathways ranked by NES. NES: Normalized Enrichment Scores; GO: gene ontology; KEGG: Kyoto Encyclopedia of Genes and Genomes.

Mutation landscape related to SLC15A2 expression in primary PCa. We subsequently examined the role of SLC15A2 in primary PCa at the mutation level. We visualized the top 20 most frequently mutated genes and the top 10 CNVs in primary PCa patients from the TCGA-PRAD cohort. As illustrated in Figure 7A, TP53 and SPOP exhibited the highest mutation frequencies, each at 11%. Notably, we found that the mutation frequency of TP53 was significantly elevated in the low SLC15A2 expression group (16.6%), while the mutation frequency of KMT2D was significantly reduced (2.7%) (Figure 7B). Additionally, we observed marked differences in the frequency of copy number alterations between the high and low SLC15A2 expression groups. In the low SLC15A2 expression group, the frequencies of amplifications, such as 8q23-3-Amp (81.6%), 8q24-21-Amp (78%), 8q22-3-Amp (79.8%), 8q21-13-Amp (76.2%), and 8q21-11-Amp (72.6%) were significantly increased, whereas deletions, including 8p21-3-Del (73.5%), 8p23-1-Del (62.3%), 16q24-1-Del (56.5%), and 6q14-3-Del (48.4%), were also more prevalent (Figure 7C). These findings suggest that the poor prognosis associated with low SLC15A2 expression may be linked to the heterogeneity of gene mutations and CNVs.

Figure 7.
Figure 7.

Features of SLC15A2 using TCGA multi-omics dataset. (A) Landscape of SLC15A2 expression levels with mutations and copy number variation (CNVs). (B) Analysis of mutational differences in 20 frequently mutated genes between high and low expression groups of SLC15A2. (C) Analysis of mutational differences in the top 5 amplification (AMP) and deletion (DEL) chromosome fragments between high and low expression groups of SLC15A2. Statistical significance was assessed by the Wilcoxon test. *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001.

Methylation status of SLC15A2. DNA methylation is a prevalent epigenetic alteration in cancer, closely associated with the progression of various malignancies and often resulting in poor patient prognosis (37). We employed the SMART database to examine the DNA methylation levels of SLC15A2 in PCa patients. The findings indicated that the methylation levels in PCa tissues were significantly higher than those in normal tissues (Figure 8A). SLC15A2 was found to have five methylation probes, such as cg10523671, cg02034887, cg15066489, cg18636558, and cg16710348, all of which are located on human chromosome 3 (Figure 8B). Specifically, the methylation levels of cg10523671 and cg02034887 in PCa tissues were significantly elevated compared to those in normal tissues, while cg16710348 exhibited an inverse trend (Figure 8C). Additionally, there was a significant negative correlation between the methylation levels of cg10523671 and cg02034887 and SLC15A2 expression, whereas cg16710348 showed a significant positive correlation with SLC15A2 expression (Figure 8D).

Figure 8.
Figure 8.

Relationship of SLC15A2 with methylation. (A) Methylation levels of SLC15A2 in PCa tissues compared to normal tissues. (B) Chromosomal distribution of the methylation probes associated with SLC15A2. (C) Methylation levels of probes in PCa tissues compared to normal tissues. (D) Relationship between probe methylation levels and SLC15A2 expression in PCa. Statistical significance was assessed by the Wilcoxon test. *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001.

Related drug screening for primary PCa treatment. Based on the aforementioned analyses, we determined that low expression levels of SLC15A2 are often associated with poor prognosis in patients. Consequently, we conducted CMap analysis to explore potential therapeutic agents linked to SLC15A2 in PCa. As illustrated in Figure 9, we identified 20 candidate small molecule drugs targeting SLC15A2 based on differentially expressed genes between the high and low expression groups (|fold change (FC)| >2, false discovery rate (FDR) <0.05), including indiplon, clindamycin, otilonium, rucaparib, and curcumin. These small molecules may exert inhibitory effects on the onset and progression of PCa and warrant further investigation.

Figure 9.
Figure 9.

Screening for candidate small molecule drugs in prostate cancer (PCa). (A) Bubble plot representing Cmap analysis. (B) Drug-related signaling pathways derived from Cmap analysis.

Discussion

PCa is a heterogeneous disease that poses a significant threat to men’s health. Although the incidence of PCa in China is notably lower than that in Europe and the United States, it has been rapidly increasing year by year due to changing dietary habits and an aging population (38). Currently, the management of PCa has evolved into a comprehensive treatment paradigm that includes active surveillance, surgery, androgen deprivation therapy (ADT), and radiation therapy (39). More than 80% of patients with primary PCa can survive for over five years; however, advanced PCa typically progresses within 2 to 3 years following initial treatment, gradually developing resistance to ADT and ultimately leading to castration-resistant prostate cancer (CRPC) (40, 41). CRPC is associated with a poor prognosis, and there are currently no effective treatments available in clinical practice (42, 43). Consequently, there is an urgent need to identify reliable prognostic biomarkers for risk stratification, which could guide treatment decisions and improve outcomes for PCa patients.

SLC15A2 is a member of SLC family, involved in the transmembrane transport of various solutes, including ions, metabolites, peptides, and drugs (13, 44). SLC15A2 has been implicated in various tumors; for example, Greim et al. reported that SLC15A2 mediates the uptake of dipeptides in chronic myeloid leukemia stem cells. They found that combining cefadroxil (a substrate of SLC15A2) with the tyrosine kinase inhibitor imatinib extended survival in mice with chronic myeloid leukemia (45). Hou et al. demonstrated that SLC15A2 overexpression is associated with increased fluorescence intensity of Protoporphyrin IX (PpIX) through in vitro experiments, suggesting that SLC15A2 may enhance fluorescence-guided resection in grade II/III gliomas (27). However, its role in PCa remains unclear.

In this study, we first conducted survival analyses using clinical cohorts of PCa from public databases such as TCGA. We found that patients with low SLC15A2 expression experienced BCR significantly earlier than those with high expression levels. Higher SLC15A2 expression generally correlated with better patient prognosis. Moreover, both univariate and multivariate Cox regression analyses confirmed that SLC15A2 could serve as an independent factor for BCR in primary PCa patients. Notably, in the Taylor and CancerMap cohorts, multivariate Cox regression analysis showed no significant correlation between SLC15A2 and BCR in PCa patients (Taylor: p=0.067; CancerMap: p=0.168), potentially attributable to inconsistencies in sequencing platforms across different cohorts. To enhance clinical applicability, we validated our findings using a tissue microarray cohort, revealing that SLC15A2 demonstrates strong predictive capability for prognosis in actual clinical practice. Additionally, our cellular experiments indicated that SLC15A2 inhibits the proliferation and invasion abilities of PCa cells. These results suggest that SLC15A2 holds promise as a novel biomarker for prognostic prediction in primary PCa patients.

Cancer is characterized by abnormal and uncontrolled cell proliferation, primarily driven by genetic mutations (46). In our mutation analysis, TP53 emerged as the gene with the highest mutation frequency (11%), with a significantly higher mutation frequency observed in the low SLC15A2 expression group (16.6%), when compared to the high expression group (5.6%). TP53 is a tumor suppressor gene encoding the tumor-associated protein p53, one of the most frequently mutated genes in various human cancers, with mutation rates exceeding 50% (47). Functionally, p53 exerts its tumor-suppressive effects mainly by inducing apoptosis, repairing damaged DNA, promoting metabolism, and inhibiting angiogenesis (48). Furthermore, p53 can participate in cellular activities, such as autophagy, iron reduction, and reactive oxygen species generation through protein-protein interactions, thereby impeding tumor progression (49). Previous studies have indicated that TP53 mutations can drive neuroendocrine subtype transformation in PCa (50). TP53 mutations represent potential biomarkers for poor patient prognosis and insensitivity to various treatment modalities (51, 52). Additionally, the frequency of CNV at 8q24.21 was significantly higher in the low SLC15A2 expression group (78%) compared to the high expression group (58.6%). The chromosomal region 8q24.21 is the most common amplification area in PCa, where the oncogene MYC is located. MYC is an important regulatory gene that influences cell proliferation and apoptosis by inducing or repressing transcription, playing a crucial role in the occurrence and progression of various malignancies (53, 54). Studies have shown that PCa patients with MYC amplification exhibit increased tumor invasiveness and higher early mortality rates (55, 56). These findings suggest that exploring the relationship between SLC15A2, TP53 mutations, and 8q24.21 CNV could provide new insights for personalized treatment strategies in PCa.

Considering SLC15A2 as a promising prognostic biomarker in PCa, we performed CMap analysis to screen for potential small molecule drugs targeting SLC15A2, such as indiplon, clindamycin, otilonium, and rucaparib. Among these, rucaparib is an FDA-approved targeted drug for the treatment of advanced PCa. These small molecules may offer potential advantages for patients who cannot benefit from traditional drug therapies and warrant further investigation.

However, this study inevitably has several limitations. Firstly, all samples were retrospectively collected; thus, more prospective samples need to be gathered for validation in future research. Secondly, due to time and budget constraints, we lack detailed investigations into the function and mechanisms of SLC15A2 in PCa. Future work will focus on refining relevant experiments to delve deeper into its role in PCa.

Conclusion

We utilized multi-omics data analysis to demonstrate that SLC15A2 can accurately stratify risk for prognosis in primary PCa patients, with low expression associated with earlier BCR and decreased survival rates. Moreover, in vitro experiments further confirmed the anticancer effects of SLC15A2 on PCa cells. In conclusion, SLC15A2 may serve as a novel prognostic biomarker and therapeutic target in primary PCa, contributing to the improvement of individualized treatment for patients.

Footnotes

  • Authors’ Contributions

    WJY: Conceptualization; Formal analysis; Methodology; Visualization; Writing – review & editing; PKQH: Formal analysis; Resources; Conceptualization; Methodology; Software; ZHZ: Formal analysis; Methodology; Software; JDL: Formal analysis; Methodology; Resources; ZGL: Resources; Conceptualization; Methodology; ZJW: Formal analysis; Conceptualization; Software; JHY: Conceptualization; Methodology; JML: Formal analysis; Conceptualization; Methodology; Writing – review & editing; WDZ: Formal analysis; Conceptualization; Project administration; Resources; Supervision.

  • Funding

    This study was supported by the National Natural Science Foundation of China (82072813, 82203557, 82103358), The Science and Technology Development Fund (FDCT) of Macau SAR (0090/2022/A, 0116/2023/RIA2), GuangDong Basic and Applied Basic Research Foundation (2022A1515010342) and Guangzhou Municipal Science and Technology Project (202201010053).

  • Supplementary Material

    Supplementary material can be obtained at: https://doi.org/10.5281/zenodo.14017917

  • Conflicts of Interest

    The Authors declare that they have no competing interests.

  • Received October 10, 2024.
  • Revision received November 6, 2024.
  • Accepted November 14, 2024.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).

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SLC15A2 Serves as a Novel Prognostic Biomarker and Target for Prostate Cancer
WENJUN YIN, PINGKAIQI HE, ZHIHAO ZOU, JUNDONG LIN, ZHENGUO LIANG, ZHENJIE WU, JIANHENG YE, JIANMING LU, WEIDE ZHONG
Anticancer Research Jan 2025, 45 (1) 153-172; DOI: 10.21873/anticanres.17402
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