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Clinical significance and expression of SLC35F6 in bladder urothelial carcinoma

Diagnostic Pathology volume 19, Article number: 150 (2024) Cite this article

Abstract

Background

SLC35F6 negatively regulates outer mitochondrial membrane permeability and positively regulates apoptotic signaling pathways and cell population proliferation. The biological function of SLC35F6 in bladder cancer (BC) remains inadequately established. This study evaluates the expression and clinical significance of SLC35F6 in BC, assesses its prognostic value and explores its relationship with key immune-related molecules in the tumor microenvironment.

Methods

Combining bioinformatics tools and immunohistochemistry (IHC) analysis, the expression of SLC35F6 was analyzed through IHC in the tissues of 145 BC patients treated at the Affiliated Hospital of Nantong University from 2004 to 2009. The relationship between SLC35F6 expression levels and significant clinicopathological factors was examined using the chi-square test. Prognostic values were analyzed using the COX regression model and the Kaplan-Meier survival curve. Analysis of the receiver operating characteristic curve was conducted to assess the predictive performance of SLC35F6 in BC patients.

Results

The expression levels of both SLC35F6 mRNA and protein were elevated in BC tissue relative to benign tissue. Kaplan-Meier analysis indicated that patients exhibiting elevated SLC35F6 protein expression had a worse prognosis. Multivariate Cox regression analysis confirmed that SLC35F6, TNM stage and grade are independent risk factors for bladder cancer. SLC35F6, when analyzed alongside clinical pathological factors, enhances the accuracy of survival predictions for Bladder Urothelial Carcinoma (BLCA) patients.

Conclusion

SLC35F6 is upregulated in BC patients compared to normal individuals and is linked to a worse prognosis. SLC35F6 analyzed alongside clinical pathological factors can enhance the accuracy of survival predictions for BLCA patients, suggesting its potential value as a prognostic and predictive biomarker.

Introduction

Bladder cancer (BC) affects over 430,000 people annually, ranking as the tenth cancer type [1, 2]. It primarily occurs in men, with a significantly higher incidence than in women [3]. BC, accounting for 90–95% of Urothelial carcinomas, is typically diagnosed at an advanced age, with a median patient age of 73 years [4, 5]. Standard therapies for BC mainly involve surgical resection and chemotherapy, but they carry a substantial risk of recurrence and a 5-year overall survival(OS) rate of 15–20% [6]. Non-muscle-invasive BC is treated with Bacillus Calmette-Guerin immunotherapy, which has a high risk of recurrence or progression [7]. The complex prognosis and limited treatment options for BLCA pose significant clinical challenges, underscoring the urgent need for new diagnostic techniques or novel molecular biomarkers to provide insights into BC patient prognosis.

The tumor microenvironment (TME) is an environment of tumor origin. Cells can be divided into two categories, immune-suppressive cells and immune-stimulatory cells, based on their function in the antitumor immune response [8]. TME is most frequently associated with poor patient prognosis, which has a significant impact on tumor growth and metastasis and is closely related to clinical outcomes [9,10,11,12]. Amidst the importance of TME in treatment outcomes, an in-depth understanding of potential novel and reliable biomarkers of bladder cancer is crucial [13].

One such promising biomarker is SLC35F6, a protein that has been investigated in pancreatic ductal adenocarcinoma as a potential therapeutic target [14]. SLC35F6 belongs to the human nucleoside transporter SLC35 solute carrier family which has been shown to play a regulatory role in various tumors and cancers [15]. SLC35F6 is located within the mitochondria and has been observed to interact with adenine nucleotide translocase 2(ANT2) [14]. ANT2 is a key molecule essential that correlates with cancer for cell remodeling and cell survival and its deficiency has a severe impact on mitochondrial function and cellular energy homeostasis [16, 17].

However, there is limited research on SLC35F6 in BC and its expression concerning clinicopathological characteristics has yet to be explored. Considering the non-linear correlation between mRNA and protein expressions, we plan to employ tissue microarray (TMA) and multiplex IHC to analyze the relationship between relevant markers and in the TME [18]. This approach aims to provide new insights and potential directions for clinical diagnosis. Alongside SLC35F6 expression analysis, we will also investigate the correlation of PD-L1 in a consecutive cohort of 145 BC patients.

In this study, we analyzed the protein expression of SLC35F6 in tumor tissues of 145 BC patients by immunohistochemistry and assessed its prognostic value. Then, based on the correlation between SLC35F6 and PD-L1 mRNA expression by bioinformatic techniques, PD-L1 in BC tissues was further analyzed, aiming to explore the potential role of SLC35F6 in the TME of BC.

Materials and methods

Bioinformatics analysis

The relationship between the SLC35F6 mRNA expression and OS of BLCA patients was analyzed by using the GEPIA (Gene Expression Profiling Interactive Analysis) database (cancer-PKU.cn). Additionally, we utilized the TIMER (Tumor Immune Estimation Resource) tool (shinyapps.io) at https://cistrome.shinyapps.io/timer/ to explore the correlation between SLC35F6 and PD-L1.

Patients and samples

A total of 145 BC tissue samples and 157 normal bladder mucosa tissue sections were collected for this study from October 2004 to August 2009. Clinicopathological data and patient prognoses were retrospectively examined from the patients’ medical records. The patients had not undergone radiation, chemotherapy, or biological immunotherapy prior to surgery. TMA was prepared by the Department of Clinical Biobank at the Affiliated Hospital of Nantong University. Each TMA core represented a 2-millimeter sample and multiple samples from the same subject were averaged. The research procedure was approved by the Human Research Ethics Committee of the Affiliated Hospital of Nantong University (Jiangsu, China). Tumor staging was performed according to the AJCC 2017 criteria and tumor grading was determined using the 2016 World Health Organization grading system.

Immunohistochemistry (IHC)

Formalin-fixed and paraffin-embedded TMA sections were deparaffinized and rehydrated using alcohol and xylene. Antigen retrieval was conducted by microwave-heating the TMA sections in sodium citrate buffer (0.01 M, pH 6.0). After blocking endogenous peroxidase activity with 5% BSA, the sections were incubated with rabbit anti-PD-L1 (1:100, 13684T, Cell Signaling Technology), rabbit anti-SLC35F6 (1:100, NBP193972, NOVUS). The outcome of antibody binding was examined using the Maxim Biotechnologies EliVision Plus DAB Kit (Kit-0015; Fuzhou, China). All slides were scanned using the Vectra Automated Quantitative Pathology Imaging System (version 3.0, PerkinElmer, USA).

The proportion of cells positively stained for SLC35F6 was counted and the final staining score was calculated based on the intensity and percentage of positive cells. The percentage of cells with positive marker staining was estimated using the inForm Image Analysis Software (version 2.4.1, PerkinElmer, USA). Staining intensity was classified into four levels: 0 (no staining), 1+ (mild staining), 2+ (medium staining)and 3+ (severe staining). The overall score, ranging from 0 to 300, was calculated by multiplying the staining intensity score by the proportion of positively stained cells. The optimal cutoff value for SLC35F6 protein expression was set at an H score of 98 using X-tile software (version: 3.6.1, Yale University) based on the patients’ 5-year survival time. Cases with scores from 0 to 98 were defined as low/negative cytoplasmic expression, while scores from 99 to 300 were considered positive/high cytoplasmic expression.

Statistical analysis

Correlations between SLC35F6 expression and clinicopathological variables were assessed using Pearson’s χ2 test. Factors identified in the univariate model as having a significant prognostic impact were further evaluated using a multivariate Cox regression model. Survival analysis was performed using the Kaplan-Meier method and the log-rank test was employed for comparison. A p-value of less than 0.05 was considered statistically significant. Hazard ratios (HR) with 95% confidence intervals (CI) were calculated for both univariate and multivariate analyses. The data were presented as the median and interquartile range. Statistical analysis was conducted using GraphPad Prism software (version 5.0, USA), SPSS statistical software (version 24.0, USA)and R software (version 4.1.1, USA).

Results

Expression of SLC35F6 mRNA in BLCA

We observed that SLC35F6 mRNA expression was increased in BC tissues compared to normal bladder tissues on TCGA database (Fig. 1A), which was further found to be correlated with unfavorable clinical outcomes in these patients (Fig. 1B, P = 0.028). Additionally, GEPIA analysis demonstrated a strong correlation between SLC35F6 expression and CD274 (PD-L1) (Fig. 1D, r = 0.509).

Fig. 1
figure 1

Expression and prognostic analysis between BC and adjacent non-tumor tissues based on the TCGA database and GEPIA (A) The expression of SLC35F6 was significantly higher in bladder tumor tissues than in the normal tissues, according to the TCGA samples; (B) GEPIA showed overall survival curves of SLC35F6 expression in BLCA; (C) The correlation between SLC35F6 mRNA expression and PD-L1. * P < 0.05

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IHC analysis of SLC35F6

Since mRNA and protein expression levels were not positively correlated, we performed IHC staining to measure the protein levels of SLC35F6 in the TMA of BC tissues. Representative photomicrographs of normal urothelial and carcinoma tissues stained for SLC35F6 are illustrated. Benign urothelial tissue showed negative to weak immunoreactivity to SLC35F6(Fig. 2A). SLC35F6 staining was observed in the cytoplasm and membrane of tumor cells (Fig. 2C). SLC35F6 protein expression was considerably higher in BLCA tissues (97, 66.90%) than in tumor-free bladder tissues (48, 33.10%), with a significant statistical difference (Pearson χ2 = 9.076, P = 0.003) observed in the normal epithelial tissue (Fig. 3)

Fig. 2
figure 2

Representative immunohistochemical staining images of SLC35F6 and PD-L1 expression (A) Low expression of SLC35F6 in benign tissue; (B) Low expression of PD-L1 in benign tissue; (C) High expression of SLC35F6 in cancerous tissue; (D) High expression of PD-L1 in cancerous tissue

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Fig. 3
figure 3

Overall survival curves for patients with SLC35F6 (p = 0.003). Patients with high SLC35F6 expression showed significantly worse 5-year survival rates than patients with low SLC35F6 expression

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Association of Clinicopathological Characteristics with SLC35F6 expression

In univariate analysis, we observed a significant correlation between SLC35F6 expression and several clinical features of BC patients. High SLC35F6 expression was associated with tumor grade (Pearson χ2 = 7.145, P = 0.028) and TNM stage (Pearson χ2 = 4.120, P = 0.042) (Table 1).

Table 1 Relationship between the expression of SLC36F6 and clinicopathological characteristics in patients with bladder cancer
Full size table

Role of SLC35F6 expression in BLCA prognosis

In the multivariate analysis, high expression of SLC35F6 (P = 0.019) was found to be significantly associated with poor OS, similar to the TNM stage and grades (Table 2). Ultimately, three variables, including SLC35F6 expression (p = 0.037), grade (p = 0.001) and TNM stage (p = 0.001), were independent risk factors affecting patients’ OS.

Table 2 Univariate and multivariable analysis of prognostic factors for overall survival in patients with bladder cancer
Full size table

The predictive value of SLC35F6 and clinicopathological factors on patient survival

SLC35F6, grade and TNM stage were identified as the independent risk factors being utilized to assess the Receiver Operating Characteristic (ROC) curve for predicting patient survival rates at 1, 3 and 5 years. Two ROC curves were constructed to compare prognostic abilities. One group utilized only clinicopathological factors (TNM stage and grade) for prediction, while the other group incorporated SLC35F6 along with clinicopathological factors (TNM stage and grade) to predict patient survival. Statistical analysis was conducted on the significant indicators. Figure 4(A) illustrates that the ROC curve for the combination of clinicopathological factors (TNM stage and grade) yielded an area under the curve (AUC) of 0.769 at 1 year, 0.797 at 3 years and 0.770 at 5 years. The AUC for the combination of TNM stage, grade and SLC35F6 in Fig. 4(B) at 1 year, 3 years and 5 years was 0.811, 0.829 and 0.781, respectively. This indicates that the integration of clinicopathological factors (TNM stage and grade) with SLC35F6 offers a more provides prediction of survival in BLCA patients.

Fig. 4
figure 4

Receiver operating characteristic curve analysis for predicting the factors affecting patient survival. (A) The ROC curve model constructed by the combination of Grade and TNM stage at 1 year, 3 years, and 5 years; (B) The ROC curve model constructed by the combination of Grade, TNM stage, and SLC35F6 at 1 year, 3 years, and 5 years

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Biological processes enriched in SLC35F6

GEPIA analysis demonstrated a correlation between SLC35F6 and PD-L1 (Fig. 1D). Since the mRNA correlation between SLC35F6 and PD-L1 (r = 0.509, P < 0.05) is significant, we used IHC to reveal a positive correlation between the expression of SLC35F6 and PD-L1 on protein level (r = 0.256, P = 0.002). BLCA tissues with high SLC35F6 expression also demonstrate high expression of PD-L1. Typical IHC staining images of SLC35F6 and PD-L1 are shown in Fig. 2.

Discussion

BC is a heterogeneous disease identifying key targets for treatment is crucial to overcome drug insensitivity challenges [19]. The study demonstrated elevated SLC35F6 mRNA levels in BLCA tissues based on the TCGA database. We assessed SLC35F6 expression in BLCA tumor tissues by immunohistochemistry. The expression of SLC35F6 mRNA and protein was elevated in BLCA tissues compared to benign tissues. Kaplan-Meier analysis indicated that patients with elevated SLC35F6 protein expression had a worse outcome. Furthermore, elevated levels of SLC35F6 protein were associated with tumor TNM stage and grade, suggesting its potential involvement in disease progression. Multivariate Cox regression study further confirmed that SLC35F6, TNM stage and grade were independent risk factors for BLCA. Moreover, SLC35F6, in conjunction with clinicopathological variables, might more precisely forecast the survival of BLCA patients. This indicates that SLC35F6 may serve as a potential prognostic molecular marker for predicting survival and prognosis in BLCA patients.

SLC is a membrane-integrated protein that is located on the surface of cells and in the membranes of organelles [20]. It comprises 65 subfamilies and a total of 458 members and plays a significant role in the occurrence and development of cancer [21]. Previous studies have indicated the correlation between SLC activation and various types of cancer, such as head and neck squamous cell carcinoma, liver cancer and gastrointestinal cancer [15, 22, 23]. The SLC35F6 gene is located within a region of 2p23.3 that frequently exhibits common variation in oral cancer and may augment the induction of T-cell receptor endocytosis which correlates with cancer [24,25,26]. SLC35F6 is involved in maintaining mitochondrial membrane potential and energy homeostasis and it plays a role in cell apoptosis, making it a potential candidate molecular target for Pancreatic ductal adenocarcinoma therapy [14]. Although there is currently less research on SLC35F6, the molecular mechanism of SLC35F6 in bladder cancer cells is still worthy of further discussion.

This study utilized immunohistochemical analysis of 145 cases of bladder cancer tissue samples to clarify the significance of SLC35F6 in bladder cancer. The results demonstrated that increased SLC35F6 expression serves as a predictive marker linked to negative outcomes in BLCA patients. This is the first study to clarify the prognostic association between SLC35F6 and cancer. Previous studies have demonstrated that SLC35F6 is essential for cellular viability. The silencing of SLC35F6 using short interfering RNA has been shown to trigger apoptosis in PDAC cells and impede cancer cell proliferation [14]. To clarify the function of SLC35F6 in BLCA, we used a univariate logistic analysis to investigate the relationship between SLC35F6 and PD-L1 expression. PD-L1 is an essential immunological checkpoint that suppresses T cell activation, facilitating immune evasion by hindering the immune system’s ability to target self-tissues and obstructing the immune response against cancer cells that express PD-L1 [27]. Tumor-induced immune evasion frequently leads to a restricted number of patients benefiting from immunotherapy. Prior research has shown that increased PD-L1 expression correlates with more aggressive and progressing bladder cancer tumors and a worse prognosis [28,29,30,31,32]. The findings revealed a positive association between SLC35F6 and PD-L1 expression levels, suggesting a possible role in BLCA immune evasion. Considering the function of SLC35F6 in cancer immune evasion, immunotherapy may exhibit diminished efficacy in BLCA patients with elevated SLC35F6 expression. Inhibiting its expression, enhancing its degradation and obstructing its downstream pathways may represent a more significant strategy for these BLCA patients.

This study has limitations, including its monocentric design and absence of a validation data set. Additionally, PD-L1 detection presents notable limitations, such as varying sensitivities of antibodies and the subjective nature of scoring and cutoff determination [33]. Future research should prioritize multicenter studies with larger sample sizes to improve the generalizability of the results. Furthermore, the role of SLC35F6 in BC remains undetermined. Additional experimentation is necessary to clarify the specific function of the tumor immune microenvironment. Further research is required to clarify the molecular mechanisms that may underlie the function of SLC35F6 in BLCA cancer.

In summary, this study indicates that SLC35F6 expression, along with TNM stages and grade, can serve as independent predictors of OS in BLCA patients. High expression of SLC35F6 is correlated with unfavorable prognosis in BLCA. The classification system developed utilizing the TNM and grade variables demonstrated greater efficacy compared to the standalone TNM and grade systems. The findings indicate that SLC35F6 may serve as a potential prognostic and predictive biomarker.

Conclusion

This study underscores the prognostic significance of SLC35F6 in BLCA patients. SLC35F6 was found to be highly expressed in BLCA tissues. In conclusion, this is the first study to investigate the expression and clinical significance of SLC35F6 in BLCA patients.

Data availability

No datasets were generated or analysed during the current study.

Abbreviations

BC:

Bladder cancer

IHC:

Immunohistochemistry

BLCA:

Bladder Urothelial Carcinoma

TME:

Tumor microenvironment

TMA:

Tissue microarray

HR:

Hazard ratios

CI:

Confidence intervals

OS:

Overall survival

ROC:

Receiver Operating Characteristic

AUC:

The area under the curve

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Acknowledgements

We would like to express our gratitude to all individuals who have provided valuable suggestions and comments, contributing to the enhancement of our paper’s quality. We extend our sincere appreciation for the unwavering support provided by all the funding agencies for this study.

Funding

1: Foundation of Jiangsu Province Research Hospital, YJXYY202204-XKB17.

2: The Science and Technology Project of Nantong City (MS22022111).

3: Project of the 14th Five Year Plan for Strengthening Science, Education, and Health of Nantong City, Cancer Clinical Medical Center (NTYXZX18).

4: National Natural Science Foundation of China Grants (No.81570184).

5: Jiangsu Province Capability Improvement Project through Science, Technology and Education (ZDXK202234).

6: The Foundation of Affiliated Hospital of Nantong University (BSH202203, Tdb2107).

7: The 2024 Provincial Basic Research Special Fund (Natural Science Foundation) General Project: The Role and Mechanism of Abnormal Arginine Metabolism in the Progression of Peripheral T-cell Lymphoma (BK20241837).

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Author notes

  1. Jinling Zhang, Siqi Liu and Meng Wu have contributed equally to this work.

Authors and Affiliations

  1. Department of Oncology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, 226001, China

    Jinling Zhang, Siqi Liu, Meng Wu, Wenyu Shi & Yihong Cai

  2. Medical School of Nantong University, Nantong, Jiangsu, 226001, China

    Jinling Zhang & Siqi Liu

  3. Clinical and Translational Research Center, Department of Oncology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, Jiangsu, 226001, China

    Jinling Zhang

  4. Department of Chemotherapy, Affiliated Hospital of Nantong University, Nantong, Jiangsu, 226001, China

    Meng Wu, Wenyu Shi & Yihong Cai

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Contributions

Jinling Zhang analyzed and interpreted data, and wrote the paper. Siqi Liu and Meng Wu collected, investigated and performed the research. Yihong Cai and Wenyu Shi provided technical support, funding acquisition and resources. All authors read and approved the final paper. All authors reviewed the manuscript.

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Correspondence to Wenyu Shi or Yihong Cai.

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The informed consent of all patients was obtained before the study. The Ethics Committee of the Affiliated Hospital of Nantong University approved this research.

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Zhang, J., Liu, S., Wu, M. et al. Clinical significance and expression of SLC35F6 in bladder urothelial carcinoma. Diagn Pathol 19, 150 (2024). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s13000-024-01582-2

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Keywords

Diagnostic Pathology

ISSN: 1746-1596

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