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Elevated Stanniocalcin-1 Expression in Uveal Melanoma Predicts Poor Patient Prognosis

SHIN-NOSUKE YAMASHITA, YOSHIATSU TANAKA, SHAJEDUL ISLAM, HONOKA KOTAKE, MAKI TANAKA, TAKAO KITAGAWA, KAZUHIRO TOKUDA, DURGA PAUDEL, SARITA GIRI, TOHRU OHTA, FUMIYA HARADA, HIROKI NAGAYASU and YASUHIRO KURAMITSU
Cancer Genomics & Proteomics July 2025, 22 (4) 624-631; DOI: https://doi.org/10.21873/cgp.20526

Abstract

Background/Aim: Uveal melanoma (UVM) is the most prevalent primary intraocular malignancy, accounting for 3-5% of all melanomas. Despite its rarity, particularly in Japan (~2 cases per 100,000 individuals annually), UVM exhibits highly aggressive behavior, with nearly 50% of patients developing distant metastases. Once metastasized, the prognosis remains dismal, with a median survival of only 4-5 months. Identifying prognostic biomarkers and potential therapeutic targets is imperative to improve clinical outcomes. Stanniocalcin-1 (STC-1) is a glycoprotein hormone implicated in calcium and phosphate homeostasis. Recent studies have linked STC-1 overexpression to tumor progression, poor prognosis, and increased metastatic potential in various malignancies. However, the prognostic significance and mechanistic role of STC-1 in UVM remain unexplored.

Materials and Methods: To elucidate the clinical relevance of STC-1 in UVM, we analyzed publicly available transcriptomic datasets using GEPIA2 and UALCAN, assessing STC-1 mRNA expression across disease stages and its correlation with patient survival. In parallel, single-cell RNA sequencing (scRNA-seq) datasets were utilized to identify the cellular sources of STC-1 within the UVM tumor microenvironment and to investigate its association with specific functional cellular states.

Results: STC-1 expression was significantly up-regulated in stage IV UVM tumors compared to stage III (n=4 and 36, respectively). Moreover, elevated STC-1 expression was inversely correlated with overall survival, suggesting its potential role in disease progression. scRNA-seq analysis revealed that STC-1 is expressed by both tumor cells and fibroblasts, indicating a possible cooperative mechanism that may drive tumor progression.

Conclusion: These findings suggest that STC-1 serves as a potential prognostic biomarker in UVM, providing novel insights into its role in tumor biology. Further investigation is warranted to explore its therapeutic implications and mechanistic contributions to UVM progression.

Keywords:

Introduction

Uveal melanoma (UVM), although rare, is the most common primary intraocular malignancy in adults, with an age-adjusted incidence rate of approximately 4.3 new cases per million people in the United States (1). Despite its relative rarity, the prognosis for patients with extraocular spread, recurrence, or metastasis is poor, with median survival times for those diagnosed with distant metastasis reported to be as short as 4 to 5 months (2-7). Currently, there is no effective treatment for metastatic UVM. Somatic mutations in the GNAQ or GNA11 genes are found in 83% of UVM, suggesting that the constitutive activation of these pathways plays a significant role in the development of the disease (8). Gao et al. has reported that a pan-RAF Inhibitor LY3009120 showed a significant concentration-dependent anti-proliferative effect on a UVM cell line in vitro (9). However, therapeutic targeting of these genes has not yielded clinically successful outcomes, and advanced UVM continues to have a dismal prognosis. In contrast, BRCA1-associated protein 1 (BAP1) has emerged as an important prognostic marker in UVM (10), On the other hand, Laliscia et al. reported that Iodine-125 (125I) plaque brachytherapy offers an effective and safe approach for selected cases of UVM (11). Nevertheless, there is a lack of effective clinical biomarkers or targeted therapies for this disease.

Recently, we identified the elevated expression of DDX39, a DEAD-box RNA helicase, as being associated with poor prognosis in patients with UVM (12), underscoring the urgent need for novel biomarkers and therapeutic strategies. One such potential target is Stanniocalcin-1 (STC-1), a secreted glycoprotein hormone involved in calcium and phosphate homeostasis (13). Mammals have two STC homologous genes, STC-1 and STC-2, with STC-1 exhibiting significant sequence and functional conservation across species (14). STC-1 is produced in various tissues and acts primarily as a paracrine or autocrine factor, regulating a range of biological functions (15). Its involvement in cancer progression and clinical prognosis has been reported in multiple cancer types, including colorectal, hepatocellular, breast, and ovarian cancers, among others (16-20). Moreover, STC-1 has been implicated in promoting the progression and metastasis of cancers, with studies showing that its inhibition can suppress tumor growth and metastasis in several models. Xu et al. showed that the overexpression of STC-1 enhances the migration, invasion and proliferation of esophageal squamous cell carcinoma cells (21). Wang et al. reported that knockdown of STC-1 inhibits growth and glycolysis in oral squamous cell carcinoma cells (22). Furthermore, Choi et al. elucidated that microRNA-606 inhibits the growth and metastasis of triple-negative breast cancer by targeting STC-1 (23). However, to date, no reports have assessed the expression level of STC-1 in UVM or explored the relationship between STC-1 expression and the prognosis of patients with this malignancy. Prognostic biomarkers are very important factors in the management of malignant tumors. Zupa et al. recently reported that NRASQ61K/R/L mutant allele frequency may be a prognostic biomarker for melanoma (24). We examined whether STC-1 could be a prognostic biomarker for UVM. In this study, we utilized independent online bioinformatics tools and the TCGA database to investigate the expression and prognostic significance of STC-1 in patients with UVM, aiming to identify its potential as a novel biomarker and therapeutic target.

Materials and Methods

Evaluation of STC-1 expression in tumor tissues from patients with uveal melanoma at different stages. To investigate STC-1 mRNA expression levels in UVM, the gene name “STC1” was queried in The Cancer Genome Atlas (TCGA) database. Using the UALCAN platform (25), we analyzed STC-1 expression across different tumor stages (based on American Joint Committee on Cancer) in patients with UVM. For the evaluation of the significance of differences in the expression levels between tumor subgroups, Welch’s t-test was used. A p-value <0.05 was considered statistically significant in all analyses.

Survival analysis according to STC-1 mRNA expression levels in uveal melanoma tissues. To evaluate the prognostic significance of STC-1 in UVM, survival analysis was conducted using the GEPIA2 platform (26). The gene name “STC1 ” was entered into the GEPIA2 database, and a median cutoff value was applied to generate Kaplan-Meier survival curves for patients with UVM. A p-value <0.05 was considered statistically significant in all analyses.

Single cell RNA sequencing analysis of uveal melanoma and correlation with functional states. To gain deeper insights into STC-1 expression within the TME of UVM, we analyzed publicly available single-cell RNA sequencing (scRNA-seq) datasets (GSE139829) using the Tumor Immunotherapy Gene Expression Resource (TIGER) database (27). This analysis aimed to characterize STC-1 expression patterns across immune and non-immune compartments within the TME, providing a comprehensive understanding of its potential role in tumor progression. In brief, scRNA-seq was performed on human UVM tumors to characterize the TME and subclonal architecture. Fresh tumor tissues from eight primary and three metastatic UVM cases were collected immediately after surgical resection. Single-cell suspensions were processed using the Chromium Single Cell 3′ and 5′ Library and Gel Bead Kit (10× Genomics), and libraries were sequenced on an Illumina NextSeq 500 platform. Data were processed in R (versions 3.5.1 and 3.5.2) using Seurat (v2.3.4), with raw gene-barcode matrices imported via the Read10X() function. Data from all 11 tumor samples were aggregated into a single Seurat object without batch correction. Quality control filtering retained cells with >400 unique molecular identifiers (UMIs), 100-8,000 detected genes, and <10% mitochondrial gene content, resulting in 59,915 high-quality single cells. Data normalization was performed using the “LogNormalize” method with a scale factor of 10,000. Highly variable genes were identified based on a normalized expression range of 0.125-3 and quantile-normalized variance >0.5 (28).

Additionally, scRNA-seq data from six primary UVM tumors (GSE160883) (29) were analyzed using the TISCH2 platform (30) to examine STC-1 expression. Single-cell encapsulation, barcoded bead synthesis, and cDNA library preparation followed a modified in Drops protocol, yielding 17,074 high-quality cells with a median of 1,619 transcripts per cell. Genes detected in fewer than 10 cells or with low expression were excluded, resulting in a dataset of 17,074 cells and 14,642 genes. Gene expression was normalized by dividing each transcript count by the total counts per cell and scaling to the median molecule count across all cells (28).

To further elucidate the potential role of STC-1 in UVM tumorigenesis, we assessed its correlation with defined cellular functional states using multiple single-cell datasets available through the Cancer Single-cell State Atlas (Cancer SEA) (28, 31, 32). Correlation analyses were performed to evaluate associations between STC-1 expression and various functional states, including DNA damage, DNA repair, angiogenesis, and inflammation. Associations were considered statistically significant if they met a threshold of |R| ≥0.3 with a p-value <0.001. For these analyses, raw gene expression matrices were downloaded, and correlation matrices were generated using GraphPad Prism (GraphPad Software, version 10.0.3, Boston, MA, USA).

Results

STC-1 mRNA expression was increased in uveal melanoma tissues from stage IV patients compared with stage III patients. To assess whether STC-1 mRNA expression levels in UVM tissues are stage-dependent, we analyzed the TCGA dataset using the UALCAN platform. Our analysis revealed no significant difference in STC-1 mRNA expression between tumor tissues from stage II and stage III patients. However, STC-1 mRNA expression was significantly elevated in tumor tissues from stage IV patients compared with those from stage III patients (Figure 1; p<1×10−12).

Figure 1.
Figure 1.

Expression of stanniocalcin-1 (STC-1) in uveal melanoma tissues according to individual tumor stages. Box plots were downloaded from UALCAN based on the uveal melanoma dataset from The Cancer Genome Atlas (TCGA). STC-1 expression in uveal melanoma tissues was stage 2 (n=39), stage 3 (n=36), and stage 4 (n=4) according to individual tumor stage. p<0.05 was regarded as statistically significant.

High expression levels of STC-1 are inversely correlated with prolonged survival in patients with uveal melanoma. To evaluate the prognostic significance of STC-1 in UVM, we performed overall and disease-free survival analyses using the GEPIA2 platform (26). Kaplan-Meier survival curves were generated for patients with high and low STC-1 expression in UVM tissues. Patients with higher STC-1 expression exhibited significantly shorter survival times compared to those with lower expression (p=0.018; Figure 2A, B). These findings suggest that STC-1 may serve as a potential prognostic biomarker for UVM, with elevated expression levels indicating a more aggressive disease course.

Figure 2.
Figure 2.

Kaplan–Meier survival plots for uveal melanoma patients with high stanniocalcin-1 (STC-1) levels. (A) Overall survival analysis and (B) disease-free survival analysis based on STC-1 expression were performed by using the Gene Expression Profiling Interactive Analysis 2 (GEPIA2) platform. Overall survival and disease-free survival curves of uveal melanoma (UVM) patients were compared between the high STC-1 expression group (n=39) and the low STC-1 expression group (n=39). p<0.05 was regarded as statistically significant.

STC-1 expression in fibroblasts and tumor cells drive uveal melanoma progression. Single-cell RNA sequencing (scRNA-seq) analysis of UVM revealed that STC-1 is predominantly expressed by tumor cells and cancer-associated fibroblasts (CAFs), with fibroblasts exhibiting significantly higher and more consistent expression levels compared to tumor cells (Figure 3A, B). In contrast, STC-1 expression was undetectable in immune cell populations within the UVM TME, including B cells, myeloid cells, plasma cells, and T lymphocytes (Figure 3A). These findings suggest that STC-1 is primarily derived from stromal and tumor compartments and may contribute to tumor progression via non-immune mechanisms. To independently validate these findings, we interrogated an additional scRNA-seq dataset via the Tumor Immune Single-cell Hub 2 (TISCH2) platform. Consistent with our primary analysis, STC-1 expression was confined to tumor cells, with no expression in immune subsets (Figure 3C, D).

Figure 3.
Figure 3.

Single-cell transcriptomic analysis of stanniocalcin-1 (STC-1) expression across cell populations and functional states in UVM and retinoblastoma. (A) UMAP plot depicting cell clusters based on transcriptional similarity, with each cluster color-coded according to annotated cell types. Fibroblasts and tumor cells are highlighted in yellow and purple, respectively. (B) STC-1 expression levels overlaid on the same UMAP embedding, with cell-type annotations in bold text. Color intensity reflects the magnitude of STC-1 expression, ranging from white (low or absent expression) to dark red (high expression), with a normalized expression scale from −3 to +3. (C) UMAP plot depicting cell clusters based on transcriptional similarity, with each cluster color-coded according to annotated cell types. (D) STC-1 expression levels overlaid on the same UMAP embedding, with cell-type annotations in bold text. (E) STC-1 expression distribution in UVM and in retinoblastoma, along with correlation matrices representing associations between STC-1 expression and various functional cellular states (e.g., DNA damage, DNA repair, angiogenesis, and inflammation). Correlations with p<0.05 were considered statistically significant. Malignant PRAME: tumor cells that express preferentially expressed antigen in melanoma, a cancer-testis antigen often associated with aggressive tumor behavior and poor prognosis; Malignant no PRAME: tumor cells that do not express antigen PRAME; PRE cells: photoreceptor like retinal epithelial cells.

To investigate the potential biological relevance of STC-1 in tumorigenesis, we assessed its correlation with defined functional states using the Cancer Single-cell State Atlas (Cancer SEA). In UVM, STC-1 expression demonstrated a significant negative correlation with DNA damage (p<0.001) and DNA repair pathways (p<0.001) (Figure 3E). To validate these findings across tumor types, we analyzed single-cell data from retinoblastoma samples. Consistent with UVM, STC-1 expression in retinoblastoma was also negatively correlated with DNA damage (p<0.001) and DNA repair (p<0.001) (Figure 3E). Moreover, in retinoblastoma, STC-1 exhibited strong positive correlations with tumor angiogenesis (p <0.001) and tumor-associated inflammation (p<0.001) (Figure 3E). Collectively, these data indicate that STC-1 may contribute to tumorigenesis through multiple mechanisms, including suppression of DNA damage response pathways and promotion of angiogenic and inflammatory processes. While its involvement in DNA damage and repair appears prominent in UVM, alternative mechanisms may also play a context-dependent role in other tumor types. Further functional studies are warranted to delineate the mechanistic basis of STC-1–mediated tumor-promoting activities.

Discussion

In this study, we analyzed STC-1 mRNA expression and Kaplan-Meier survival in patients with UVM by using the bioinformatics platforms GEPIA2 and UALCAN. Results showed that STC-1 mRNA expression levels were significantly increased in UVM tissues from stage IV patients compared to stage III patients with UVM. Furthermore, increased expression of STC-1 was found to be inversely correlated with prolonged overall and disease-free survival in patients with UVM.

Given the significantly higher STC-1 expression in advanced-stage UVM, we explored existing literature to assess whether STC-1 up-regulation is a common feature across malignancies. Previous studies have reported that STC-1 mRNA is highly expressed in multiple cancer types, including endometrioid endometrial cancer, esophageal squamous cell carcinoma, colorectal cancer, hepatocellular carcinoma, papillary thyroid cancer, and glioblastoma multiforme, compared to normal tissues (16, 33-36).

Furthermore, we checked the UALCAN platform to examine STC-1 expression between cancer and normal tissues across various cancer types. Our analysis revealed that STC-1 expression was significantly elevated in tumor tissues compared to normal tissues in patients with adrenocortical carcinoma, colon adenocarcinoma, head and neck squamous cell carcinoma, hepatocellular carcinoma, rectum adenocarcinoma, skin cutaneous melanoma (primary vs. metastatic), and gastric cancer. In contrast, STC-1 expression was significantly reduced in cancer tissues from kidney chromophobe, renal papillary cell carcinoma, and thyroid carcinoma. This suggests that STC-1 expression is increased in most types of cancer tissues, although the opposite is true in a few types of cancer tissues. Notably, elevated STC-1 expression in cancer tissues was associated with significantly shorter survival in only two cancer types: UVM and glioblastoma multiforme. This suggests that STC-1 may have a specific role in the progression of these cancers. For instance, Xiong et al. demonstrated that STC-1 regulates migration and invasion of glioblastoma cells via the TGF-β/SMAD4 signaling pathway, thereby promoting glioblastoma malignancy (36). Similarly, Huang et al. reported that macrophage-capping protein enhances breast cancer metastasis by promoting STC-1 transcription through competition with arginine methyltransferase 5 for binding to the STC-1 promoter (37). These findings suggest that STC-1 might exert unique effects on tumor cells in UVM and glioblastoma multiforme, possibly contributing to their aggressive behaviors.

The results of scRNA-seq analysis revealed that STC-1 expression was much higher in fibroblasts than in tumor cells in the UVM TME. Since STC-1 is a secreted glycoprotein hormone, STC-1 secreted from fibroblasts may transmit malignant signals to tumor cells via the paracrine system. Since STC-1 has been reported to enhance cell motility via activation of PI3K/Akt (38), it is suggested that the signal transmitted from STC-1 secreted from fibroblasts to tumor cells may be related to the PI3K/Akt pathway. Such activation of the PI3K/Akt pathway by STC-1 signaling may promote angiogenesis and inflammation and inhibit DNA damage and repair, thereby promoting the malignant transformation of UVM.

Taken together, these results suggest that STC-1 may play a pivotal role in promoting the migration and invasion of UVM cells, enhancing metastasis to distant organs, and contributing to poor prognosis. Future research should focus on elucidating the underlying mechanisms by which STC-1 drives these aggressive behaviors in UVM, which could open new avenues for targeted therapeutic strategies to improve patient outcomes.

Footnotes

  • Authors’ Contributions

    All Authors contributed to the conception and design of the study. Data collection and analysis were performed by Shin-nosuke Yamashita, Yoshiatsu Tanaka, Shajedul Islam and Yasuhiro Kuramitsu. Shin-nosuke Yamashita and Yoshiatsu Tanaka wrote the first draft of the manuscript, Takao Kitagawa and Yasuhiro Kuramitsu commented on an earlier version of the manuscript. All Authors read and approved the final manuscript.

  • Conflicts of Interest

    The Authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

  • Received April 15, 2025.
  • Revision received May 4, 2025.
  • Accepted May 5, 2025.

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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Elevated Stanniocalcin-1 Expression in Uveal Melanoma Predicts Poor Patient Prognosis
SHIN-NOSUKE YAMASHITA, YOSHIATSU TANAKA, SHAJEDUL ISLAM, HONOKA KOTAKE, MAKI TANAKA, TAKAO KITAGAWA, KAZUHIRO TOKUDA, DURGA PAUDEL, SARITA GIRI, TOHRU OHTA, FUMIYA HARADA, HIROKI NAGAYASU, YASUHIRO KURAMITSU
Cancer Genomics & Proteomics Jul 2025, 22 (4) 624-631; DOI: 10.21873/cgp.20526
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