Research ArticleArticles
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Pan-cancer Analysis Reveals Cancer-dependent Expression of SOX17 and Associated Clinical Outcomes

LI XU, YOUHUANG BAI, YIHANG CHENG, XIUJIE SHENG and DEQIANG SUN
Cancer Genomics & Proteomics September 2023, 20 (5) 433-447; DOI: https://doi.org/10.21873/cgp.20395

Abstract

Background/Aim: SRY-box containing gene 17 (SOX17) plays a pivotal role in cancer onset and progression and is considered a potential target for cancer diagnosis and treatment. However, the expression pattern of SOX17 in cancer and its clinical relevance remains unknown. Here, we explored the relationship between the expression of SOX17 and drug response by examining SOX17 expression patterns across multiple cancer types. Materials and Methods: Single-cell and bulk RNA-seq analyses were used to explore the expression profile of SOX17. Analysis results were verified with qPCR and immunohistochemistry. Survival, drug response, and co-expression analyses were performed to illustrate its correlation with clinical outcomes. Results: The results revealed that abnormal expression of SOX17 is highly heterogenous across multiple cancer types, indicating that SOX17 manifests as a cancer type-dependent feature. Furthermore, the expression pattern of SOX17 is also associated with cancer prognosis in certain cancer types. Strong SOX17 expression correlates with the potency of small molecule drugs that affect PI3K/mTOR signaling. FGF18, a gene highly relevant to SOX17, is involved in the PI3K-AKT signaling pathway. Single-cell RNA-seq analysis demonstrated that SOX17 is mainly expressed in endothelial cells and barely expressed in other cells but spreads to other cell types during the development of ovarian cancer. Conclusion: Our study revealed the expression pattern of SOX17 in pan-cancer through bulk and single-cell RNA-seq analyses and determined that SOX17 is related to the diagnosis, staging, and prognosis of some tumors. These findings have clinical implications and may help identify mechanistic pathways amenable to pharmacological interventions.

Key Words:

SRY-box containing gene (SOX17), a well-known member of the SOX transcription factor family, performs a wide range of complex functions in various physiological and pathological processes (1). SOX17 is an important antagonist of the canonical Wnt/β-catenin signaling pathway in several types of malignant tumors (2), and plays an essential role in embryonic development, regulation of postnatal vascular development (3) and human primordial germ cell fate (4), generation and maintenance of hematopoietic stem cells (5), and in the onset and metastasis of cancer (6).

A decrease in SOX17 expression has been documented in a variety of cancers, except in ovarian and endometrial cancers, and it is frequently associated with cancer development, metastasis, and poor prognosis, particularly in lung cancer (7-9), breast cancer (10-12), colorectal cancer (13), cervical cancer (14,15), liver cancer (16), gastric cancer (17), glioma (18), and melanoma (19). Bioinformatics analyses predicted that SOX17 is involved in the development of ovarian cancer and could be a novel target for anti-cancer therapies (20). However, our understanding of the relationship between the expression patterns of SOX17 in cancer and the associated clinical outcomes is inadequate.

In the present study, we evaluated the expression and distribution of SOX17 in 19,131 tumor and normal tissue samples accessed using the Cancer Genome Atlas (TCGA), Genotype-Tissue Expression Project (GTEx), and Therapeutically Applicable Research to Generate Effective Treatments (TARGET) databases. The correlation between SOX17 expression and clinical features or overall survival (OS) in the TCGA database and the expression level of SOX17 in the Cancer Cell Line Encyclopedia (CCLE) database were subsequently investigated. Single-cell RNA-seq analysis was performed to explore the expression profile of SOX17 at single-cell resolution. In addition, drug response and co-expression analyses of SOX17 expression in 1019 cell lines were performed. These data are clinically relevant for future cancer interventions.

Materials and Methods

Expression of SOX17 in normal tissues. The mRNA expression data of 7,862 samples from 29 normal tissue types were downloaded from the official website of the GTEx project (21), and the distribution of SOX17 expression was examined.

Expression and clinical relevance of SOX17 in primary tumors. The gene expression profiles based on RNA-seq of 19,131 samples from TCGA, GTEx, and TARGET databases were accessed using Xena (https://xenabrowser.net/) (22). The SOX17 mRNA expression data for 35 cancer types and their normal samples was extracted, including adrenocortical carcinoma (ACC), cholangiocarcinoma (CHOL), lymphoid neoplasm diffuse large B-cell lymphoma (DLBC), kidney renal clear cell carcinoma (KIRC), acute myeloid leukemia (LAML), brain lower grade glioma (LGG), liver hepatocellular carcinoma (LIHC), ovarian serous cystadenocarcinoma (OV), pancreatic adenocarcinoma (PAAD), pheochromocytoma and paraganglioma(PCPG), sarcoma (SARC), thymoma (THYM), testicular germ cell tumors (TGCT), uterine corpus endometrial carcinoma (UCEC), uterine carcinosarcoma (UCS), bladder urothelial carcinoma (BLCA), breast invasive carcinoma (BRCA), cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), colon adenocarcinoma (COAD), esophageal carcinoma (ESCA), glioblastoma multiforme (GBM), head and neck squamous cell carcinoma (HNSC), kidney chromophobe (KICH), kidney renal papillary cell carcinoma (KIRP), lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC), prostate adenocarcinoma (PRAD), stomach adenocarcinoma (STAD), rectum adenocarcinoma (READ), skin cutaneous melanoma (SKCM) and thyroid carcinoma (THCA), mesothelioma (MESO), stomach and esophageal carcinoma (STES), acute lymphoblastic leukemia (ALL), and acute myeloid leukemia (LAML). A t test was performed to assess significant differences between SOX17 expression in cancer tissue and the corresponding normal tissue. The clinical characteristics of SOX17 were analyzed using Gene Expression Profiling Interactive Analysis (GEPIA, http://gepia.cancer-pku.cn/) (23). Kruskal’s test was performed to assess the correlation between SOX17 mRNA expression and clinical stage in 33 tumor types, with ALL and LAML datasets being excluded due to incomplete data. Subsequently, we evaluated the correlation between SOX17 expression and OS in all tissues. The cutoff-high and cutoff-low in the OS analysis was 50%. A p <0.05 was considered significant.

Expression of SOX17 in tumor cell lines. The mRNA expression data for 1225 tumor cell lines and the DNA methylation data for 712 tumor cell lines and 23 tumor types were retrieved from the CCLE database (https://sites.broadinstitute.org/ccle/) (24).

Cell culture and qPCR. The ovarian epithelial cell line IOSE-80 and ovarian cancer cell line A2780 were purchased from GENOM. Both cell lines were cultured in DMEM (ThermoFisher, Waltham, MA, USA) supplemented with 10% FBS (BioInd, Kibbutz Beit-Haemek, Israel) and 1% penicillin-streptomycin (ThermoFisher). The endometrial cancer cell line RL95-2 and normal cell line CTCC-008-0014 were purchased from Procell Life Science & Technology Co., Ltd. (Wuhan, PR China) and Meisen Cell (Zhejiang, PR China), respectively. RL95-2 cells were cultured in DMEM/F12 (Procell) with 10% FBS, 5 μg/ml insulin, and 1% penicillin-streptomycin. CTCC-008-0014 cells were cultured in DMEM/F12 (Meisen, Zhejiang, PR China) supplemented with 10% FBS, 10 μg/ml insulin, 1% penicillin-streptomycin, and 5ng/ml EGF. To determine gene expression, total RNA was extracted using the Cell/Tissue total RNA isolation kit (Vazyme, Nanjing, PR China) and quantified using a NanoDrop spectrophotometer (ThermoFisher). RNA was reverse-transcribed to cDNA using the all-in-one RNA SuperMix Perfect for quantitative real-time PCR (qPCR, Vazyme) with an oligo dT21 primer. For gene expression analysis, qPCR was performed using the Universal SYBR qPCR Master Mix (Vazyme) on a LightCycler® 480 real-time PCR System (Roche, Shanghai, PR China). The primers used are listed in Supplementary Table I.

Expression pattern of SOX17 in single cells. Single-cell RNA-seq data for lung cancer (LC), ovarian cancer (OVC), and colorectal cancer (CRC) were downloaded from the VIB.be website (http://blueprint.lambrechtslab.org) (25). Gene expression data from eight patients with LC, five patients with OVC, and seven patients with CRC were obtained. The count matrices for each sample were processed using Seurat with default parameters (26). We filtered cells that had >25% mitochondrial counts, which represent low-quality or dying cells, using the PercentageFeatureSet and Subset functions. The filtered data were scaled and processed by principal component analysis (PCA) using the ScaleData and RunPCA functions in Seurat. Two-dimensional map coordinates were generated using RunUMAP. Cluster analysis was performed using FindNeighbours and FindClusters functions at appropriate resolutions. The expression level of SOX17 in different clusters was extracted and displayed using the Feature plot function.

Correlation of SOX17 expression and drug response. Drug response data were retrieved from The Genomics of Drug Sensitivity in Cancer (https://www.cancerrxgene.org/) (27) with response profiles for 265 drugs in ~1019 cell lines with RNA-seq expression data. Pearson’s correlation coefficient was used to assess the association between SOX17 and drug responses in cell lines.

Co-expression analysis of SOX17 in tumor cells. Co-expression analysis was used to screen SOX17 co-expression genes in 1,019 tumor cells (|Pearson correlation coefficient|>0.4 and p<0.05). Subsequently, Cytoscape v3.71 (28) was used to visualize the connections between SOX17 co-expressed genes. The TRANSFAC database (version 7.4) was used to predict miRNA or co-expressed transcription factor genes (29).

Results

SOX17 mRNA expression level in tumor and normal tissues. The expression pattern of SOX17 mRNA was first evaluated in 29 different normal tissue types using data retrieved from the GTEx database. The anatogram images (Figure 1a and 1b) and violin plot (Figure 1c) indicate that SOX17 mRNA expression levels are heterogenous and tissue-specific in normal tissue samples. SOX17 mRNA is most highly expressed in adipose, fallopian tube, nerve, and breast tissue, followed by bladder, cervix uteri, lung, spleen, and uterine tissue.

Figure 1.
Figure 1.

Expression of SOX17 mRNA in normal and tumor tissue retrieved from the GTEX, TCGA, and TARGET databases. (a, b) Anatogram image shows the expression of SOX17 mRNA in different organs. (c) Violin plot showing the expression and distribution of SOX17 mRNA in 29 normal tissue types. (d, e) Boxplot showing the expression of SOX17 mRNA in 35 tumor and paired normal tissue types, marked red and blue, respectively. Asterisks (*) indicate the statistical significance of gene expression between cancer and normal tissue: ns: non-significant, *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001. The y-axis signifies the log2 mRNA expression of SOX17. GTEX: Genotype-Tissue Expression Project; TCGA: Cancer Genome Atlas; TARGET: Therapeutically Applicable Research to Generate Effective Treatments; ACC: adrenocortical carcinoma; BLCA: bladder urothelial carcinoma; BRCA: breast invasive carcinoma; CESC: cervical squamous cell carcinoma and endocervical adenocarcinoma; CHOL: cholangio-carcinoma; COAD: colon adenocarcinoma; DLBC: lymphoid neoplasm diffuse large B-cell lymphoma; ESCA: esophageal carcinoma; GBM: glioblastoma multiforme; HNSC: head and neck squamous cell carcinoma; KICH: kidney chromophobe; KIRC: kidney renal clear cell carcinoma; KIRP: kidney renal papillary cell carcinoma; LGG: brain lower grade glioma; LIHC: liver hepatocellular carcinoma; LUAD: lung adenocarcinoma; LUSC: lung squamous cell carcinoma; MESO: mesothelioma; OV: ovarian serous cystadenocarcinoma; PAAD: pancreatic adenocarcinoma; PCPG: pheochromocytoma and paraganglioma; PRAD: prostate adenocarcinoma; READ: rectum adenocarcinoma; SARC: sarcoma; SKCM: skin cutaneous melanoma; STAD: stomach adenocarcinoma; STES: stomach and esophageal carcinoma; TGCT: testicular germ cell tumors; THCA: thyroid carcinoma; THYM: thymoma; UCEC: uterine corpus endometrial carcinoma; UCS: uterine carcinosarcoma; UVM: ocular melanomas; ALL: acute lymphoblastic leukemia; LAML: acute myeloid leukemia.

Next, the expression of SOX17 mRNA was further analyzed in tumor tissue using data from the TCGA, GTEx, and TARGET databases, including 35 tumor types and 31 paired normal tissue samples. Previous studies have demonstrated that SOX17 expression is down-regulated in most types of human cancer, and it appears to act as a tumor suppressor. Consistent with these observations, our study also showed that the median expression of SOX17 mRNA is significantly down-regulated in 13 cancer types compared with that in matched normal tissue samples: ESCA, p=5.49×10−44; BRCA, p=2.31×10−135; KICH, p=4.26×10−12; UVM, p=6.69×10−5; LUAD, p=3.47×10−178; BLCA, p=2.83×10−13; LUSC, p=3.30×10−36; COAD, p=5.99×10−66; SKCM, p=2.74×10−206; KIRP, p=8.23×10−13. In contrast, SOX17 was over-expressed in OV (p=3.44×10−59), UCEC (p=5.85×10−19), TGCT (p=1.80×10−20), PAAD (p=1.03×10−16), and LIHC (p=9.27×10−12) compared with that in matched normal tissue samples (Figure 1d). Moreover, the expression levels of SOX17 in UCEC and OV were significantly higher than those in other tumor types. Thus, the expression of SOX17 could be associated with the progression of OV, UCEC, TGCT, and LIHC. In addition to solid tumors, log2(TPM+0.001) in ALL and LAML ranged from −9.9658 to −1.7322, and the expression level of SOX17 was extremely low, even undetectable in most of the samples. However, in ALL, SOX17 expression was significantly higher in the tumor samples than in the normal tissue samples (Figure 1e).

SOX17 expression level correlates with clinical cancer outcomes. SOX17 is involved in cancer metastasis. Therefore, the correlation between SOX17 expression and tumor staging was analyzed using 10,237 RNA-seq and 11,167 clinical features. The mRNA expression of SOX17 varied significantly during progression in six tumor types, including UCEC (p=1.835×10−8), BRCA (p=0.0002), KIRC (p=0.0007), SKCM (p=0.003), STAD (p=0.01), and THCA (p=0.05) (Figure 2a, b, and Figure S1). For example, SOX17 expression gradually decreased during the different stages of UCEC, which suggests that SOX17 may act as a tumor suppressor gene during UCEC progression (Figure 2a). The expression of SOX17 was more significantly related to tumor stages in UCEC, BRCA, and KIRC compared with that in other cancers (Figure S1). In STAD, the expression of SOX17 is lower at stage I than in the other stages (Figure 2b). These data indicate that SOX17 displays distinct expression patterns during different stages of several different cancer types.

Figure 2.
Figure 2.

Box plots showing significant differences in the expression and staging of SOX17 mRNA in UCEC and STAD tissue. The expression levels of SOX17 in (a) UCEC (p=1.835×10−8) and (b) STAD (p=0.01) was significantly different at different cancer stages. N represents the number of samples. UCEC: Uterine corpus endometrial carcinoma; STAD: stomach adenocarcinoma.

We next determined the association between SOX17 expression and OS for each cancer type. As shown in Figure 3a-f, the expression level of SOX17 was significantly associated with the OS rate of KIRC, UVM, MESO, STAD, LUSC, PAAD, and READ. Patients with KIRC and PAAD with higher expression levels of SOX17 exhibited promising OS rates, suggesting that higher expression of SOX17 is a potentially useful prognostic marker for these tumors. In contrast, for UVM, MESO, STAD and LUSC, higher expression levels of SOX17 were significantly associated with poor OS. SOX17, therefore, has potential cancer-specific prognostic applications.

Figure 3.
Figure 3.

Overall survival (OS) curves demonstrating the correlation between the mRNA expression of SOX17 in different tumor types and patient OS. Curves were generated by performing KM survival analysis of samples with high and low expression levels of SOX17 in (a) KIRC, p=7×10−4, (b) UVM, p=0.00029, (c) MESO, p=0.00055, (d) STAD, p=0.016, (e) LUSC, p=0.031, (f) PAAD, p=0.035, and (g) READ, p=0.04. KIRC: Kidney renal clear cell carcinoma; UVM: ocular melanomas; MESO: mesothelioma; STAD: stomach adenocarcinoma; LUSC: lung squamous cell carcinoma; PAAD: pancreatic adenocarcinoma; READ: rectum adenocarcinoma.

SOX17 expression is regulated by DNA methylation in tumor cell lines. A key step in achieving accurate detection of differential SOX17 expression in cancer is the comparison of sequencing data from a tumor sample to its paired normal control. The sensitivity is greatly reduced when the tumor sample is contaminated with matched normal tissue. To overcome this limitation, 1,183 tumor cell lines reflecting 23 cancer types from the CCLE database were used to analyze the expression and methylation of SOX17 in tumor cell lines. According to the RNA-seq and Reduced Representation Bisulfite Sequencing (RRBS) data in CCLE, the mRNA expression levels of SOX17 in ovarian and endometrial/uterine cancer cells were much higher than in other cancer cells (Figure 4), which was consistent with our findings in tumor tissue. Conversely, the methylation level of the promoter (1kb upstream of the TSS) of SOX17 in the ovarian cancer cell lines was the lowest, and the methylation ratio in endometrial/uterine cancer cells was marginally higher than that of ovarian cancer. In addition, the expression levels of SOX17 in pancreatic, lymphoma, head, and neck, esophageal, and bile duct cancer lines were extremely low, but their methylation ratios were high. Therefore, we conclude that the expression level of SOX17 in cancer is negatively correlated with the DNA methylation level in the promoter region. This suggests that abnormal DNA methylation plays a fundamental role in regulating the expression of oncogenes or tumor suppressor genes.

Figure 4.
Figure 4.

mRNA expression and DNA methylation profile of SOX17 in tumor cell lines. Box plots showing the distribution of SOX17 expression in 23 cancer cell lines, with the methylation ratio of SOX17 at 1kb upstream of the TSS and log2 (TPM+1), indicated in red and blue, respectively. TSS: Transcription start site; TPM: transcripts per million.

To determine whether the expression level of SOX17 in ovarian cancer is higher than in normal cells, we performed quantitative PCR (qPCR) analysis on A2780 versus IOSE-80 cell lines (Figure 5a) and RL95-2 versus CTCC-008-0014 cell lines (Figure 5c). One microgram of total RNA from each cell line was used for reverse transcription, followed by the quantification of the expression level of SOX17 relative to GAPDH. The relative expression level of SOX17 was significantly higher in ovarian cancer line A2780 (p=0.0175) and endometrial cancer cell line RL95-2 (p=0.0015), compared to the ‘normal’ cell lines IOSE-80 and CTCC-008-0014. Immunohistochemistry analysis showed that SOX17 was expressed at higher levels in OV (Figure 5b) and UCEC (Figure 5d) tissue than in normal tissue in the Human Protein Atlas, verifying the qPCR results. These data are consistent with those collected from cancer tissue. We, therefore, conclude that the expression level of SOX17 affects the development of ovarian and endometrial cancer, and we speculate that this also occurs in TGCT and LIHC.

Figure 5.
Figure 5.

The mRNA expression pattern of SOX17 in OV and UCEC. Real-time PCR analysis of SOX17 (a) in the ovarian cancer cell line A2780 (gray bar) versus normal ovary cell line IOSE-80 (black bar) and (b) in the UCEC cell line RL95-2 (gray bar) versus normal endometrial cell line CTCC-008-0014 (black bar). The expression is relative to GAPDH, *p<0.05, **p<0.01. (c, d) Immunohistochemistry analysis of SOX17 expression in OV and UCEC tissue (right) compared with that in normal tissue (left) in the Human Protein Atlas (antibody HPA068399). PCR: Polymerase chain reaction; OV: ovarian serous cystadenocarcinoma; UCEC: uterine corpus endometrial carcinoma.

Single-cell RNA-seq analysis of SOX17 expression. To further investigate the expression profile of SOX17 in cancer, we performed single-cell RNA-seq analysis for LC, CRC, and OVC. Single-cell data of 131,404 tumor-origin cells and 51,969 paired normal-origin cells were obtained, including LC scRNA-seq data from 66,309 cells originating from malignant tissue and 27,266 cells originating from non-malignant tissue, CRC scRNA-seq data from 30,626 tumor-origin cells and 14,058 normal-origin cells, and OVC scRNA-seq data from 34,469 tumor-origin cells and 10,645 normal-origin cells (Figure 6f).

Figure 6.
Figure 6.

Cell typing in different cancers. (a-c) UMAP representation of LC (93,575 cells), CRC (44,684 cells), and OVC (45,115 cells). The figures are color-coded for cell type and sample origin separately. (d) Bar plots representing the percentage of cells per cancer type. (e) Bar plots representing the cell fraction per tissue origin. (f) Bar plots representing the cell amount originating from different cancer types and matched normal tissue. UMAP: Uniform manifold approximation and projection; LC: lung cancer; CRC: colorectal cancer; OVC: ovarian cancer.

To perform cell typing of tumor and normal tissue, we clustered cells from each cancer type separately, generated UMAP plots with the appropriate resolution, and assigned cell types using the standard procedure of Seurat. LC-originating cells were clustered into 11 cell types, including cancer cells, alveolar cells, B cells, endothelial cells, epithelial cells, and fibroblasts (Figure 6a), while CRC-originating cells were clustered into nine cell types, including endothelial, cancer, and epithelial cells (Figure 6b). OVC-originating cells were clustered into six cell types, including cancer cells, T cells, B cells, fibroblasts, endothelial cells, and myeloid cells (Figure 6c). Cells were clustered based on cell types, enabling the assessment of the contribution of different cancer and tumor types compared to normal tissue to each cell type (Figure 6d and e). We observed that B cells, T cells, fibroblasts, endothelial cells, and myeloid cells frequently existed across different cancer types.

To determine the specific cell types expressing SOX17, we analyzed the RNA expression profile of SOX17 at single-cell resolution in different tissues. UMAP plots revealed that SOX17 is primarily enriched in one cluster corresponding to endothelial cells in LC and CRC tissue (Figure S2a). Violin plots further demonstrated that SOX17 was expressed at higher levels in endothelial cells than in other cell types (B cells, T cells, and myeloid cells) in LC and CRC (Figure S2b). In the present study, the expression pattern of SOX17 in OVC was distinct from that in LC and CRC. SOX17 is mainly expressed in cancer, endothelial, fibroblast, and myeloid cells and is expressed at very low levels in B and T cells.

To further compare the characteristics of SOX17 expression in normal tissue with those in tumor tissue at single-cell resolution, we classified the single-cell RNA transcript data into normal and tumor groups. UMAP plots (Figure 7a-d) reveal higher expression levels of SOX17 in normal lung and colorectal tissue than those in the corresponding tumor tissue. For OVC, the expression level of SOX17 was notably higher in the tumor tissue than in normal tissue (Figure 7e and f), which is consistent with our previous mRNA expression analysis results. Similar to normal lung and colorectal tissue, SOX17 is mainly expressed in endothelial cells in normal ovarian tissue. However, in ovarian cancer tissue, the expression level of SOX17 is higher in cancer cells, fibroblasts, myeloid cells, and T cells. In conclusion, SOX17 is specifically expressed in endothelial cells in normal organs (e.g., lung, colorectum, and ovary), and the expression level of SOX17 decreases with the development of LC and CRC. In contrast, the expression of SOX17 is not limited to endothelial cells and extends to other cell types (mainly in cancer cells) in OVC tissue. Therefore, SOX17 could play a significant role in the development of OVC and is a potential diagnostic marker for ovarian cancer.

Figure 7.
Figure 7.

Expression patterns of SOX17 in different cell types. (a, c, e) UMAP plots color-coded for different cell types in LC, CRC, and OVC. (b) Per-cell expression level of SOX17 in LC and paired normal samples visualized as a UMAP plot. (d) UMAP plot representing SOX17 expression level per cell in CRC and paired normal samples. (f) UMAP plot representing SOX17 expression pattern per cell in OVC and paired normal samples. UMAP: Uniform manifold approximation and projection; LC: lung cancer; CRC: colorectal cancer; OVC: ovarian cancer.

Drug response and co-expression analysis of SOX17. To determine associations between drug response and SOX17 gene expression, we analyzed the correlation between SOX17 expression and 265 drug responses in 1,019 cell lines and found that the response to nine drugs was significantly correlated with high expression levels of SOX17. Among these, the correlation of eight drugs was greater than or equal to 0.1 (Figure 8a and Table I). The most relevant drugs are aminoimidazole-4-carboxamide ribonucleotide (AICA ribonucleotide) and 17-AAG (Cor=0.12, p=0.0005). AICA ribonucleotide is an adenosine monophosphate-activated protein kinase (AMPK) activator and a purine nucleoside with a wide range of metabolic effects, including the activation of AMPK and the inhibition of angiogenesis and inflammation by suppressing mTOR phosphorylation (30). Notably, the two negatively correlated drugs ZSTK474 (Cor=−0.08, p=0.015) and MK-2206 (Cor=−0.10, p=0.007) target the PI3K/mTOR signaling pathway. ZSTK474 targets PI3K, suggesting that SOX17 may be involved in PI3K/mTOR signaling.

Figure 8.
Figure 8.

Drug response and co-expression analysis of SOX17. (a) The volcano map shows the most significant associations between SOX17 expression and drug response. Each dot represents Pearson’s correlation coefficient and −log10(p-Value). The red and blue dots represent significant positive and negative correlations, respectively, with p<0.05. (b) The network diagram shows the regulation of the co-expressed genes and transcription factors of SOX17. Red, yellow, and blue circles represent correlation coefficients of >0.6, 0.5, and 0.4, respectively. The purple circle represents upstream transcription factor regulation.

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Table I.

Correlation between high SOX17 expression and drug response in cell lines.

To further explore the novel molecular mechanisms by which SOX17 affects tumorigenesis, a co-expression analysis was performed. We found 14 co-expressed genes in 1,019 tumor cells (Figure 8b and Table II): C1orf186, PAX8, RP11-65I12.1, WNT7A, CLDN16, SLC34A2, FGF18, DCDC2, COL26A1, EMX2, SPON1, BASP1P1, NUS1P2 and MEOX1, which were positively correlated with SOX17. TRANSFAC motif analysis showed that SOX17, EMX2, DCDC2, CLDN16, MEOX1, and WNT7A belong to the same transcription factor group MAZ_Q6, which includes genes with the 3′UTR containing the motif GGGGAGGG, which matches the annotation for MAZ (MYC-associated zinc finger protein, a purine-binding transcription factor). In these co-expressed genes, WNT7A and SOX17 were enriched in the WNT signaling pathway, which is consistent with a previous study (32). Additionally, the SOX17 expression pattern was correlated (Pearson’s correlation, r=0.664) with the expression of FGF18, which enhances migration and epithelial-mesenchymal transition in breast cancer by regulating the AKT/GSK3β/β-catenin signaling pathway (33).

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Table II.

Co-expressed genes associated with SOX17 with a correlation coefficient ≥0.4 in tumor cells.

Discussion

SOX17 is involved in the tumorigenesis, metastasis, and prognosis of tumors by regulating the Wnt/β-catenin signaling pathway and is therefore a potential biomarker or therapeutic target. However, most previous studies have reported limited and even controversial clinical relevance for SOX17, possibly due to insufficient sample size and cohort design. The expression, clinical significance, and molecular mechanisms of SOX17 in different tumor types have not been adequately investigated. Therefore, it is imperative to investigate the expression pattern and signaling pathways of SOX17 and determine its relevance to clinical outcomes.

In the present study, we performed an in-depth analysis of SOX17 expression in 29 normal tissue types, 33 tumor tissue types, and more than 1000 tumor cell lines. In addition to the relative expression of SOX17 in different tissues or cells, we also evaluated the association between SOX17 expression and clinical stage, OS, and drug response. SOX17 is highly expressed in adipose, nerve, and breast tissues. Furthermore, based on the analysis of bulk RNA-seq data, SOX17 mRNA expression is lower in most cancer tissues but is significantly higher in UCEC and OV tissues than in other cancer tissues and matched normal tissues. The difference in SOX17 mRNA expression between OV tissue and normal ovaries was the most significant, suggesting that SOX17 may be a candidate master transcription factor driving ovarian cancer development. The expression level of SOX17 had a statistically significant correlation with the staging of six cancers (UCEC, BRCA, KIRC, SKCM, STAD, and THCA). In particular, the expression level of SOX17 gradually decreased during UCEC staging. The correlation between SOX17 expression and survival was statistically significant in patients with the following seven cancer types: KIRC, UVM, MESO, STAD, LUSC, PAAD, and READ, suggesting that SOX17 expression may be an essential prognostic factor for these seven cancer types. A previous study found that inhibition of the Wnt pathway may lead to the development of cisplatin resistance in ovarian cancer (31). As an antagonist of the Wnt pathway, SOX17 may be involved in platinum drug resistance in ovarian cancer.

Epigenetic alterations (such as promoter DNA methylation) of SOX17 in LC (32), breast cancer (33), cervical cancer (34), and hepatocellular carcinoma (35) may contribute to the aberrant activation of the Wnt/β-catenin signaling pathway. In esophageal squamous cell carcinoma, the promoter DNA hypermethylation of SOX17 contributes to the SOX17low/NRF2high signature which is significantly correlated with poor concomitant chemo-radiation therapy and poor survival (36). In the present study, the expression level of SOX17 was negatively associated with DNA methylation in the promoter region, especially in ovarian cancer, endometrial cancer, and gallbladder carcinoma.

Through the analysis of single-cell RNA-seq data, we verified the expression level of SOX17 in different cancer cells and determined that SOX17 expression is cell-specific in normal tissues and some cancer tissues. Variations in SOX17 expression level have previously been implicated in the onset and development of cancer. These results coincide with those of a previous study, which found that SOX17 expression in the lungs is restricted to the endothelial cells of the developing pulmonary vasculature and that SOX17 plays a key role in the normal formation of the pulmonary vasculature and postnatal cardiovascular homeostasis (37). In CHOL, SOX17 overexpression reduces tumorigenic capacity; inhibits migration, anchorage-independent growth and Wnt/β-catenin-dependent proliferation; and also restores the expression of biliary markers and primary cilium length (38). In cervical cancer, SOX17 trans-suppresses β-catenin expression by directly binding to the specific region of the β-catenin promoter, which down-regulates the Wnt/β-catenin signaling pathway, ultimately leading to reduced proliferation and tumor formation (39). In colorectal cancer, SOX17 binds to the promoter of the miR-302b gene and subsequently enhances miR-302b-3p expression, and the SOX17-miR-302b-3p axis positively regulates the invasion and apoptosis of colorectal cancer cells (40). In high-grade glioma, SOX17 promotes tumor growth via vessel abnormalization, and its level determines the therapeutic outcomes of VEGFR2 inhibition. High SOX17 levels are correlated with poor survival, early recurrence, and impaired vascular function (41). In ovarian cancer, PAX8 and SOX17 promote the secretion of angiogenic factors by suppressing the expression of SERPINE1, which encodes a proteinase inhibitor with anti-angiogenic effects (42), and the genetic disruption of SOX17 or PAX8 analogously inhibits neoplastic cell viability and down-regulates a spectrum of lineage-related transcripts (43). Additionally, PAX8, MECOM, and SOX17 are identified as master transcription factors in high-grade serous ovarian carcinomas (HGSOC), and the maintenance of their expression contributes to the HGSOC cell viability (44). In LC, up-regulated SOX17 drives the gene expression program facilitating metastasis of LAUD (45). Based on the available data, we conclude that SOX17 may act as a tumor suppressor in some cancers, whereas it may be oncogenic in others, owing to its diverse binding with different interacting partners. In the present study, we further explored the cell types in which SOX17 expression levels change and revealed that the variation in SOX17 expression levels in OVC can be attributed to a dramatic increase in SOX17 expression in cancer cells, T cells, fibroblasts, and myeloid cells.

The phosphoinositide 3-kinase/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling pathway is usually hyperactivated in cancer and affects tumor cell proliferation and survival. Therefore, many drugs targeting critical nodes of this pathway have been developed (46, 47). In the present study, we found that the expression of SOX17 was correlated with the strength of the clinical response to drugs targeting the PI3K/mTOR signaling pathway and protein stability and degradation pathways, including ZSTK474, MK-2206, CCT018159, and 17-AAG. However, the molecular mechanism by which SOX17 affects PI3K/mTOR signaling has not yet been elucidated. Several studies have demonstrated that the activity of the Wnt/β-catenin signaling pathway is attenuated by SOX17 (18, 32, 35). Interestingly, the Wnt signaling pathway, regulated by SOX17, is upstream of the mTOR signaling pathway. These results suggest that SOX17 may also be involved in the mTOR signaling pathway. In the present study, the co-expression analysis identified 14 co-expressed genes related to SOX17, including WNT7A and FGF18. In previous reports (48, 49, 50), the conditional knockout of SOX17 increased the mRNA expression of WNT7A, leads to the ablation of mouse uterine adenogenesis. FGF18, a fibroblast growth factor, was shown to activate receptor tyrosine kinase (RTK), thus causing auto-phosphorylation and promoting the activation of PIK3, which is also consistent with the drug response results obtained in the present study. The mTOR pathway positively regulates the expression of SOX17 in endothelial cells (51). Taken together, these data suggest that SOX17 may be involved in PI3K/mTOR signaling by crosstalk with the Wnt/β-catenin signaling pathway.

One limitation of the present study is the relatively small sample size for rare tumors (CHOL, DLBC, UCS, KICH, ACC). The clinical correlation results between SOX17 and these rare tumors are therefore not sufficiently robust, and further studies are warranted.

Conclusion

In summary, we demonstrated that SOX17 is highly expressed in some tumors and is correlated with specific tumor stages and patient survival. SOX17 is significantly down-regulated in the tissue of 13 cancer types, including THCA, BRCA, KICH, ESCA, PRAD, UVM, LUAD, BLCA, LUSC, COAD, SKCM, CESC and KIRP, but is overexpressed in OV, UCEC, TGCT, LIHC and PAAD. In particular, the expression level of SOX17 is related to the clinical stage of patients with UCEC. SOX17 expression level is associated with prognosis in KIRC, UVM, MESO, STAD, LUSC, PAAD and READ, suggesting that it may be a prognostic biomarker and a promising therapeutic target in these cancers. At single-cell resolution, the expression level of SOX17 is higher in OVC tumor tissue-origin cells than in paired normal-origin cells, contrary to LC and CRC. In OVC, the overall increase in SOX17 expression is attributed to the augmentation of SOX17 expression in cancer cells, fibroblasts, T cells, and myeloid cells. Single-cell RNA-seq analysis revealed that SOX17 is involved in the development of OVC and may be a potential diagnostic marker and drug target for OVC. Drug response and co-expression analysis indicated that SOX17 may be involved in the PI3K/AKT/mTOR signaling pathway; however, the precise molecular mechanisms should be studied further.

Acknowledgements

This research was funded by the National Natural Science Foundation of China (CN) (grant number 81773012). APC was funded by The Second Affiliated Hospital, School of Medicine, Zhejiang University.

Footnotes

  • ↵# These Authors contributed equally to this study.

  • Data Availability

    Publicly available datasets were analyzed in the present study. Gene expression data and clinical information were obtained from several large genome databases including Genotype-Tissue Expression (https://www.gtexportal.org/home/), The Cancer Genome Atlas (https://portal.gdc.cancer.gov/), and Cancer Cell Line Encyclopedia (https://portals.broadinstitute.org). The drug response data were obtained from Genomics of Drug Sensitivity in Cancer (https://www.cancerrxgene.org/), and single-cell RNA sequencing data were obtained from VIB-KU LEUVEN CENTER FOR CANCER BIOLOGY (http://blueprint.lambrechtslab.org).

  • Supplementary Material

    The supplementary material can be downloaded through this link: https://figshare.com/s/43c4274f532f21d715e6

  • Conflicts of Interest

    The Authors declare that there are no conflicts of interest regarding the publication of this paper.

  • Authors’ Contributions

    DQ Sun, XJ Sheng, YH Bai, and Li Xu designed this study. Li Xu and YH Cheng contributed to data preparation. Li Xu performed the data analysis and contributed to the writing of the manuscript. YH Bai and DQ Sun revised the manuscript.

  • Received May 6, 2023.
  • Revision received July 10, 2023.
  • Accepted July 14, 2023.

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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Pan-cancer Analysis Reveals Cancer-dependent Expression of SOX17 and Associated Clinical Outcomes
LI XU, YOUHUANG BAI, YIHANG CHENG, XIUJIE SHENG, DEQIANG SUN
Cancer Genomics & Proteomics Sep 2023, 20 (5) 433-447; DOI: 10.21873/cgp.20395
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