While the global incidence of gastric cancer (GC) is declining, it remains one of the most common causes of cancer-related death worldwide. There are three major subtypes of GC under the Lauren classification system but four subtypes under the World Health Organization (WHO) classification system (1, 2). Many GCs are associated with various pathogenic infections, including Helicobacter pylori and the Epstein-Barr virus (EBV) (3). While significant effort has been made in diagnosing and treating GC, the clinical outcomes of patients with advanced GC remain poor. The 5-year survival rate of GC patients is about 20−30% in most areas of the world (4). Only recently have researchers started to appreciate how heterogeneous GC is. Nevertheless, GC remains a deadly disease. Current treatment options or earlier detection strategies have not provided meaningful control of GC. Therefore, it remains crucial to provide novel strategies for reducing GC risk.

The SET binding protein 1 (SETBP1) gene encodes a large protein of 1542 amino acids localized in the cell nucleus and cytoplasm (5, 6). SETBP1 was originally found to interact with SET, a small protein inhibitor of tumor suppressors protein phosphatase 2 phosphatase activator (PP2A) and non-metastatic protein 23 H1 (NM23-H1) (7–9). It is now widely recognized as a tumor-associated gene (5), and alteration of SETBP1 expression has been implicated in several tissue-specific diseases (10–12), including cancer. The downregulation of SETBP1 expression has been reported to promote non-small cell lung cancer progression by inducing cellular epithelial-mesenchymal transition (EMT) and disordered immune status (5). In addition, SETBP1 accumulation has been found to induce P53 inhibition and genotoxic stress in neural progenitors underlying neurodegeneration in Schinzel-Giedion syndrome (13). Furthermore, overexpression of tripartite motif-containing 29 (TRIM29) is closely associated with adverse clinical outcomes in ovarian cancer and promotes the proliferation, migration, and invasion of ovarian cancer cells via the SETBP1/SET/PP2A carcinogenic signal axis (14).

SETBP1 mutations in patients have also received wide attention, especially in blood diseases (15–18). Carratt et al. demonstrated that mutant SETBP1 enhances activation of the mitogen-activated protein kinase 1 (MAPK) pathway by the proto-oncogene GTPase NRAS, promoting aggressive leukemia (19). In addition, SETBP1 mutations have been reported to drive leukemic transformation in ASXL transcriptional regulator 1 (ASXL1)-mutated myelodysplastic syndrome (MDS) (20). Moreover, a father and son diagnosed with atypical chronic myeloid leukemia (aCML) were both found to carry SETBP1 mutations, which are present in 24.3% of aCML patients (21). Therefore, SETBP1 mutations are believed to be a biomarker in disease diagnosis (22, 23). However, their relationship with GC progression remains unclear.

This study examines the relationship between SETBP1 expression and the clinicopathological features of GC patients to advance understanding of the underlying signaling pathways related to SETBP1 expression and GC progression. Our findings provide additional evidence of its suitability as a prognostic biomarker for GC.

SETBP1 expression has been extensively studied in various diseases, including cancers, where it is abnormal compared with normal tissues. These studies have involved several cancer types, including non-small cell lung cancer (5), hematologic malignancies (26), colorectal cancer (27), ovarian cancer (14), breast cancer (12), and gastric cancer (28, 29). However, SETBP1 appears to play a dual role in different cancer types. It has been shown that SETBP1 is highly expressed in some cancers, driving carcinogenesis. SETBP1 has been reported to be overexpressed in acute myeloid leukemia (AML), protecting the SET protein from proteasome degradation, and leading to increased levels of full-length SET protein. Patients with SETBP1 overexpression have a significantly shorter overall survival (30). In addition, TRIM29 can facilitate SETBP1 transcriptional activation via the vascular endothelial zinc finger 1 (VEZF1) transcription factor, promoting ovarian cancer progression (14). Moreover, SETBP1 was identified as an oncogene contributing to breast cancer development (12).

Conversely, lower SETBP1 expression was found to promote non-small cell lung cancer progression by inducing cellular EMT and disordered immune status (5). It has also been reported that SETBP1 expression is similar or lower in colorectal cancer tissue compared to normal colonic mucosa (27). Furthermore, SETBP1 mutations have been found to be involved in serval cancers, including myeloid neoplasms (15), lung cancer (31, 32) and colorectal cancer (27). Therefore, the role of SETBP1 in cancer remains controversial and in GC remains obscure.

Our study uncovered a relationship between SETBP1 and GC. We showed that SETBP1 expression was significantly lower in GC tissues than in adjacent non-tumor tissues in the TCGA database ( Figure 1A ). However, the small number of normal tissue samples (32) may increase the risk of bias due to sampling error. We performed a meta-analysis to confirm low SETBP1 expression in GC based on the GEO database ( Figure 2B ), finding the TCGA and GEO results to be consistent. Furthermore, we showed that SETBP1 expression in GC cell lines (HGC-27, MGC-803, AGS, and MKN-28) was significantly lower than that in the GES-1 cell line ( Figure 2A ), consistent with earlier studies (5, 27). Therefore, the findings of this study indicate that SETBP1 may act as a tumor suppressor gene.

Interestingly, the Kaplan-Meier survival analysis showed that the high SETBP1 expression group had a worse overall GC survival prognosis than the low SETBP1 expression group ( Figure 3 ). In addition, the multivariate analysis showed that high SETBP1 expression was related to poor overall survival and other clinicopathological features ( Figure 4 ; Table 4 ). Interestingly, these results were consistent with those of our previous work ( Figure 1B ), with a worse prognosis associated with a lower grade (33). These findings were confirmed in our human GC cell experiments. SETBP1 expression in poorly differentiated (MGC-803) or undifferentiated (HGC-27) GC cells was higher than in well-differentiated GC cells (MKN-28). In addition, intestinal type cancers are common and reported to have a better prognosis than diffuse type cancers. In this study, SETBP1 expression in diffuse-type GC was significantly higher than in intestinal-type GC. Therefore, lower SETBP1 expression may confer better overall survival in GC patients, indicating that SETBP1 may act as an oncogene. Consequently, our findings appear contradictory and indicate that SETBP1 may have a dual role in GC development.

The SETBP1-associated signaling pathways in GC were identified via GSEA, with 10 and 10 KEGG pathways enriched in high- and low-SETBP1 expression groups, respectively ( Table 5 ). In the high SETBP1 expression group, the neuroactive ligand receptor interaction signaling pathway is related to tumor TNM stage, lymph node metastasis, and poor prognosis with GC (34). In addition, it can trigger the downstream phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signal pathway that is often associated with cancer (35). The calcium signaling pathway plays a role in multiple cellular processes involved in metabolism, secretion, fertilization, proliferation, and smooth muscle contraction (36–38). The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway is universally expressed and involved in many important biological processes, including cell proliferation, differentiation, apoptosis, and immune regulation (39). The ECM-receptor interaction pathway plays an important role in the tumor shedding, adhesion, degradation, movement, and hyperplasia processes (40). Similar to the PI3K/Akt signal pathway, the pathways in cancer, basal cell carcinoma signaling pathway (41), mTOR signaling pathway (42), Wnt signaling pathway (43) and melanogenesis signaling pathway (44) are common cancer-related pathways. The cytokine receptor signaling pathway is an immune-related signaling pathway that affects tumor progression (45). Therefore, SETBP1 may promote tumor progression by regulating various signaling pathways.

In the low SETBP1 expression group, the pyrimidine metabolism signaling pathway is critical for the generation of pyrimidines for DNA replication, RNA synthesis, and cellular bioenergetics. Increased nucleotide metabolism supports the uncontrolled growth of tumors (46). Oxidative phosphorylation is upregulated in some cancers, including leukemia, lymphoma, and pancreatic ductal adenocarcinoma (47). Proteasome (48), glutathione metabolism (49), aminoacyl tRNA biosynthesis (50), fructose and mannose metabolism (51), and amino sugar and nucleotide sugar metabolism (52, 53) are all common metabolism-related signaling pathways. DNA replication (54), nucleotide excision repair (55), and mismatch repair (56) are nucleic acid biosynthesis-related signaling pathways contributing to the cell cycle. Therefore, SETBP1 can function either as an oncoprotein or tumor suppressor, and further studies on its role in GC are required.

GC is a heterogeneous disease that affects a large number of individuals per year and remains an unmet clinical problem (57). Due to the high mortality of GC, various studies have sought to identify biomarkers to support earlier detection and improve the survival status of GC patients. In this study, we have shown that SETBP1 may have a dual role in GC development. However, our study had some limitations. Further studies with larger sample sizes and on the possible dynamic regulatory mechanism by which SETBP1 contributes to GC are required to determine whether SETBP1 functions as an oncoprotein or tumor suppressor in GC. Additional studies are needed to understand how to treat GC and cancer in general. Hopefully, as research progresses, their findings will provide important insights into these critical issues.

Publicly available datasets were analyzed in this study. This data can be found here: TCGA database (https://portal.gdc.cancer.gov/). GEO: GSE13195, GSE13911, GSE26899, GSE27342, GSE29272, GSE33335, GSE37023, GSE54129, GSE63089, GSE64591, GSE65801.

FF contributed to the conception and design of the current study and was responsible for drafting the manuscript. In addition, FF also completed the experimental part. CL, QL, RX, and TZ contributed to process the data and revised the manuscript. The corresponding author (XS) is responsible for ensuring that the descriptions are accurate and agreed by all authors. All authors contributed to the article and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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