SBA is a malignant tumor with low incidence but poor prognosis. In this study, the messenger RNAs (mRNAs), miRNAs and TFs that may be associated with its occurrence were predicted using a comprehensive bioinformatics analysis. Meanwhile, the SBA risk prediction model based on hub genes with good prediction accuracy was established. Finally, analysis of the tumor immune microenvironment suggested that the invasion level of most immune cells in SBA was low, and the activation intensity of the immune pathway was weak, which might be the cause of tumor progression.
Hub genes have attracted extensive attention as potential drug targets. In this study, four hub genes (APOA4, APOB, COL1A2, FN1) were found to be significantly related to the pathogenesis of SBA. Apolipoprotein A4 (APOA4) encodes apolipoprotein A-IV, which is hydrolyzed and glycosylated to produce acidic glycoproteins mainly found in chylomicrons (CMs), very low-density lipoprotein (VLDL), and high-density lipoprotein (HDL)(33–35). It plays an important role in lipid transport and metabolism, especially in cholesterol reversal(36). Recent studies showed that APOA4 was significantly overexpressed in Helicobacter pylori-infected atrophic gastritis and intestinal metaplasia tissues, as well as gastric cancer tissues(37). Furthermore, APOA4 is considered a diagnostic marker for colorectal cancer(38, 39). As a metabolic gene, apolipoprotein B (APOB) is the most important apolipoprotein on chylomicrons and low-density lipoprotein(40, 41). APOB has been confirmed to be associated with the pathogenesis of a variety of gastrointestinal malignancies, including liver cancer, gallbladder cancer, esophageal cancer and pancreatic duct adenocarcinoma(42–45). Abdominal obesity has been identified as a risk factor for SBA(46). In this study, APOA4 and APOB were significantly downregulated in SBA, suggesting that lipid metabolism disorders may play an important role in the occurrence of SBA. In addition, functional enrichment analysis showed that CGs were enriched in multiple metabolically related pathways. Unfortunately, no studies have been found on APOA4 or APOB and SBA. Therefore, further research is necessary to clarify the role of lipid metabolism in SBA.
Collagen, Type I, Alpha 2 (COL1A2) is distributed in collagen and cytoplasm and is involved in bone development and the signal transduction pathway of transmembrane receptor protein tyrosine kinase(47, 48). COL1A2 was confirmed to be significantly overexpressed in gastric cancer tissues(49–51). Similarly, COL1A2 was believed to be significantly overexpressed in colorectal cancer tissues and blood samples, but the specific mechanism remains unclear(52, 53). Increasing evidence shows that COL1A2 is considered to be a diagnostic and prognostic biomarker due to its significant upregulation in many cancers(54–56). In contrast, COL1A2 was significantly downregulated in bladder cancer, malignant melanoma and head and neck cancer(57–59). In this study, COL1A2 was significantly overexpressed in SBA. Fibronectin 1 (FN1) is a glycoprotein distributed in the extracellular matrix and plays an important role in carcinogenesis and metastasis(60–62). FN1 expression was upregulated by the transcription factor CP2, which is involved in the metastasis of hepatocellular carcinoma(63). FN1 promotes ovarian cancer metastasis by activating the PI3K/Akt pathway(64). High expression of FN1 has been shown to be carcinogenic in esophageal cancer(65). In addition, FN1, as an oncogene, is involved in aggressive and poor prognosis of colon cancer(66). As expected, high expression of FN1 was significantly associated with poorer prognosis of gastric cancer(67, 68). This study suggests that the highly expressed FN1 plays an important role in the carcinogenesis of SBA.
As innate immune cells, macrophages play an important role in the tumor microenvironment. High macrophage infiltration has been associated with tumor progression or poor prognosis in a variety of solid tumors, including neck squamous cell carcinoma, gliomas, breast cancer, bladder cancer, prostate cancer, and melanoma(69–74). Conversely, high macrophage infiltration was associated with a better prognosis of gastrointestinal malignancies, such as gastric cancer and colorectal cancer(75). This study suggested that the level of macrophage infiltration in SBA was low, which may be one of the reasons for the poor prognosis of SBA. In addition, the low infiltration of most immune cells and the weak activation of immune pathways may be important factors for the occurrence and progression of SBA.
In conclusion, four mRNAs (APOA4, APOB, COL1A2, FN1) were predicted to be associated with the occurrence of SBA, and an excellent SBA risk prediction model was established based on these genes. Meanwhile, in SBA, it is speculated that the infiltration level of immune cells was low and the activation state of immune pathways was weak. Finally, TFs and miRNAs that may be involved in the pathogenesis of SBA were predicted. Due to the rarity of SBA, the results could not be verified. Therefore, multicenter, large-sample research and validation are necessary.
This study predicted that four target mRNAs (APOA4, APOB, COL1A2, FN1) might be involved in the occurrence and progression of SBA. In addition, low infiltration of immune cells and weak activation of immune pathways may be immunological characteristics of SBA.