Despite continued advances in treatment for OC, only 19% patients were diagnosed at early stage due to the lack of specific clinical symptoms and rapid cancer progression . Approximately 20–30% of patients would progress or developed disease recurrence in 6 months after completing chemotherapy and had a median OS of only 12–18 months . Therefore, investigating the effective biomarkers and identifying their effects in the diagnosis, development and treatment of OC is a matter of urgency. In this study, we integrated the four expression data sets (GSE36668, GSE12470, GSE14407, and GSE27651) and obtained 192 common DEGs. GO analysis showed that common DEGs were enriched in cartilage development, negative regulation of epithelial cell differentiation, palate development, negative regulation of keratinocyte proliferation, extracellular exosome, nucleus. KEGG pathways showed that the pathways regarding the abovementioned DEGs were significantly associated with the biological behavior of OC, including PI3K-Akt signaling pathway, Pathways in cancer, p53 signaling pathway, Rap1 signaling pathway, Cell cycle, Alanine, aspartate and glutamate metabolism, Melanoma and Biosynthesis of amino acids.
After systematic expression and survival analysis, six genes (RIPK4, SCNN1A, SLC4A11, ELF3, CLDN4, and SOBP) were recognized as key genes which may be associated with the development of OC. Expression levels of RIPK4, SCNN1A, SLC4A11, ELF3, and CLDN4 were amplified and their upregulation was linked to poor prognosis of patients with OC. The five genes have been described to act as oncogenes in various human tumors and link to tumor progression. Moreover, several studies have also confirmed that the five genes may provide as capable biomarkers for cancer. For example, RIPK4 expression is upregulated in nasopharyngeal, pancreatic, bladder urothelial and cervical squamous cell carcinoma, and is associated with a poor outcome [30–33]. Increased SCNN1A contributed to unfavorite prognosis in pulmonary adenocarcinoma and ovarian cancer [34–35]. Equally, Qin et al. also showed high expression of SLC4A11 was an independent prognostic factor for poor OS in grade 3 or 4 serous OC through a bioinformatic analysis . ELF3 overexpression is significantly linked to poor outcomes in hepatocellular, colorectal cancer and lung adenocarcinoma patients, and that ELF3 enhance cell growth, migration in these cancers [37–40]. Based on the previous studies, CLDN4 showed high expression in many epithelial malignant tumors, such as ovarian and pancreatic cancer. [41–44]. All these studies together with ours showed that RIPK4, SCNN1A, SLC4A11, ELF3, and CLDN4 genes may be the five key oncogenes in the progression of OC. Regrading to SOBP (sine oculis-binding protein) gene (also named JXC1), it has rarely been reported in human diseases and never been studied in tumors. Chen’s results showed SOBP is crucial for cochlear growth, cell fate, and patterning of the organ of Corti . Birk et al indicated that SOBP is altered in intellectual disability and is over expression in the brain limbic system . In this study, we creatively explored the role of SOBP in OC patients. The results confirmed that SOBP was low expression in mRNA and protein levels in OC tissues, and the downregulated of SOBP was related to poor OS and RFS in OC patients. Hence, SOBP could be considered a favorable prognostic marker, and potential mechanisms continue to be revealed.
Recently, the microenvironment including several kinds of cell bunches (such as tumor cells, immune cells, and fibroblasts) in tumor has been a hot topic. According to the mRNA expression level of SOBP, we obtained nine types of tumor-infiltrating lymphocytes in OC tissues, containing B cells, CD8 + T cells, Th 1, Treg, T cell exhaustion, macrophages (TAM, M1 and M2), neutrophils, dendritic and natural killer cells from TIMER. The infiltration of these TILs was discovered to be inversely correlated with SOBP. Meanwhile, we identified 10 key upregulated pathways about immune response in low SOBP group, such as IL 5 signaling pathway, CTL (Cytotoxic T lymphocytes) mediated immune response against target cells, IL 17 signaling pathway, NO2-dependent IL 12 Pathway in NK cells, Dendritic cells in regulating TH1 and TH2 development, T helper cell surface molecules, B lymphocyte cell surface molecules, T cytotoxic cell surface molecules, Th1/Th2 dfferentiation and Cytokine network. These findings submitted that SOBP expression were strictly related to the level of TILs in OC tissues, and further analyses will focus on detailed mechanisms of SOBP modifying these infiltrating immune cells in OC. The intersection between SOBP expression and immune functions in OC implies a potential target of SOBP for next treatment of ovarian cancer patients.Meanwhile, the roles of lncRNAs have drawn more and more attention . Several studies indicated that lncRNAs may act as competitive endogenous RNA (ceRNAs) in a new triple regulatory network by competitively binding their shared miRNAs [48–51]. However, neither lncRNAs nor miRNAs have been described to engage in the direct modulation of SOBP in OC. In this work, we noticed the existence of various lncRNAs and miRNAs which may lead to aberrant expression of SOBP. Furthermore, by correlation of expression and prognosis, we assumed a regulatory axis of lncRNA-miRNA-mRNA must affect the development and progression of OC.
In our study, three databases (starBase, Targetscan, and miRBD) were used to predict that hsa-miR-378d as the upstream miRNA of SOBP simultaneously. The negative correlation occurred between the expression of hsa-miR-378d and SOBP, and the high hsa-miR-378d was associated with poor prognostic value in OC. Similarly, lncRNA MEG8 could be regarded as the upstream of hsa-miR-378d with a negative correlation in expression, and the lower MEG8 was bound up with unfavorable prognosis in OC. Even more, the same related immune pathway, Cytokines pathway, was found among MEG8 and SOBP. In previous studies, hsa-miR-378d was upregulated in colorectal cancer and might be a potential biomarker in diagnosis [52, 53]. MEG8 suppresses activation of epithelial-mesenchymal transition of hepatocytes by the Notch pathway . Therefore, under a comprehensive analysis and previous reports, we have abundant reasons to establish MEG8-miR378d-SOBP axis and speculate that it may act a crucial role in the tumor progression and immune function of OC by regulating cytokines pathway.
There were several limitations in this study. First, we explored the expression of SOBP in OC using multiple public databases, and we did not prove these findings in our own clinical samples. Second, further studies should be conducted to support the consistency with protein level and causality relation between different variables using western blot. Although we creatively launched a novel lncRNA-miRNA-mRNA sub-network in OC and predicted potential immune-related pathway implicated in its function, more studies are warranted to elucidate the specific roles of MEG8-miR378d-SOBP and underlying mechanisms that affect tumor development and progression.