Abstract
Epithelial ovarian cancers (EOCs) are fatal and obstinate among gynecological malignancies in advanced stage or relapsed status, with serous carcinomas accounting for the vast majority. Unlike EOCs, borderline ovarian tumors (BOTs), including serous BOTs, maintain a semimalignant appearance. Using gene ontology (GO)-based integrative analysis, we analyzed gene set databases of serous BOTs and serous ovarian carcinomas for dysregulated GO terms and pathways and identified multiple differentially expressed genes (DEGs) in various aspects. The SRC (SRC proto-oncogene, non-receptor tyrosine kinase) gene and dysfunctional aryl hydrocarbon receptor (AHR) binding pathway consistently influenced progression-free survival and overall survival, and immunohistochemical staining revealed elevated expression of related biomarkers (SRC, ARNT, and TBP) in serous BOT and ovarian carcinoma samples. Epithelial–mesenchymal transition (EMT) is important during tumorigenesis, and we confirmed the SNAI2 (Snail family transcriptional repressor 2, SLUG) gene showing significantly high performance by immunohistochemistry. During serous ovarian tumor formation, activated AHR in the cytoplasm could cooperate with SRC, enter cell nuclei, bind to AHR nuclear translocator (ARNT) together with TATA-Box Binding Protein (TBP), and act on DNA to initiate AHR-responsive genes to cause tumor or cancer initiation. Additionally, SNAI2 in the tumor microenvironment can facilitate EMT accompanied by tumorigenesis. Although it has not been possible to classify serous BOTs and serous ovarian carcinomas as the same EOC subtype, the key determinants of relevant DEGs (SRC, ARNT, TBP, and SNAI2) found here had a crucial role in the pathogenetic mechanism of both tumor types, implying gradual evolutionary tendencies from serous BOTs to ovarian carcinomas. In the future, targeted therapy could focus on these revealed targets together with precise detection to improve therapeutic effects and patient survival rates.
Highlights
Ovarian tumors occupy a certain place among gynecological diseases and most cases are benign in clinical and pathological features such as follicular cysts, corpus luteum cysts, serous or mucinous cystadenomas, endometriomas, and teratomas [1,2]
The key biological functions and genes involved in the pathogenesis of serous Borderline ovarian tumors (BOTs) and all stages of serous ovarian carcinomas were determined by identifying genome-wide and gene ontology (GO)-defined functions and differentially expressed genes (DEGs)
We performed a comprehensive bioinformatics method based on GO to explore and analyze all relational disordered functions of serous ovarian tumors, including serous BOTs and all stages of serous ovarian carcinomas [70]
Summary
Ovarian tumors occupy a certain place among gynecological diseases and most cases are benign in clinical and pathological features such as follicular cysts, corpus luteum cysts, serous or mucinous cystadenomas, endometriomas, and teratomas [1,2]. SC is less likely to be found in the early stages (International Federation of Gynecology and Obstetrics (FIGO) stages I and II), which have higher survival rates because they are easier to treat, whereas patients at advanced stages (FIGO stages III and IV) have poor prognosis and high recurrence rates even after complete debulking surgery combined with chemotherapy (carboplatin and paclitaxel) due to resistance to chemotherapy [6,8,9]. BOTs account for approximately 10–15% of EOCs and usually occur in younger women, resulting in an excellent prognosis [12]. Compared with ovarian cancer patients, who almost always require chemotherapy after a debulking operation, patients with BOTs usually have better prognoses after adequate surgery with an extremely low probability of recurrence or metastasis [13,14]. Serous BOTs, comprising approximately 65% of BOTs, occur mostly in North
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