OC is one of the diseases with poor prognosis in gynecological malignancies. In recent years, finding effective prognostic biomarkers for OC has become a hot spot, and it is also an urgent problem to improve the prognosis of OC patients.As is one of the important processes in the regulation of protein diversification. Abnormal regulation of AS can affect human health and also play a role in some cancers.Previous reports have explored the relationship between AS and OC. In this report,the features of the relationship among prognosis, AS and SFs of OC were explored in a more comprehensive way.Besides,some independent prognostic factors of OC were analyzed, providing important basis for systematic analysis.
Prognostic exploration of OC mainly focuses on genomics, in addition to proteomics, immunology, cytokines and other aspects, among which there are complex relationships.For example, the tumor suppressor genes BRCA1 and BRCA2, whose mutations undergo a large number of splicing events, are important components of inherited breast and OC [20–22].Further investigation revealed that the elimination of BRCA1 mutations through selective mRNA splicing would benefit patients resistant to OC[23].Recent studies have shown that AAT, NFkB, PMVK and some other proteins are significantly higher in high grade serous ovarian carcinoma than in normal tissue, which can be used as biomarkers for predicting good prognosis[24].Correspondingly, such as PD-1, PD-L1, VAP1, FABP4, and PF4 are associated with poor prognosis[25];.Interleukin is a series of cytokines produced by many kinds of cells and used a series of cells. There are 38 kinds of interleukin in this family, which can regulate a variety of immune processes.Among them, IL-17[26, 27], IL-6[28], IL-8[28], IL-33[27], CYR61 [29]and some other cytokines may be involved in the occurrence and development of OC and may be used as prognostic markers of OC.
In this study, we used data from TCGA database, combined with high-throughput sequencing technology and bioinformatics to analyze the relationship between AS, SF and the prognosis of OC.In addition, independent prognostic factors of OC, GO, KEGG analysis of pathways for prognostic related SFs were also explored.Consistent with other studies, our study shows that AS events and SFs play a role in OC, and many splicing events are associated with OC.With the increase of the sample size in this study, the number of AS events in OC was also 48049, with the highest number of ES type[15].After further treatment, the AS events of TSEN54, MYB, SERF1B, ZNF630 and AGO2 were most closely associated with the prognosis of OC, and they were all good prognostic factors.tRNA splicing endonuclease(TSEN) catalyz tRNA intron removal in eukaryotes,and TSEN54 is a TSEN is one of the core subunits.The gene mutation of TSEN54 mostly leads to nervous system lesions, most studied cause of pontocerebellar hypoplasia.There has been a lack of research on the relationship between OC[30–32].Previously,MYB is one of the proto-oncogenes, it has become a consensus that there is a relationship between MYB overexpression and poor prognosis of OC. Using the correlation between MYB and OC to evaluate the prognosis and explore potential therapeutic targets has attracted much attention[33–35].But,the study found that MYB-77867-ES for OC prognosis is favorable AS event. The results suggest that splicing may change the role of genes.AGO2 is a Protein Coding gene, which have effect on cervical cancer, breast cancer and other tumors[36–38].AGO2 fail in our study it happened happened AGO2-85285-ES is beneficial to the prognosis of OC, but in other studies, AGO2 can have opposite effects on the prognosis of OC through different pathways[39–41].Few studies have been done on SERF1B and ZNF630,we get SERF1B-72406-RI、ZNF630-88949-AP close contact with OC, they may be effective prognostic biomarkers and therapeutic targets.Among the remaining results, there are many previous studies on CD44 gene.As a non-kinase transmembrane receptor,CD44 can be used as an effective biomarker to predict the prognosis of OC and negatively affect the outcome of OC[42].CD44 plays a multi-functional role, such as related to cancer stem cells and tumor-associated macrophages, leading to drug resistance of recurrent chemotherapy drugs in OC. It is expected to further dig out effective therapeutic targets to reduce the recurrence rate and drug resistance rate of OC[43, 44].It interacts with STAT3 to affect a series of processes such as angiogenesis and immune regulation in OC[45–47].CD44 and STAT3 work together on OC in a variety of way,which can provide various ideas for OC treatment. Consistent with previous researchs, we get CD44-15112-ES can negatively affect the prognosis of OC.
Our carefully designed analysis scheme, it lays the foundation for the feasibility of the prediction models.LASSO regression has unique advantages for survival analysis, which can reduce the complexity of prognostic features, select good model data, and improve the feasibility and accuracy of subsequent survival models[48].We made full use of the advantages of LASSO regression model in Cox model to further optimize the construction of previous survival models.The survival model was evaluated by ROC curve, and the AUC of the eight models was between 0.68 and 0.757, all of which had good accuracy and feasibility.
Independent prognostic factors are often used as a part of prognostic monitoring and usually divided into clinical features and molecular biology.Common clinical features such as age, performance status, grade, Figo stage, and histology were considered independent prognostic factors for OC[49, 50].On the other hand, researchers found that low level of AK7, high expression of KIF23, P-gp protein, and SIX-gene signature(TGFBI, SFRP1, COL16A1, THY1, PPIB, BGN) could all be considered independent prognostic factors for OC[51–54].In this study, we analyzed some clinical traits and found that age can be used as an independent prognostic factor for OC.However, grade and stage were not significant as independent prognostic factors of OC in our study,this may be due to differences in research data and experimental methods.At the same time, we added the score of risk calculated by the prognostic model for evaluation, and risk score was also an independent prognostic factor. This result further demonstrates the strong applicability of the prognostic models, and this design method is relatively new in independent prognostic analysis.
The influence of AS on cancer is beyond question. SF gene indirectly affects the occurrence and development of cancer by affecting AS process[55, 14].There have been studies on the prognostic relationship between SFs and OC, and the SF we studied came from the data obtained after comprehensive analysis. More SF numbers may lead to more prognostic markers[15].In this study, 109 SF genes were found to be most relevant for OC prognosis, among which MSI1 is an RNA binding protein that regulates the expression of target mRNAs at the translation level.Initial studies have shown that miR-761 reduces the proliferation and aggressiveness of OC by regulating MSI1[56].The increased expression of MSI1 can enhance the malignant characteristics of OC.In addition, MSI1 can increase the expression of p-Bcl-2 by activating the ERK signaling pathway and indirectly increase the drug resistance of chemotherapy drugs[57].We found that MSI1 can produce positive and negative regulation on different AS events. Incidentally, MSI1 produces positive regulation on negative AS events, while produces negative regulation on positive AS events, and ultimately has negative effects on OC outcomes.RBM3 is the members of the cold shock protein family, it has been shown in a series of studies to be related to the prognosis of breast cancer[58], stomach cancer[59], OC[60], colorectal cancer[61], prostate cancer[62] and other malignant tumors..Asa Ehlen and his team suggest that RBM3 may be an independent prognostic factor for OC, increasing the sensitivity of patients to chemotherapeutic agents and extending the survival of OC patients[63].Inhibition of Protein Coding gene DDX39B high expression can improve the efficacy of chemotherapy drugs for OC. This is the only study between OC and DDX38B[64].we found that RBM3 as SF negatively regulates the COPS7B-57975 -ES, and COPS7B- 57975-ES is a good prognostic factors.In other words, RBM3 has a negative prognostic effect on OC.Similarly, the results of this study showed that DDX39b positively affected the prognosis of OC by affecting AS events. This difference may be caused by the mechanism involved in RBM3 and DDX39b that has not been found yet, which needs to be further explored.Among the remaining SFs, the relationship between SFs such as PPIL1, SNRNP200, PQBP1, GPATCH8 and OC have not been explored yet, which can be further studied in the future.
In this paper, the relationship between the prognosis of OC,AS, SF were further explored, but there are still shortcomings.First, the study lacked a control cohort due to the lack of adjacent normal samples around the tumor tissue.Second, the data analyzed in this study came from TCGA and relevant literature, all of which were online data, and the results may not be applicable to clinical patients.Third, the current lack of network data research results applicable to clinical OC patients, the urgent need to establish a clinical cohort to verify the results.Finally, the mechanism of the pathway obtained by GO and KEGG enrichment analysis can be further excavated.