In this work, a number of key genes involved in tumors were identified, which aimed to provide clues for further studying the role of abnormal epigenetic modification patterns in preeclampsia. Our study obtained 178 DEGs, including 57 upregulated and 121 downregulated DEGs. Then, the GO enrichment analysis and KEGG pathway of DEGs indicated that these genes were mainly enriched in the regulation of platelet activation, miRNA binding, sphingolipid signaling pathway, and sphingolipid metabolism (Fig. 3A, B, C and D). These genes may participate in the pathogenetic process of preeclampsia. By GSE 10588 validation from placental tissue, the genes SMAD4, POU5F1, MAP2K1, and RAB1A were more strongly associated with the diagnosis of preeclampsia in our study, which may provide interesting insight into the pathological mechanism of preeclampsia from the perspective of bioinformatics analysis.
Tumor cell proliferation, invasion and migration are critically important steps in tumorigenesis(25). Studies have shown that the SMAD4(26), POU5F1(27), MAP2K1(28, 29), and RAB1A(30) genes are closely related to tumorigenesis and metastasis. For example, SMAD4 has been identified as a tumor suppressor gene that is deleted, mutated, or inactivated in many human tumors(31). Clinical evidence suggests that POU5F1-mediated cell proliferation, invasion, and migration play a key role in endometrial carcinoma and rectal cancer(27, 32). Abnormal expression of the RAB1A gene is closely related to various malignant tumors(33). Notably, there are considerable similarities between the invasion and migration of trophoblast cells in normal pregnancy and the infiltration and distant metastasis of tumor cells. The occurrence of preeclampsia is closely related to the impaired proliferation, invasion, and migration ability of trophoblastic cells. It can lead to shallow placental implantation and extremely insufficient remodeling of uterine spiral arteries and ultimately lead to hypertension and proteinuria during pregnancy. In summary, our study found similar phenotypic changes between preeclampsia and tumors.
In GSE48424, the expression levels of SMAD4, MAP2K1, and RAB1A were lower in blood circulation in preeclamptic samples than in healthy samples (p < 0.05). The gene POU5F1 expression levels were higher in preeclamptic samples than in healthy samples (p < 0.05) (Fig. 6). These genes have a certain value for preeclamptic diagnosis (AUC = 0.799, 0.849, 0.815, and 0.830, respectively). Furthermore, we were surprised to discover that the expression trends of SMAD4, MAP2K1, and POU5F1 in placental tissue in GSE 10588 were the same as those in blood circulation. They also have a certain value for preeclampsia diagnosis (AUC = 0.783, 0.805 and 0.726, respectively). To further verify the above conclusions, we eventually selected POU5F1 and RAB1A for further validation from
plasma. Associations between preeclampsia and POU5F1 or RAB1A were determined with univariate binary logistic regression analysis. We found that POU5F1 was significantly correlated with preeclampsia (p < 0.05). Compared to nonpreeclamptic pregnant women, the expression levels of POU5F1 were increased in the plasma of preeclamptic patients. Moreover, POU5F1 has a certain value for the diagnosis of preeclampsia (AUC = 0.733).
GO and KEGG analyses demonstrated that POU5F1 regulates stem cell pluripotency by negatively regulating miRNA-mediated gene silencing, binding ubiquitin protein ligases, and regulating DNA-binding transcription repressor activity and RNA polymerase II specificity. The POU5F1 gene (also known as OCT4) is a critical regulator of early embryonic development(34). Evidence has shown that POU5F1 is expressed in human inner cell mass cells, embryonic stem cells, germ cells, embryonic cancer cells, and various adult stem cells(35). Takada, Yuki, et al. indicated that the synthesis of POU5F1 protein during oogenesis and early stages of embryogenesis is controlled at the translational level and emphasized that precise control of the protein quantity by translational regulation is critical for oocyte and early embryonic development(36). Loss of pluripotency will lead embryonic stem cells to differentiate into the original germ cell or one of the three major germ layers—the endoderm, mesoderm or ectoderm. POU5F1 mRNA is expressed at all stages of embryonic development(37). The self-renewal ability of ESCs is precisely regulated by POU5F1 expression (38). The development of preeclampsia caused by premature placental senescence and apoptosis(39) is related to the abnormal self-renewal ability of embryonic stem cells regulated by POU5F1.
In the present study, we identified several hub genes that are closely associated with preeclampsia, some of which were not mentioned in the literature in the context of preeclampsia. These findings may provide new insights into the regulation of tumor-related genes, identifying novel candidate genes. Taken together, our findings will provide relevant evidence for the role of abnormal epigenetic modification patterns in preeclampsia. However, further studies are necessary to explore the deeper mechanisms of preeclampsia.