WNT signaling has a significant influence on the embryonic development of the ovary and is also involved in normal follicular development and ovarian function. The WNT signaling pathway is involved in ovarian cancer development via multiple, diverse mechanisms, including gene mutations and changes in pathway components such as extracellular inhibitors and intranuclear transcription cofactors. According to Wang et al,the WNT signaling pathway passes signals to the Notch signaling pathway. The Notch signaling pathway is known to be responsible for maintaining a balance between cell proliferation and death and, as such, plays an important role in the for mation of many types of human tumors. In our compu tational results, WNT signaling connects the Notch signaling pathway through DVL gene, which indicates DVL is a critical gene for passing signals through path ways.

In addition, the computational evidence provided by the values of betweenness centrality, degree and p value indicate that DVL may be involved in platinum based chemoresistance. The signature chemoresistance associated genes Most of the results analyzed in the previous section are supported by known biological evidence, which indicates that this work is able to predict candidate chemoresis tance associated genes. We were particularly interested in CEPBD and its transcriptional regulated gene, SOD1. Several reports have implicated CEBPD as a suppressor gene. According to Hour et al,the expression of the CEPBD was induced by cisplatin and specifically elevated in a cisplatin resis tant subline and transactivated SOD1 gene expression in the human bladder urothelial carcinoma NTUB1 cell line.

This study revealed a novel role for CEBPD in conferring drug resistance. GSK-3 Therefore, we suspected CEBPD is involved in ovarian and lung chemoresistance as well. Moreover, as shown in Figure 5, pathways including the gene CEBPD and SOD1 were the shortest pathways in our computational results, which indicates SOD1 does not interact with other genes or pathways. We were curious about what caused the chemoresistant mechanism after SOD1 was regu lated. Cisplatin caused DNA damage as well as reactive oxygen species, which triggered cell cycle arrest or/and apoptosis. Cisplatin induced CEBPD by an as of yet unidentified mechanism which activated the SOD1 gene expression. Superoxide anion is dismutated by SOD1 and converted to H2O2 which can be further neutralized to water and oxygen by catalase. The reduced ROS levels in their model caused the cisplatin resistant phenotype. These results call for an assessment of CEBPD and SOD1 expression in bladder tumors as a potential means of predicting cisplatin resistance.