Table_1_Bioinformatics Identification of the Expression and Clinical Significance of E2F Family in Endometrial Cancer.docx

BackgroundBesides being one of the most prevalent cancers among women, incidence and mortality rates of endometrial cancer (EC) are still increasing. The E2F family of transcriptional factors is involved in cell differentiation, apoptosis, and inhibition of DNA damage response, thus affecting growth and invasion of tumor cells.
MethodsWe used multiple bioinformatics tools to explore the role of E2F family in endometrial cancer.
ResultsThe expression of E2F1/2/3/7/8 was significantly upregulated in endometrial cancer tissues, converse to E2F4, which was downregulated. Methylation downregulates all E2Fs except for E2F2. Accordingly, E2F1/2/3/5/7/8 are potential diagnostic biomarkers for EC. In particular, EC patients displaying upregulated E2F1, and E2F3 expression had a worse overall survival and relapse-free survival. E2F8, E2F7, and E2F1 were the top three, most-frequently altered genes in endometrial cancer. E2F family activates apoptosis pathways, regulates cell cycle, and impairs DNA damage response pathways. Drug-sensitivity analysis demonstrated that the level of E2F2/3/8 negatively correlated with drug resistance. Meanwhile, immune infiltrations analysis revealed that E2F family is associated with recruitment of several immune cells. Enrichment analysis on its part revealed that the E2F family is mainly associated with cell cycle, sequence-specific DNA binding, nuclear transcription factor complex, PI3K-Akt signaling, and p53 signaling pathway. We also identified multiple E2Fs-associated miRNA and kinase targets in endometrial cancer.
ConclusionOur study revealed the unique expression signature and clinical significance of E2F family in EC, demonstrating the potential clinical utility of these transcription factors (TF) in endometrial cancer.

背景：子宫内膜癌（endometrial cancer, EC）是女性最高发的恶性肿瘤之一，其发病率与死亡率仍持续攀升。E2F家族转录因子参与细胞分化、细胞凋亡及DNA损伤应答抑制过程，可通过相关机制影响肿瘤细胞的生长与侵袭能力。
方法：本研究采用多种生物信息学工具，探究E2F家族在子宫内膜癌中的生物学功能与作用机制。
结果：研究发现，子宫内膜癌组织中E2F1、2、3、7、8的表达水平显著上调，而E2F4的表达则显著下调。除E2F2外，DNA甲基化可抑制其余所有E2F家族成员的表达。据此，E2F1、2、3、5、7、8可作为子宫内膜癌潜在的诊断生物标志物。尤为关键的是，E2F1与E2F3表达上调的子宫内膜癌患者，其总生存期与无复发生存期均显著缩短。E2F8、E2F7与E2F1是子宫内膜癌中发生频率最高的前三位变异基因。E2F家族可激活细胞凋亡通路、调控细胞周期进程，并削弱DNA损伤应答通路。药物敏感性分析结果显示，E2F2、3、8的表达水平与肿瘤耐药性呈负相关。同时，免疫浸润分析表明，E2F家族与多种免疫细胞的招募过程密切相关。富集分析结果揭示，E2F家族主要与细胞周期、序列特异性DNA结合、核转录因子复合物、PI3K-Akt信号通路以及p53信号通路相关。本研究还在子宫内膜癌中鉴定出多个与E2F家族相关的miRNA及激酶靶标。
结论：本研究阐明了E2F家族在子宫内膜癌中独特的表达特征与临床意义，证实了这类转录因子（transcription factors, TF）在子宫内膜癌诊疗领域的潜在临床应用价值。