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Abstract：
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with limited treatment options, illustrating an urgent need to identify new drugable targets in PDACs.
OBJECTIVE: Using the similarities between tumor development and normal embryonic development, which is accompanied by rapid cell expansion, we aimed to identify and characterize embryonic signaling pathways that were reinitiated during tumor formation and expansion.
RESULTS: Here, we report that the transcription factors E2F1 and E2F8 are potential key regulators in PDAC. E2F1 and E2F8 RNA expression is mainly localized in proliferating cells in the developing pancreas and in malignant ductal cells in PDAC. Silencing of E2F1 and E2F8 in PANC-1 pancreatic tumor cells inhibited cell proliferation and impaired cell spreading and migration. Moreover, loss of E2F1 also affected cell viability and apoptosis with E2F expression in PDAC tissues correlating with expression of apoptosis and mitosis pathway genes, suggesting that E2F factors promote cell cycle regulation and tumorigenesis in PDAC cells.
CONCLUSIONS: Our findings illustrate that E2F1 and E2F8 transcription factors are expressed in pancreatic progenitor and PDAC cells, where they contribute to tumor cell expansion by regulation of cell proliferation, viability, and cell migration making these genes attractive therapeutic targets and potential prognostic markers for pancreatic cancer.
OBJECTIVE: Using the similarities between tumor development and normal embryonic development, which is accompanied by rapid cell expansion, we aimed to identify and characterize embryonic signaling pathways that were reinitiated during tumor formation and expansion.
RESULTS: Here, we report that the transcription factors E2F1 and E2F8 are potential key regulators in PDAC. E2F1 and E2F8 RNA expression is mainly localized in proliferating cells in the developing pancreas and in malignant ductal cells in PDAC. Silencing of E2F1 and E2F8 in PANC-1 pancreatic tumor cells inhibited cell proliferation and impaired cell spreading and migration. Moreover, loss of E2F1 also affected cell viability and apoptosis with E2F expression in PDAC tissues correlating with expression of apoptosis and mitosis pathway genes, suggesting that E2F factors promote cell cycle regulation and tumorigenesis in PDAC cells.
CONCLUSIONS: Our findings illustrate that E2F1 and E2F8 transcription factors are expressed in pancreatic progenitor and PDAC cells, where they contribute to tumor cell expansion by regulation of cell proliferation, viability, and cell migration making these genes attractive therapeutic targets and potential prognostic markers for pancreatic cancer.
摘要：
背景：胰腺导管腺癌（PDAC）是治疗选择有限的最致命的癌症之一，说明迫切需要在PDAC中确定新的药物靶标。
目的：利用肿瘤发育与正常胚胎发育的相似性，伴随着快速的细胞扩增，我们旨在鉴定和表征肿瘤形成和扩展过程中重新启动的胚胎信号通路.
结果：这里，我们报道转录因子E2F1和E2F8是PDAC中潜在的关键调节因子.E2F1和E2F8RNA表达主要位于发育中的胰腺中的增殖细胞和PDAC中的恶性导管细胞中。PANC-1胰腺肿瘤细胞中E2F1和E2F8的沉默抑制了细胞增殖并损害了细胞扩散和迁移。此外，E2F1的缺失也影响细胞活力和凋亡，PDAC组织中E2F的表达与凋亡和有丝分裂途径基因的表达相关，提示E2F因子促进PDAC细胞的细胞周期调控和肿瘤发生。
结论：我们的研究结果表明，E2F1和E2F8转录因子在胰腺祖细胞和PDAC细胞中表达，它们通过调节细胞增殖来促进肿瘤细胞的扩增，生存能力，和细胞迁移使这些基因成为胰腺癌的有吸引力的治疗靶标和潜在的预后标志物。
目的：利用肿瘤发育与正常胚胎发育的相似性，伴随着快速的细胞扩增，我们旨在鉴定和表征肿瘤形成和扩展过程中重新启动的胚胎信号通路.
结果：这里，我们报道转录因子E2F1和E2F8是PDAC中潜在的关键调节因子.E2F1和E2F8RNA表达主要位于发育中的胰腺中的增殖细胞和PDAC中的恶性导管细胞中。PANC-1胰腺肿瘤细胞中E2F1和E2F8的沉默抑制了细胞增殖并损害了细胞扩散和迁移。此外，E2F1的缺失也影响细胞活力和凋亡，PDAC组织中E2F的表达与凋亡和有丝分裂途径基因的表达相关，提示E2F因子促进PDAC细胞的细胞周期调控和肿瘤发生。
结论：我们的研究结果表明，E2F1和E2F8转录因子在胰腺祖细胞和PDAC细胞中表达，它们通过调节细胞增殖来促进肿瘤细胞的扩增，生存能力，和细胞迁移使这些基因成为胰腺癌的有吸引力的治疗靶标和潜在的预后标志物。
