Abstract：
Cancer stem cells (CSCs) are critical for progression, invasion, metastasis, and chemotherapy resistance of pancreatic ductal adenocarcinoma (PDAC). Presenilin enhancer 2 (Pen2), a vital component of the gamma-secretase complex, is overexpressed in various cancers and plays a significant role in carcinogenesis. Here, we investigated the association between Pen2 expression and the stem-like properties of PDAC cells. We analyzed Pen2 and its downstream target, Erb-B2 Receptor Tyrosine Kinase 4 (ErbB4), using public databases. The expression of Pen2 in CSC populations, marked by CD133+, CD44+, or epithelial cell adhesion molecule (EpCAM)+, was evaluated. Pen2-positive cells were sorted from Pen2-negative ones in PDAC cells transduced with a vector designed to express green fluorescent protein (GFP) under the Pen2 promoter. Stemness was examined in vitro and in vivo in Pen2-positive versus Pen2-negative cells. Our results showed that Pen2 was significantly upregulated, while ErbB4 was significantly downregulated in PDAC tissues compared to adjacent non-tumorous tissues, with an inverse relationship between Pen2 and Erbb4 levels. PDACs with high Pen2 expression are associated with considerably poorer patient survival. The CSC populations identified by CD133+, CD44+, and EpCAM+ markers displayed significantly higher Pen2 and lower EpCAM levels. Compared to Pen2-negative PDAC cells, Pen2-positive cells formed more tumor spheres, were more invasive and migratory, and showed significantly increased resistance to chemotherapy-induced apoptosis. Altering Pen2 levels reversed these oncogenic effects. In vivo, Pen2-positive cells formed larger tumors in immunodeficient mice. Overall, our findings suggest that Pen2 is highly expressed in CSCs within PDAC cells, being a novel therapeutic target.
摘要：
癌症干细胞（CSC）对进展至关重要，入侵,转移,胰腺导管腺癌（PDAC）的化疗耐药性。早老素增强剂2（Pen2），γ-分泌酶复合物的重要组成部分,在各种癌症中过度表达，并在癌症发生中起重要作用。这里,我们研究了Pen2表达与PDAC细胞干细胞样特性之间的关联.我们分析了Pen2和它的下游目标,Erb-B2受体酪氨酸激酶4(ErbB4),使用公共数据库。Pen2在CSC种群中的表达，标记为CD133+，CD44+,或上皮细胞粘附分子（EpCAM）+，进行了评估。Pen2阳性细胞从PDAC细胞中的Pen2阴性细胞中分选,所述PDAC细胞用设计成在Pen2启动子下表达绿色荧光蛋白(GFP)的载体转导。在Pen2阳性与Pen2阴性细胞的体外和体内检查了干性。我们的结果显示Pen2显著上调,而与邻近的非肿瘤组织相比，ErbB4在PDAC组织中显著下调，Pen2和Erbb4水平之间呈反比关系。具有高Pen2表达的PDAC与相当差的患者生存率相关。由CD133+识别的CSC群体，CD44+,和EpCAM+标记显示显著较高的Pen2和较低的EpCAM水平。与Pen2阴性PDAC细胞相比，Pen2阳性细胞形成更多的肿瘤球，更具侵入性和迁徙性，并显示对化疗诱导的细胞凋亡的抗性显著增加。改变Pen2水平可以逆转这些致癌作用。在体内,Pen2阳性细胞在免疫缺陷小鼠中形成更大的肿瘤。总的来说,我们的发现表明Pen2在PDAC细胞内的CSC中高度表达，是一种新的治疗靶点。
