Department of Hepatobiliary Pancreatic Surgery, Changhai Hospital, Naval Medical University, Shanghai 200433, China.
Department of Gastrointestinal Surgery, Changhai Hospital, Naval Medical University, Shanghai 200433, China.
Biochim Biophys Acta Mol Basis Dis. 2024 Oct;1870(7):167316. doi: 10.1016/j.bbadis.2024.167316. Epub 2024 Jun 18.
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.
癌症干细胞 (CSCs) 对胰腺导管腺癌 (PDAC) 的进展、侵袭、转移和化疗耐药至关重要。早老素增强子 2 (Pen2) 是 γ-分泌酶复合物的重要组成部分，在各种癌症中过表达，并在癌症发生中发挥重要作用。在这里，我们研究了 Pen2 表达与 PDAC 细胞干性特征之间的关联。我们使用公共数据库分析了 Pen2 及其下游靶标 Erb-B2 受体酪氨酸激酶 4 (ErbB4)。通过 CD133+、CD44+或上皮细胞黏附分子 (EpCAM)+ 标记评估 CSC 群体中的 Pen2 表达。通过用设计为在 Pen2 启动子下表达绿色荧光蛋白 (GFP) 的载体转导 PDAC 细胞，从 Pen2 阴性细胞中分选 Pen2 阳性细胞。在 Pen2 阳性与 Pen2 阴性细胞中，体外和体内评估了干性。结果表明，与相邻非肿瘤组织相比，PDAC 组织中 Pen2 显著上调，而 ErbB4 显著下调，Pen2 水平与 Erbb4 水平呈负相关。高 Pen2 表达的 PDAC 与患者生存明显较差相关。通过 CD133+、CD44+和 EpCAM+ 标志物鉴定的 CSC 群体显示出明显更高的 Pen2 和更低的 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，具有更高的侵袭性和迁移性，并表现出明显增加的化疗诱导凋亡抗性。改变 Pen2 水平可逆转这些致癌作用。在体内，Pen2 阳性细胞在免疫缺陷小鼠中形成更大的肿瘤。总之，我们的研究结果表明，Pen2 在 PDAC 细胞中的 CSCs 中高表达，是一个新的治疗靶点。
