Yang Xiaowen, Cheng Zhijun, Zhang Lihua, Wu Guiru, Shi Run, Gao Zhenxing, Li Chaoyang
Department of the First Abdominal Surgery, Jiangxi Tumor Hospital, Nanchang, Jiangxi, 330029, People's Republic of China.
Department of Pathology, Zhongda Hospital, Southeast University, Nanjing, 210009, People's Republic of China.
Adv Exp Med Biol. 2017;1018:207-224. doi: 10.1007/978-981-10-5765-6_13.
A wealth of evidence suggests that proteins from prion protein (PrP) family contribute to tumorigenesis in many types of cancers, including pancreatic ductal adenocarcinoma (PDAC), breast cancer, glioblastoma, colorectal cancer, gastric cancer, melanoma, etc. It is well documented that PrP is a biomarker for PDAC, breast cancer, and gastric cancer. However, the underlying mechanisms remain unclear. The major reasons for cancer cell-caused patient death are metastasis and multiple drug resistance, both of which connect to physiological functions of PrP expressing in cancer cells. PrP enhances tumorigenesis by multiple pathways. For example, PrP existed as pro-PrP in most of the PDAC cell lines, thus increasing cancer cell motility by binding to cytoskeletal protein filamin A (FLNa). Using PDAC cell lines BxPC-3 and AsPC-1 as model system, we identified that dysfunction of glycosylphosphatidylinositol (GPI) anchor synthesis machinery resulted in the biogenesis of pro-PrP. In addition, in cancer cells without FLNa expression, pro-PrP can modify cytoskeleton structure by affecting cofilin/F-actin axis, thus influencing cancer cell movement. Besides pro-PrP, we showed that GPI-anchored unglycosylated PrP can elevate cell mobility by interacting with VEGFR2, thus stimulating cell migration under serum-free condition. Besides affecting cancer cell motility, overexpressed PrP or doppel (Dpl) in cancer cells has been shown to increase cell proliferation, multiple drug resistance, and angiogenesis, thus, proteins from PrP gene family by affecting important processes via multiple pathways for cancer cell growth exacerbating tumorigenesis.
大量证据表明，朊病毒蛋白（PrP）家族的蛋白质在多种癌症的肿瘤发生过程中发挥作用，包括胰腺导管腺癌（PDAC）、乳腺癌、胶质母细胞瘤、结直肠癌、胃癌、黑色素瘤等。有充分文献记载，PrP是PDAC、乳腺癌和胃癌的生物标志物。然而，其潜在机制仍不清楚。癌细胞导致患者死亡的主要原因是转移和多药耐药，这两者都与癌细胞中PrP的生理功能有关。PrP通过多种途径促进肿瘤发生。例如，在大多数PDAC细胞系中，PrP以前体PrP的形式存在，通过与细胞骨架蛋白细丝蛋白A（FLNa）结合来增加癌细胞的运动性。以PDAC细胞系BxPC-3和AsPC-1作为模型系统，我们发现糖基磷脂酰肌醇（GPI）锚定合成机制的功能障碍导致了前体PrP的生物合成。此外，在不表达FLNa的癌细胞中，前体PrP可通过影响丝切蛋白/F-肌动蛋白轴来改变细胞骨架结构，从而影响癌细胞的运动。除了前体PrP，我们还发现GPI锚定的未糖基化PrP可通过与血管内皮生长因子受体2（VEGFR2）相互作用来提高细胞迁移能力，从而在无血清条件下刺激细胞迁移。除了影响癌细胞的运动性外，癌细胞中过表达的PrP或多配体蛋白聚糖（Dpl）已被证明可增加细胞增殖、多药耐药和血管生成，因此，PrP基因家族的蛋白质通过多种途径影响癌细胞生长的重要过程，加剧了肿瘤发生。
