Hu Shanshan, Chen Xiao, Xu Xiangxiang, Zheng Chenlei, Huang Wenqian, Zhou Yi, Akuetteh Percy David Papa, Yang Hongbao, Shi Keqing, Chen Bicheng, Zhang Qiyu
Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
Front Oncol. 2020 Sep 29;10:594224. doi: 10.3389/fonc.2020.594224. eCollection 2020.
Pancreatic ductal adenocarcinoma (PDAC) has a high mortality rate and poor prognosis. , , , and are driver genes of PDAC and 30-75% patients have mutations in at least two of these four genes. Herein, we analyzed the relationship between these genes and prognosis of 762 patients in the absence of coexisting mutations, using data from three independent public datasets. Interestingly, we found that compared with mutations in other driver genes, mutation plays a significant role in leading to poor prognosis of PDAC. Additionally, we found that snoRNA-mediated rRNA maturation was responsible for the progression of cancer in PDAC patients with mutations. Inhibition of STRAP, which regulates the localization of SMN complexes and further affects the assembly of snoRNP, can effectively reduce maturation of rRNA and significantly suppress progression of -mutant or low p53 expression pancreatic cancer cells and . Our study highlighted the actual contribution rate of driver genes to patient prognosis, enriching traditional understanding of the relationship between these genes and PDAC. We also provided a possible mechanism and a new target to combat progression of -mutant PDAC patients.
胰腺导管腺癌（PDAC）死亡率高且预后差。 、 、 和 是PDAC的驱动基因，30 - 75%的患者在这四个基因中至少有两个发生突变。在此，我们使用来自三个独立公共数据集的数据，分析了这四个基因与762例不存在共存突变患者的预后之间的关系。有趣的是，我们发现与其他驱动基因突变相比， 突变在导致PDAC预后不良方面起显著作用。此外，我们发现小核仁RNA（snoRNA）介导的核糖体RNA（rRNA）成熟与存在 突变的PDAC患者的癌症进展有关。抑制STRAP（其调节运动神经元存活蛋白（SMN）复合物的定位并进一步影响小核仁核糖核蛋白（snoRNP）的组装）可有效减少rRNA的成熟，并显著抑制 突变或p53低表达胰腺癌细胞 和 的进展。我们的研究突出了驱动基因对患者预后的实际贡献率，丰富了对这些基因与PDAC之间关系的传统认识。我们还提供了一种可能的机制以及对抗 突变型PDAC患者疾病进展的新靶点。
