LncRNA HNF1A-AS1通过E2F1上调OTUD7A的表达促进胰腺癌干性的机制研究

癌干细胞是导致肿瘤转移复发的主要原因之一，胰腺癌中癌干细胞比例相对较高，导致其预后不良。然而，胰腺癌干细胞高比例的调控机制目前还不清楚。我们构建胰腺癌悬浮球细胞作为胰腺癌干细胞模型，通过转录组测序发现HNF1A-AS1在该细胞中表达上调。对HNF1A-AS1进行过表达，可增加胰腺癌细胞干性表型。通过pull down联合质谱分析，发现HNF1A-AS1能与E2F1相互作用，促进OTUD7A表达，OTUD7A可减少干性基因CD133的泛素化，但其泛素化机制不清楚。因此申请人提出科研假设： HNF1A-AS1通过结合并增加E2F1的转录稳定性，增强E2F1介导的OTUD7A转录，进而减少CD133泛素化，促进胰腺癌干性。本研究探讨HNF1A-AS1对胰腺癌干性的影响，并深入解析CD133形成的复合物及OTUD7A对CD133的泛素化及去泛素化机制，为临床克服胰腺癌干性提供新的思路。

Cancer stem cells are one of the main causes of tumor metastasis and recurrence. The proportion of cancer stem cells in pancreatic cancer is relatively high, leading to poor prognosis. However, the regulatory mechanism of the high proportion of pancreatic cancer stem cells is still unclear. We constructed pancreatic cancer suspension spheres cells as a pancreatic cancer stem cell model, and transcriptome sequencing showed that HNF1A-AS1 was up-regulated in these cells. Overexpression of HNF1A-AS1 increased the stemness of pancreatic cancer cells. Through pull down combined mass spectrometry analysis, it was found that HNF1A-AS1 binds with E2F1 to promote the expression of OTUD7A, and OTUD7A reduced the ubiquitination of stemness gene CD133. However, its ubiquitination mechanism was not fully understood. Therefore, the applicant proposes a scientific hypothesis: HNF1A-AS1 enhances E2F1-mediated OTUD7A transcription by binding and increasing the transcriptional stability of E2F1, thereby reducing CD133 ubiquitination and promoting pancreatic cancer stemness. In this study, the effect of HNF1A-AS1 on the stemness of pancreatic cancer was explored, the complex formed by CD133 and the mechanism of CD133 ubiquitination and deubiquitination by OTUD7A were further analyzed, providing a novel strategy for overcoming the stemness of pancreatic cancer.