YAP相互作用lncRNA LRRC75A-AS1介导甲羟戊酸途径调控PD-L1促进结直肠癌进展的机制

申请者前期发现lncRNA uc.134能抑制LATS1泛素化降解并激活Hippo-YAP信号网络抑制肿瘤进展（J Hematol Oncol，2017）；进一步通过RIP-sequence结合RNA pull-down发现YAP能特异性结合lncRNA LRRC75A-AS1，LRRC75A-AS1通过甲羟戊酸途径调控YAP核转位，沉默LRRC75A-AS1能促进YAP磷酸化并抑制PD-L1的表达；辛伐他汀能通过抑制LRRC75A-AS1进而抑制PD-L1的转录。基此，提出假设：LRRC75A-AS1通过甲羟戊酸途径介导YAP磷酸化调控PD-L1的转录促使肿瘤发生免疫逃逸。我们拟进一步采用CHIRP-sequence、EMSA、荧光素酶报告基因等方法，通过体内外模型，明确LRRC75A-AS1调控结直肠癌进展的机制，为确立LRRC75A-AS1作为结直肠癌新的治疗靶点提供充分的理论依据。

A growing body of evidence indicates that Hippo-YAP kinase signaling is inactivated in many cancers. We have reported that a novel lncRNA, uc.134, represses tumor progression by inhibiting the CUL4A-mediated ubiquitination of LATS1 and increasing YAPS127 phosphorylation（J Hematol Oncol，2017）. However, it remains to be investigated whether there are lncRNAs that directly regulate the signal transduction of YAP. We performed RIP-sequence and RNA pull-down assay to identify that lncRNA LRRC75A-AS1 directly bound to YAP. LRRC75A-AS1 regulates YAP nuclear translocation through mevalonate pathway. Further studies showed that knock down of LRRC75A-AS1 upregulated pYAPS127 and inhibited PD-L1. While simvastatin could depressed expression of LRRC75A-AS1 and PD-L1. On the basis of these studies, we propose the hypothesis that LRRC75A-AS1 could regulate PD-L1 expression through mevalonate pathway in CRC. Furthermore, we will explore the mechanism that LRRC75A-AS1 regulates PD-L1 expression through mevalonate pathway in CRC by CHIRP-sequence, EMSA and luciferase reporter assay system. The research will provide new targets for tumor therapy and possess the profound scientific implication and superb value for clinical application.