| Popis: |
Background p53 mutations are considered to be the second most common type of mutation in PC, and significantly promote its metastasis. However, the underlying molecular mechanisms, especially the regulatory relationship with long noncoding RNAs (lncRNAs) remain unclear. Methods Based on TCGA and GTEx databases and integrating bioinformatics analyses, the overexpression of lncRNA LINC00857 in PC tissues was detected and further validated in a cohort of PC tissues. The effects of LINC00857 on EMT, migration and invasion were determined by in vitro and in vivo experiments. RNA pull-down, RNA immunoprecipitation (RIP), chromatin isolation by RNA purification (ChIRP) and fluorescence in situ hybridization (FISH) were carried out to reveal the interaction between LINC00857 and FOXM1, OTUB1. Chromatin immunoprecipitation (ChIP) and Luciferase reporter assay were used to evaluate the regulatory effect of mutant p53 on LINC00857. Results lncRNA LINC00857 exhibited a significantly elevated level in PC and was involved in poor prognosis, and its expression was significantly upregulated in the p53 mutant group compared with the p53 wild-type group. Moreover, LINC00857 remarkably suppressed tumour metastasis in vitro and in vivo in a FOXM1 dependent manner. Mechanistically, LINC00857 simultaneously bound to FOXM1 and the deubiquitinase OTUB1, serving as a protein scaffold to enhance the interaction between FOXM1 and OTUB1, which inhibited FOXM1 degradation through the ubiquitin–proteasome pathway. Interestingly, we found that mutant p53 promoted the transcription of LINC00857 by binding to its promoter region. Finally, atorvastatin, a commonly applied lipid-lowering drug in the clinic, was suggested to inhibit PC metastasis by inhibiting the mutant p53-LINC00857 axis. Conclusions Taken together, our results uncovered new insights into the biology driving PC metastasis and indicated that the mutant p53-LINC00857 axis might serve as a novel therapeutic target for PC metastasis. |
