STRAP as a New Therapeutic Target for Poor Prognosis of Pancreatic Ductal Adenocarcinoma Patients Mainly Caused by TP53 Mutation

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Abstract
Pancreatic ductal adenocarcinoma (PDAC) has a high mortality rate and poor prognosis. KRAS, TP53, CDKN2A, and SMAD4 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, TP53 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 TP53 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 TP53-mutant or low p53 expression pancreatic cancer cells in vitro and in vivo. 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 TP53-mutant PDAC patients.
Funding Information
  • National Natural Science Foundation of China (81570853, 81770630, 81800567)

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