244P - NOP14 promotes invasion and metastasis by maintaining mutant p53-induced oncogenic signaling in pancreatic cancer

Date 17 December 2016
Event ESMO Asia 2016 Congress
Session Poster lunch
Topics Pancreatic Cancer
Translational Research
Presenter Yongxing Du
Citation Annals of Oncology (2016) 27 (suppl_9): ix68-ix85. 10.1093/annonc/mdw582
Authors Y. Du1, L. You1, Z. Li1, C. Liu2, Z. Liu1, Y. Zhao1
  • 1General Surgery, Peking Union Medical College Hospital, 100730 - Beijing/CN
  • 2Biochemistry And Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, 100730 - Beijing/CN

Abstract

Background

Mutant p53 (mutp53) proteins accumulate and promote invasion and metastasis in pancreatic ductal adenocarcinoma (PDAC). However, the mechanism underlying the sustained activation of mutp53 oncogenic signaling is currently unclear. Here, we investigate the function of NOP14 in PDAC metastasis by enhancing the mRNA stability of mutp53, thereby leading to blunted microRNA-17-5p/P21 signaling.

Methods

NOP14 expression was evaluated in paired PDAC samples by immunohistochemistry analysis. Wound-healing, in vitro transwell and invasion assays were employed to investigate the impact of NOP14 on PDAC cell movement. In vivo invasion assays were conducted on established subcutaneously/orthotopically/intravenously injected tumor mouse models to examine the function of NOP14 in PDAC metastasis. In addition, the functional targets of NOP14 were identified by RNA sequencing and quantitative real-time PCR analyses. Further, the correlations among NOP14, mutp53, and the related signaling molecules were assessed by RNA stability, chromatin immunoprecipitation, and immunoblotting assays.

Results

Increased NOP14 expression was associated with PDAC progression. NOP14 overexpression promoted cell movement, whereas NOP14 inhibition decreased the invasive capacity of PDAC cells. In vivo invasion assays indicated NOP14 as a promoter of PDAC metastasis. Mechanistically, microRNA-17-5p-mediated P21 signaling was validated as a functional target of NOP14, and NOP14 exerted its regulatory function by increasing the mRNA stability of mutp53 in PDAC cells.

Conclusions

Our findings define a novel mechanism for understanding the function of NOP14 in PDAC metastasis. Targeting of NOP14 allows for the effective suppression of tumor cell invasion in a manner that is likely to involve mutp53-induced microRNA-17-5p/p21 signaling, implicating a potential approach for attenuating metastasis in p53 mutant tumors.

Clinical trial indentification

Legal entity responsible for the study

Yupei Zhao

Funding

The National Nature Science Foundation of China

Disclosure

All authors have declared no conflicts of interest.