Pancreatic Cancer Progression Relies upon Mutant p53-Induced Oncogenic Signaling Mediated by NOP14.

Abstract

Mutant p53 (mutp53) proteins promote tumor invasion and metastasis in pancreatic ductal adenocarcinoma (PDAC). However, the mechanism underlying sustained activation of mutp53 oncogenic signaling is currently unclear. In this study, we report that NOP14 nucleolar protein (NOP14) expression is upregulated in PDAC tumors and metastatic tissue specimens. NOP14 overexpression promoted cell motility, whereas NOP14 inhibition decreased invasive capacity of PDAC cells. In vivo invasion assays conducted on established subcutaneously, orthotopically, and intravenously injected tumor mouse models also indicated NOP14 as a promoter of PDAC metastasis. Mechanistically, mutp53 was validated as a functional target of NOP14; NOP14 primed tumor invasion and metastasis by increasing the stability of mutp53 mRNA. The NOP14/mutp53 axis suppressed p21 expression at both the transcriptional and posttranscriptional levels via induction of miR-17-5p in PDAC cells. In vivo, high NOP14 expression in PDAC patient tumors correlated with local metastasis and lymph invasion. Overall, our findings define a novel mechanism for understanding the function of NOP14 in the metastatic cascade of PDAC. Targeting NOP14 allows for effective suppression of tumor invasion in a mutp53-dependent manner, implicating NOP14 inhibition as a potential approach for attenuating metastasis in p53-mutant tumors. Cancer Res; 77(10); 2661-73. ©2017 AACR.

• Authors: Yongxing Du, Ziwen Liu, Lei You, Pengjiao Hou, Xiaoxia Ren, Tao Jiao, Wenjing Zhao, Zongze Li, Hong Shu, Changzheng Liu, Yupei Zhao
• Journal: Cancer research (Cancer Res) Vol. 77 Issue 10 Pg. 2661-2673 (05 15 2017) ISSN: 1538-7445 [Electronic] United States
• PMID: 28280038 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2017 American Association for Cancer Research.

Chemical References

• Biomarkers
• MIRN17 microRNA, human
• MicroRNAs
• NOP14 protein, human
• Nuclear Proteins
• Tumor Suppressor Protein p53

Topics

• Animals
• Biomarkers
• Cell Line, Tumor
• Cell Movement (genetics)
• Cluster Analysis
• Disease Models, Animal
• Disease Progression
• Gene Expression
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• Heterografts
• Humans
• Mice
• MicroRNAs (genetics)
• Models, Biological
• Mutation
• Neoplasm Invasiveness
• Neoplasm Metastasis
• Nuclear Proteins (antagonists & inhibitors, metabolism)
• Pancreatic Neoplasms (genetics, metabolism, pathology)
• RNA Interference
• RNA Stability
• Signal Transduction
• Tumor Burden
• Tumor Suppressor Protein p53 (genetics, metabolism)
• Xenograft Model Antitumor Assays