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.

Updates and Critical Evaluation on Novel Biomarkers for the Malignant Progression of Intraductal Papillary Mucinous Neoplasms of the Pancreas

“…The inactivation of P53 seems to display at a late stage in the carcinogenesis of IPMN. A recent study demonstrated that NOP14 overexpression promoted cell motility, whereas NOP14 inhibition decreased invasive capacity of pancreatic adenocarcinoma cells via P53 mutation stability that was validated as a functional target of NOP14 (49). The NOP14/mutP53 axis suppressed P21 expression at both the transcriptional and post-transcriptional levels via induction of microRNA-17-5p in pancreatic adenocarcinoma cells (49).…”

“…A recent study demonstrated that NOP14 overexpression promoted cell motility, whereas NOP14 inhibition decreased invasive capacity of pancreatic adenocarcinoma cells via P53 mutation stability that was validated as a functional target of NOP14 (49). The NOP14/mutP53 axis suppressed P21 expression at both the transcriptional and post-transcriptional levels via induction of microRNA-17-5p in pancreatic adenocarcinoma cells (49). We should mention that in IPMNs, the inactivation of P53, concomitant with the inactivation of the P16, are found in 20% of borderline tumors, 33% of the non-invasive carcinomas, in all the invasive carcinomas and in any adenoma (50).…”

Integrated analysis of RNA binding proteins in human colorectal cancer

“…As indicated by Zhou et al [47] , the NOP14 in pancreatic cancer cells is capable to promote motility, proliferation and metastatic capacity. According to the ndings of Du et al [48] , NOP14 primed tumor invasion and metastasis by improving the stability of mutp53 mRNA. By inhibiting the Wnt/ β-catenin pathways, NOP14 suppresses breast cancer [49].…”

Gemcitabine exhibits a suppressive effect on pancreatic cancer cell growth by regulating processing of PVT1 to miR1207

“…Immunohistochemistry (IHC) was conducted to measure SRC and RhoA expression as described previously (Du et al, 2017). In brief, paraffin-embedded tissue was pretreated at 65°C for 2 h, followed by deparaffinization using standard procedures.…”

“…All animal procedures were performed as described previously (Du et al, 2017;He et al, 2015). The animal experiments were conducted in accordance with the national Animal Experimentation guidelines (D.L.116/92) upon approval of the experimental protocol by the Institutional Animal Experimentation Committee of Peking Union Medical College.…”