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Open Full Page Author Manuscript Published OnlineFirst on March 9, 2017; DOI: 10.1158/0008-5472.CAN-16-2339 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Title Page Title: Pancreatic cancer progression relies upon mutant p53-induced oncogenic signaling mediated by NOP14 Yongxing Du1,§, Ziwen Liu1, §, Lei You1, Pengjiao Hou2, Xiaoxia Ren1, Tao Jiao2, Wenjing Zhao1, Zongze Li1, Hong Shu1, Changzheng Liu2,*, Yupei Zhao1,* 1 Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100730, PR China 2 Department of Biochemistry and Molecular Biology, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences，School of Basic Medicine, Peking Union Medical College, Beijing 100005, PR China § Authors share co-first authorship. * To whom correspondence should be addressed: Yupei Zhao, E-mail: [email protected], Fax: 86-10-65124875; Changzheng Liu, E-mail: [email protected], Fax: 86-10-65253005. Running Title: NOP14 primes mutp53-driven cancer progression Key words: Pancreatic ductal adenocarcinoma, Mutant p53, NOP14, Cancer metastasis Abbreviations: Mutp53, Mutant p53; PDAC, Pancreatic ductal adenocarcinoma; NOP14, NOP14 nucleolar protein; rRNA, ribosomal RNA; PDGFRb, Platelet-derived 1 Downloaded from cancerres.aacrjournals.org on September 26, 2021. © 2017 American Association for Cancer Research. Author Manuscript Published OnlineFirst on March 9, 2017; DOI: 10.1158/0008-5472.CAN-16-2339 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. growth factor receptor b; MAPK3, Mitogen-activated protein kinase 3; CDK2, Cyclin dependent kinase 2; MMP9, Matrix metallopeptidase 9; RhoA, Ras homolog family member A; p53, Tumor protein p53; P21, Cyclin dependent kinase inhibitor 1A; H&E, hematoxylin-eosin; ATCC, the American Type Culture Collection; DMEM, Dulbecco’s modified Eagle medium; cDNA, complementary DNA; messenger RNA; siRNA, small interfering RNA; UTR, untranslated region; qRT-PCR, quantitative reverse-transcription polymerase chain reaction; Scr, scramble; miRNA, microRNA; MYO10, myosin X; SLUG, Snail family transcriptional repressor 2; TGFB1, Transforming growth factor beta 1; ZEB1, zinc finger E-box binding homeobox 1; EGFR, Epidermal growth factor receptor; ITGB1, Integrin subunit beta 1; SMAD2, SMAD family member 2; TWIST1, Twist family bHLH transcription factor 1; ZNF652, Zinc finger protein 652; CCNG2, Cyclin G2; SHARP1, Basic helix-loop-helix family member e41; TP63, Tumor protein p63; PERP, PERP TP53 apoptosis effector ; DAB2IP, DAB2 interacting protein; S100A4, S100 calcium binding protein A4; PIM1, Pim-1 proto-oncogene, serine/threonine kinase; E2F1, E2F transcription factor 1; TP53I3, Tumor protein p53 inducible protein 3; c-Myc, v-myc avian myelocytomatosis viral oncogene homolog; BCL2, BCL2 apoptosis regulator; NIH, National Institutes of Health; PBS, Phosphate Buffered Saline; SCID mice, Severe combined immunodeficient mice; HRP, Horseradish peroxidase; ActD, Actinomycin D; si-Con, si-control; RNA-seq, whole transcriptome sequencing; miRNA-seq, microRNA sequencing; pri-miRNA, primary microRNA; 2 Downloaded from cancerres.aacrjournals.org on September 26, 2021. © 2017 American Association for Cancer Research. Author Manuscript Published OnlineFirst on March 9, 2017; DOI: 10.1158/0008-5472.CAN-16-2339 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. pre-miRNA, microRNA precursor; IHC, Immunohistochemistry; OS, overall survival. Financial Support: This research was supported by the National Nature Science Foundation of China (2013, 81272767, to Z. W. Liu; 2015, 81572459, to Z. W. Liu; 2015, 81570780, to C. Z. Liu; and 2016, 81672443 to Y. P. Zhao). Corresponding authors: Yupei Zhao, Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100730, PR China. Phone: 86-10-69156007, Fax: 86-10-65124875, E-mail: [email protected]. Changzheng Liu, Department of Biochemistry and Molecular Biology, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing 100005, PR China. Phone: 86-10-69156424, Fax: 86-10-65253005, E-mail: [email protected] Disclosure of Potential Conflicts of Interest: No potential conflicts of interest were disclosed by the authors. Word count for the abstract: 190 Word count for the text: 5000 Total Figures: 7 3 Downloaded from cancerres.aacrjournals.org on September 26, 2021. © 2017 American Association for Cancer Research. Author Manuscript Published OnlineFirst on March 9, 2017; DOI: 10.1158/0008-5472.CAN-16-2339 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 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 post-transcriptional levels via induction of microRNA-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. 4 Downloaded from cancerres.aacrjournals.org on September 26, 2021. © 2017 American Association for Cancer Research. Author Manuscript Published OnlineFirst on March 9, 2017; DOI: 10.1158/0008-5472.CAN-16-2339 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. INTRODUCTION The concept that gain-of-function of mutant p53 (mutp53) proteins led to cancer progression was established over two decades ago, and a number of hotspots have been identified in diverse cancers, including pancreatic ductal adenocarcinoma (PDAC).(1) In human PDAC, p53 accumulation has been correlated with lymph node metastasis, and knock-in Trp53 mutations result in the acquisition of critical functions for overcoming growth arrest/senescence and driving metastasis.(2) Another study has revealed that sustained mutp53 expression is required to maintain the prometastatic phenotype and that platelet-derived growth factor receptor b (PDGFRb) is involved in mutp53-driven PDAC metastasis.(3) These findings indicate that mutp53 is a potential antimetastatic target for PDAC prevention. However, mutp53 proteins have been proven to be undruggable to date.(4-5) Efforts have been focused on searching for potential mediators of mutp53 activity in cancer progression, and targeting of these related proteins might facilitate the suppression of metastasis driven by mutp53. NOP14 has been reported to be a nucleolar protein required for maturation of 18S rRNA and for 40S ribosome production.(6) Our preliminary data have revealed that NOP14 causes increased PDAC cell growth and invasion and we have also detected NOP14 mutations in primary and metastatic PDAC tissues,(7-8) indicating a potential association between NOP14 and cancer invasion. However, the correlation between dysregulated NOP14 and PDAC 5 Downloaded from cancerres.aacrjournals.org on September 26, 2021. © 2017 American Association for Cancer Research. Author Manuscript Published OnlineFirst on March 9, 2017; DOI: 10.1158/0008-5472.CAN-16-2339 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. progression remains unclear, and little else is known about the mechanisms underlying the function of NOP14 in the metastasis of p53 mutant tumors. Herein, we demonstrated that PDAC cells with increased NOP14 expression possess an enhanced invasive capacity. We also showed that NOP14 drives PDAC metastasis by stabilizing mutp53 mRNA, thereby affecting its functional targets. Overall, our data define a mechanism of the NOP14/mutp53 regulatory axis in suppressing P21 expression at both the transcriptional and post-transcriptional levels by induction of microRNA-17-5p (miR-17-5p) in PDAC cells. MATERIALS and METHODS Clinical specimens and cell lines Tissues were collected as previously described.(9) The patient characteristics are provided in Table S1. MIA PaCa-2, Su.86.86, T3M4, PANC-1, SW1990, BxPC-3, and AsPC-1 cell lines were obtained from the American Type Culture Collection (ATCC) and grown in DMEM or RPMI1640 with 10% FBS (HyClone) at 37ºC in 5% CO2 cell culture incubator. Cell lines were tested and
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