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 Cancer Letters 477 (2020) 107–121 Contents lists available at ScienceDirect Cancer Letters journal homepage: www.elsevier.com/locate/canlet Original Articles Dysbindin promotes pancreatic ductal adenocarcinoma by T activating NF-κB/MDM2 via miR-342–3p a,1 a,1 b,1 c a a a DonglieZhu ,ShiZheng ,ChengFang ,XinGuo ,DandanHan ,MingyaoTang ,HangFu , d e d,∗∗ f,∗∗∗ a,∗ Mingzuo Jiang , Ning Xie , Yongzhan Nie , Xuebiao Yao , Yong Chen a Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi\'an, Shaanxi, 710032, China b Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200438, China c Department of Endoscopic Surgery, 986th Military Hospital, Fourth Military Medical University, Xi\'an, Shaanxi, 710054, China d State Key Laboratory of Cancer Biology 3xFLAG PEPTIDE glpbio, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi\'an, Shaanxi, 710032, China e Department of Gastroenterology, The Second Affiliated Hospital of Xi\'an Jiaotong University, Xi\'an, Shaanxi, 710004, China f Department of Hefei Laboratory for Physical Sciences at Microscale, School of Life Science, University of Science and Technology of China, Hefei, China ARTICLE INFO ABSTRACT Keywords: Pancreaticductaladenocarcinoma(PDAC)isoneofthemostinvasivesolidtumoursandhasthehighestcancer- Dysbindin relatedmortalityrate.Despiteintenseinvestigation,themolecularmechanismsunderlyingtheinvasivenessand miR-342–3p aetiology of PDAC remain elusive. MicroRNAs (miRNAs) are key regulators of tumour cell plasticity, but their Pancreatic ductal adenocarcinoma rolesinPDACmetastasishavenotbeencharacterized.Ourearlystudiesshowedthatdysbindinproteinlevelsare NF-κB/MDM2 elevatedinPDACpatientscomparedwithcontrolindividualsandthatdysbindinupregulationelicitsPDACcell Metastasis proliferation via the PI3K pathway. Here, we show that dysbindin promoted PDAC metastasis via the NF-κB/ MDM2 signalling axis. Increased dysbindin levels correlated with aggressive features in PDAC, and the over- expressionofdysbindinsignificantlypromotedPDACmetastasisandinvasioninvitroandinvivo.###http://www.glpbio.com/simage/GA11233-L-NAME-hydrochloride-1.png####Surprisingly, dysbindin was identified as a direct target of miR-342–3p, which promotes NF-κB activation and PDAC me- tastasis.Thus,dysbindin-mediatedNF-κBactivationviamiR-342–3prepresentsacontext-dependentswitchthat enables PDAC cellproliferation and metastasis.

 

Our datasuggest that dysbindin and miR-342–3p are potential leads for the development of targeted therapy for PDAC Cell Counting Kit-8 price. 1. Introduction The protein dysbindin has diverse physiological roles, particularly in the nervous system. DTNBP1, the gene that encodes dysbindin, is a Pancreatic ductal adenocarcinoma (PDAC) is one of the most ag- susceptibilitygene related to schizophrenia [6],anddysbindinprotein gressive solid malignancies and remains the fourth leading cause of levels are lower in the hippocampus of schizophrenia patients com- cancer-related death worldwide [1,2]. The five-year survival rate of pared with the healthy people [7]. However, the role of dysbindin in PDACpatientsislessthan5%,andtheaveragepatientsurvivalisonly solid tumours is not yet clear. 6–9 months after diagnosis. PDAC is predicted to become the second MDM2istheprimarynegativeregulatorofp53andplaysakeyrole leading cause of cancer-related death in the future [3]. Moreover, ap- inregulatingp53transcriptionalactivity[8,9].MDM2isoverexpressed proximately 80–85% of affected patients are not candidates for a ra- in various cancers and may play a key role in epithelial-mesenchymal dical resection due to distant metastasis or locally advanced disease transition (EMT), an essential step in the progression to metastatic [4,5]. disease [10,11]. The NF-κB family of ubiquitously expressed dimeric ∗ Corresponding author. ∗∗ Corresponding author Chloramphenicol. ∗∗∗ Corresponding author. E-mail addresses: yongznie@fmmu.edu.cn (Y. Nie), yaoxb@ustc.edu.cn (X. Yao), gdwkcy@fmmu.edu.cn (Y. Chen). 1 These authors contributed equally to this work. https://doi.org/10.1016/j.canlet.2020.02.033 Received 10 October 2019; Received in revised form 11 February 2020; Accepted 26 February 2020 0304-3835/ © 2020 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/).