文献类型：期刊文献

英文题名：Ribonucleotide reductase M2 subunit silencing suppresses tumorigenesis in pancreatic cancer via inactivation of PI3K/AKT/mTOR pathway

作者：Shan, Jinlan[1,2];Wang, Zhen[3];Mo, Qiuping[4];Long, Jingpei[1];Fan, Yangfan[1];Cheng, Lu[5];Zhang, Tao[6];Liu, Xiyong[7,8];Wang, Xiaochen[3]

机构：[1]Zhejiang Univ, Womens Hosp, Dept Surg, Sch Med, Hangzhou, Zhejiang, Peoples R China;[2]Zhejiang Univ, Dept Canc Inst, Hangzhou, Zhejiang, Peoples R China;[3]Zhejiang Univ, Affiliated Hosp 2, Dept Breast Surg & Oncol, Key Lab Canc Prevent & Intervent,Sch Med, Hangzhou, Zhejiang, Peoples R China;[4]Zhejiang Prov Peoples Hosp, Dept Breast Surg, Hangzhou, Zhejiang, Peoples R China;[5]Zhejiang Univ, Affiliated Hosp 2, Dept Pathol, Sch Med, Hangzhou, Zhejiang, Peoples R China;[6]Shaoxing Univ, Affiliated Hosp, Dept Breast & Thyroid Surg, Shaoxing, Zhejiang, Peoples R China;[7]Calif Canc Inst, Sino Amer Canc Fdn, Temple City, CA 91780 USA;[8]Calif Canc Inst, Tumor Biomarker Dev, Temple City, CA 91780 USA

年份：2022

卷号：22

期号：3

起止页码：401

外文期刊名：PANCREATOLOGY

收录：SCI-EXPANDED(收录号：WOS:000792208400010)、、Scopus(收录号：2-s2.0-85126382578)、WOS

基金：This study was supported by project grants from Natural Science Foundation of Zhejiang Province , China (Grant No. LY19H160056 and LY12H16014 ), The authors would like to thank Dr. Shizhen Zhang and Dr. Xing Yu for revising manuscript draft. Thank you Dr. Xiaoxu Ge for your help in using database.

语种：英文

外文关键词：Ribonucleotide reductase M2 subunit; Pancreatic cancer; Prognosis; PI3K/AKT/mTOR signaling; Mutant p53

外文摘要：Background/objectives: Ribonucleotide Reductase M2 subunit (RRM2) is elevated in pancreatic cancer and involved in DNA synthesis and cell proliferation. But its specific mechanism including genetic differences and upstream regulatory pathways remains unclear. Methods: We analyzed RRM2 expression of 178 pancreatic cancer patients in Gene Expression Profiling Interactive Analysis (GEPIA) database. Besides, more pancreatic cancer specimens were collected and detected RRM2 expression by immunohistochemistry. RRM2 knockdown by shRNA was applied for functional and mechanism analysis in vitro. Xenograft tumor growth was significantly slower by RRM2 silencing in vivo. Results: It showed that high RRM2 expression had a poorer overall survival and disease free survival. RRM2 expression was higher in tumor grade 2 and 3 than grade 1. Immunohistochemistry data validated that high RRM2 expression predicted worse survival. RRM2 knockdown significantly reduced cell proliferation, inhibited colony formation and suppressed cell cycle progress. Further mechanism assay showed silencing RRM2 lead to inactivation of PI3K/AKT/mTOR pathway and inhibition of mutant p53, which induce S phase arrest and/or apoptosis. In panc-1 cells, S-phase arrest mediated by mutant p53 inhibition, p21 increase and cell cycle related proteins change. While in miapaca-2 cells, induction of apoptosis and S-phase arrest mediated by CDK1 played a coordinated role. Conclusion: Taken together, high RRM2 expression was associated with worse prognosis. Importantly, RRM2 knockdown deactivated PI3K/AKT/mTOR pathway, resulting in cell cycle arrest and/or apoptosis. This study shed light on the molecular mechanism of RRM2 in pancreatic tumor progression and is expected to provide a new theoretical basis for pancreatic cancer treatment. (C) 2022 IAP and EPC. Published by Elsevier B.V. All rights reserved.