Metformin inhibits pancreatic cancer metastasis caused by SMAD4 deficiency and consequent HNF4G upregulation

被引:55
作者
Wang, Chengcheng [1 ]
Zhang, Taiping [1 ]
Liao, Quan [1 ]
Dai, Menghua [1 ]
Guo, Junchao [1 ]
Yang, Xinyu [2 ]
Tan, Wen [2 ]
Lin, Dongxin [2 ,3 ,4 ]
Wu, Chen [2 ,3 ,5 ]
Zhao, Yupei [1 ]
机构
[1] Chinese Acad Med Sci & Peking Union Med Coll, Peking Union Med Coll Hosp, Dept Gen Surg, Beijing 100730, Peoples R China
[2] Chinese Acad Med Sci & Peking Union Med Coll, Natl Canc Ctr, Dept Etiol & Carcinogenesis, Canc Hosp, Beijing 100021, Peoples R China
[3] Nanjing Med Univ, Collaborat Innovat Ctr Canc Personalized Med, Nanjing 211166, Peoples R China
[4] Sun Yat Sen Univ Canc Ctr, State Key Lab Oncol South China, Guangzhou 510060, Peoples R China
[5] Chinese Acad Med Sci, CAMS Oxford Inst COI, Beijing 100730, Peoples R China
关键词
pancreatic cancer; HNF4G; SMAD4; deficiency; SMAD4-deficient PDAC; Metformin; GENOME-WIDE ASSOCIATION; GENETIC INTERACTIONS; SUSCEPTIBILITY LOCI; CELLS; EXPRESSION; VARIANTS; SURVIVAL; PATHWAY; RISK; RNAI;
D O I
10.1007/s13238-020-00760-4
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Pancreatic ductal adenocarcinoma (PDAC) has poor prognosis due to limited therapeutic options. This study examines the roles of genome-wide association study identified PDAC-associated genes as therapeutic targets. We have identifiedHNF4Ggene whose silencing most effectively repressed PDAC cell invasiveness.HNF4Goverexpression is induced by the deficiency of transcriptional factor and tumor suppressor SMAD4. Increased HNF4G are correlated with SMAD4 deficiency in PDAC tumor samples and associated with metastasis and poor survival time in xenograft animal model and in patients with PDAC (log-rankP= 0.036; HR = 1.60, 95% CI = 1.03-2.47). We have found that Metformin suppresses HNF4G activity via AMPK-mediated phosphorylation-coupled ubiquitination degradation and inhibitsin vitroinvasion andin vivometastasis of PDAC cells with SMAD4 deficiency. Furthermore, Metformin treatment significantly improve clinical outcomes and survival in patients with SMAD4-deficient PDAC (log-rankP= 0.022; HR = 0.31, 95% CI = 0.14-0.68) but not in patients with SMAD4-normal PDAC. Pathway analysis shows that HNF4G may act in PDAC through the cell-cell junction pathway. These results indicate that SMAD4 deficiency-induced overexpression of HNF4G plays a critical oncogenic role in PDAC progression and metastasis but may form a druggable target for Metformin treatment.
引用
收藏
页码:128 / 144
页数:17
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[41]   SMAD4 loss predicts worse overall and distant metastasis-free survival in patients with resected pancreatic adenocarcinoma [J].
Anstadt, Emily J. ;
Carmona, Ruben ;
Berlin, Eva ;
Yegya-Raman, Nikhil ;
Venigalla, Sriram ;
Reddy, Vishruth ;
Williams, Graeme R. ;
Leibensperger, Mark R. ;
Wojcieszynski, Andrzej ;
Baumann, Brian C. ;
Lee, Major K. ;
Plastaras, John P. ;
Furth, Emma E. ;
Mell, Loren K. ;
Metz, James M. ;
Ben-Josef, Edgar .
CANCER, 2024, 130 (03) :476-484
[42]   TAp73 Inhibits EMT and Cell Migration in Pancreatic Cancer Cells through Promoting SMAD4 Expression and SMAD4-Dependent Inhibition of ERK Activation [J].
Ungefroren, Hendrik ;
Konukiewitz, Bjorn ;
Braun, Rudiger ;
Wellner, Ulrich Friedrich ;
Lehnert, Hendrik ;
Marquardt, Jens-Uwe .
CANCERS, 2023, 15 (15)
[43]   The expression of S100A8 in pancreatic cancer-associated monocytes is associated with the Smad4 status of pancreatic cancer cells [J].
Sheikh, Adnan A. ;
Vimalachandran, Dale ;
Thompson, Christopher C. ;
Jenkins, Rosalind E. ;
Nedjadi, Taoufik ;
Shekouh, Ali ;
Campbell, Fiona ;
Dodson, Andrew ;
Prime, Wendy ;
Crnogorac-Jurcevic, Tatjana ;
Lemoine, Nicholas R. ;
Costello, Eithne .
PROTEOMICS, 2007, 7 (11) :1929-1940
[44]   β-elemene inhibits the proliferation of T24 bladder carcinoma cells through upregulation of the expression of Smad4 [J].
Lu, Xinsheng ;
Wang, Yi ;
Luo, Hongmei ;
Qiu, Weibin ;
Han, Hu ;
Chen, Xian ;
Yang, Luoyan .
MOLECULAR MEDICINE REPORTS, 2013, 7 (02) :513-518
[45]   Higher frequency of DPC4/Smad4 alterations in pancreatic cancer cell lines than in primary pancreatic adenocarcinomas [J].
Bartsch, D ;
Barth, P ;
Bastian, D ;
Ramaswamy, A ;
Gerdes, B ;
Chaloupka, B ;
Deiss, Y ;
Simon, B ;
Schudy, A .
CANCER LETTERS, 1999, 139 (01) :43-49
[46]   Smad4 Inhibits VEGF-A and VEGF-C Expressions via Enhancing Smad3 Phosphorylation in Colon Cancer [J].
Li, Xuemei ;
Li, Xinlei ;
Lv, Xiaohong ;
Xiao, Jianbing ;
Liu, Baoquan ;
Zhang, Yafang .
ANATOMICAL RECORD-ADVANCES IN INTEGRATIVE ANATOMY AND EVOLUTIONARY BIOLOGY, 2017, 300 (09) :1560-1569
[47]   Smad4 deficiency ameliorates the progressive corneal stroma thinning caused by the loss of Tbr1 [J].
Yuan, Yong ;
Yasuda, Shingo ;
Funk, Kaitlyn L. ;
Kao, Winston ;
Saika, Shizuya ;
Kaufman, Adam ;
Liu, Chia-Yang .
OCULAR SURFACE, 2025, 36 :181-189
[48]   New insight into the role of SMAD4 mutation/deficiency in the prognosis and therapeutic resistance of pancreatic ductal adenocarcinomas [J].
Yao, Hongjuan ;
Luo, Liaoxin ;
Li, Rui ;
Zhao, Yelin ;
Zhang, Li ;
Pesic, Milica ;
Cai, Lin ;
Li, Liang .
BIOCHIMICA ET BIOPHYSICA ACTA-REVIEWS ON CANCER, 2024, 1879 (06)
[49]   Differential Expression of Multiple Genes in Association with MADH4/DPC4/SMAD4 Inactivation in Pancreatic Cancer [J].
Cao, Dengfeng ;
Ashfaq, Raheela ;
Goggins, Michael G. ;
Hruban, Ralph H. ;
Kern, Scott E. ;
Iacobuzio-Donahue, Christine A. .
INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY, 2008, 1 (06) :510-517
[50]   Restoration of Smad4 in BxPC3 pancreatic cancer cells attenuates proliferation without altering angiogenesis [J].
Yasutome, M ;
Gunn, J ;
Korc, M .
CLINICAL & EXPERIMENTAL METASTASIS, 2005, 22 (06) :461-473