Metformin Inhibits Pancreatic Cancer Metastasis Caused by SMAD4 Deficiency and Consequent HNF4G Upregulation

Overview

Journal Protein Cell

Publisher Oxford University Press

Specialties Biochemistry
Cell Biology

Date 2020 Aug 2

PMID 32737864

Citations 39

Authors

Chengcheng Wang

Taiping Zhang

Quan Liao

Menghua Dai

Junchao Guo

Xinyu Yang

Wen Tan

Dongxin Lin

Chen Wu

Yupei Zhao

Affiliations

Soon will be listed here.

Abstract

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 identified HNF4G gene whose silencing most effectively repressed PDAC cell invasiveness. HNF4G overexpression 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-rank P = 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 inhibits in vitro invasion and in vivo metastasis of PDAC cells with SMAD4 deficiency. Furthermore, Metformin treatment significantly improve clinical outcomes and survival in patients with SMAD4-deficient PDAC (log-rank P = 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.

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References

Shukla S, Cyrta J, Murphy D, Walczak E, Ran L, Agrawal P . Aberrant Activation of a Gastrointestinal Transcriptional Circuit in Prostate Cancer Mediates Castration Resistance. Cancer Cell. 2017; 32(6):792-806.e7. PMC: 5728174. DOI: 10.1016/j.ccell.2017.10.008. View

Tang Z, Li C, Kang B, Gao G, Li C, Zhang Z . GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res. 2017; 45(W1):W98-W102. PMC: 5570223. DOI: 10.1093/nar/gkx247. View

Klein A, Wolpin B, Risch H, Stolzenberg-Solomon R, Mocci E, Zhang M . Genome-wide meta-analysis identifies five new susceptibility loci for pancreatic cancer. Nat Commun. 2018; 9(1):556. PMC: 5805680. DOI: 10.1038/s41467-018-02942-5. View

Petersen G, Amundadottir L, Fuchs C, Kraft P, Stolzenberg-Solomon R, Jacobs K . A genome-wide association study identifies pancreatic cancer susceptibility loci on chromosomes 13q22.1, 1q32.1 and 5p15.33. Nat Genet. 2010; 42(3):224-8. PMC: 2853179. DOI: 10.1038/ng.522. View

Zheng J, Huang X, Tan W, Yu D, Du Z, Chang J . Pancreatic cancer risk variant in LINC00673 creates a miR-1231 binding site and interferes with PTPN11 degradation. Nat Genet. 2016; 48(7):747-57. DOI: 10.1038/ng.3568. View

Wu C, Li D, Jia W, Hu Z, Zhou Y, Yu D . Genome-wide association study identifies common variants in SLC39A6 associated with length of survival in esophageal squamous-cell carcinoma. Nat Genet. 2013; 45(6):632-8. DOI: 10.1038/ng.2638. View

Wu C, Miao X, Huang L, Che X, Jiang G, Yu D . Genome-wide association study identifies five loci associated with susceptibility to pancreatic cancer in Chinese populations. Nat Genet. 2011; 44(1):62-6. DOI: 10.1038/ng.1020. View

Yu G, Wang L, He Q . ChIPseeker: an R/Bioconductor package for ChIP peak annotation, comparison and visualization. Bioinformatics. 2015; 31(14):2382-3. DOI: 10.1093/bioinformatics/btv145. View

Golan T, Hammel P, Reni M, Van Cutsem E, Macarulla T, Hall M . Maintenance Olaparib for Germline -Mutated Metastatic Pancreatic Cancer. N Engl J Med. 2019; 381(4):317-327. PMC: 6810605. DOI: 10.1056/NEJMoa1903387. View

10.

Martin T . The role of tight junctions in cancer metastasis. Semin Cell Dev Biol. 2014; 36:224-31. DOI: 10.1016/j.semcdb.2014.09.008. View

11.

Zhou Y, Zhou B, Pache L, Chang M, Khodabakhshi A, Tanaseichuk O . Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat Commun. 2019; 10(1):1523. PMC: 6447622. DOI: 10.1038/s41467-019-09234-6. View

12.

De Pascalis C, Etienne-Manneville S . Single and collective cell migration: the mechanics of adhesions. Mol Biol Cell. 2017; 28(14):1833-1846. PMC: 5541834. DOI: 10.1091/mbc.E17-03-0134. View

13.

Kerr L, Miller D, Matrisian L . TGF-beta 1 inhibition of transin/stromelysin gene expression is mediated through a Fos binding sequence. Cell. 1990; 61(2):267-78. DOI: 10.1016/0092-8674(90)90807-q. View

14.

Wolpin B, Rizzato C, Kraft P, Kooperberg C, Petersen G, Wang Z . Genome-wide association study identifies multiple susceptibility loci for pancreatic cancer. Nat Genet. 2014; 46(9):994-1000. PMC: 4191666. DOI: 10.1038/ng.3052. View

15.

Foretz M, Hebrard S, Leclerc J, Zarrinpashneh E, Soty M, Mithieux G . Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. J Clin Invest. 2010; 120(7):2355-69. PMC: 2898585. DOI: 10.1172/JCI40671. View

16.

Iacobuzio-Donahue C, Fu B, Yachida S, Luo M, Abe H, Henderson C . DPC4 gene status of the primary carcinoma correlates with patterns of failure in patients with pancreatic cancer. J Clin Oncol. 2009; 27(11):1806-13. PMC: 2668706. DOI: 10.1200/JCO.2008.17.7188. View

17.

Laufer C, Fischer B, Billmann M, Huber W, Boutros M . Mapping genetic interactions in human cancer cells with RNAi and multiparametric phenotyping. Nat Methods. 2013; 10(5):427-31. DOI: 10.1038/nmeth.2436. View

18.

Cheng X, Wei L, Huang X, Zheng J, Shao M, Feng T . Solute Carrier Family 39 Member 6 Gene Promotes Aggressiveness of Esophageal Carcinoma Cells by Increasing Intracellular Levels of Zinc, Activating Phosphatidylinositol 3-Kinase Signaling, and Up-regulating Genes That Regulate Metastasis. Gastroenterology. 2017; 152(8):1985-1997.e12. DOI: 10.1053/j.gastro.2017.02.006. View

19.

Lau H, Ng N, Loo L, Jasmen J, Teo A . The molecular functions of hepatocyte nuclear factors - In and beyond the liver. J Hepatol. 2017; 68(5):1033-1048. DOI: 10.1016/j.jhep.2017.11.026. View

20.

Qiu W, Su G . Development of orthotopic pancreatic tumor mouse models. Methods Mol Biol. 2013; 980:215-23. PMC: 4049460. DOI: 10.1007/978-1-62703-287-2_11. View