STAT3 is a Master Regulator of Epithelial Identity and KRAS-driven Tumorigenesis

Overview

Journal Genes Dev

Specialty Molecular Biology

Date 2018 Aug 24

PMID 30135074

Citations 38

Authors

Stephen DAmico

Jiaqi Shi

Benjamin L Martin

Howard C Crawford

Oleksi Petrenko

Nancy C Reich

Affiliations

Soon will be listed here.

Abstract

A dichotomy exists regarding the role of signal transducer and activator of transcription 3 (STAT3) in cancer. Functional and genetic studies demonstrate either an intrinsic requirement for STAT3 or a suppressive effect on common types of cancer. These contrasting actions of STAT3 imply context dependency. To examine mechanisms that underlie STAT3 function in cancer, we evaluated the impact of STAT3 activity in KRAS-driven lung and pancreatic cancer. Our study defines a fundamental and previously unrecognized function of STAT3 in the maintenance of epithelial cell identity and differentiation. Loss of STAT3 preferentially associates with the acquisition of mesenchymal-like phenotypes and more aggressive tumor behavior. In contrast, persistent STAT3 activation through Tyr705 phosphorylation confers a differentiated epithelial morphology that impacts tumorigenic potential. Our results imply a mechanism in which quantitative differences of STAT3 Tyr705 phosphorylation, as compared with other activation modes, direct discrete outcomes in tumor progression.

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References

Liu K, Jiang M, Lu Y, Chen H, Sun J, Wu S . Sox2 cooperates with inflammation-mediated Stat3 activation in the malignant transformation of foregut basal progenitor cells. Cell Stem Cell. 2013; 12(3):304-15. PMC: 3594795. DOI: 10.1016/j.stem.2013.01.007. View

Ischenko I, Petrenko O, Hayman M . Analysis of the tumor-initiating and metastatic capacity of PDX1-positive cells from the adult pancreas. Proc Natl Acad Sci U S A. 2014; 111(9):3466-71. PMC: 3948305. DOI: 10.1073/pnas.1319911111. View

Chu W, Dai P, Li H, Chen J . Transcriptional activity of the DeltaNp63 promoter is regulated by STAT3. J Biol Chem. 2008; 283(12):7328-37. DOI: 10.1074/jbc.M800183200. View

Couto J, Daly L, Almeida A, Knauf J, Fagin J, Sobrinho-Simoes M . STAT3 negatively regulates thyroid tumorigenesis. Proc Natl Acad Sci U S A. 2012; 109(35):E2361-70. PMC: 3435219. DOI: 10.1073/pnas.1201232109. View

Marques I, Weiss F, Vlecken D, Nitsche C, Bakkers J, Lagendijk A . Metastatic behaviour of primary human tumours in a zebrafish xenotransplantation model. BMC Cancer. 2009; 9:128. PMC: 2697170. DOI: 10.1186/1471-2407-9-128. View

He G, Yu G, Temkin V, Ogata H, Kuntzen C, Sakurai T . Hepatocyte IKKbeta/NF-kappaB inhibits tumor promotion and progression by preventing oxidative stress-driven STAT3 activation. Cancer Cell. 2010; 17(3):286-97. PMC: 2841312. DOI: 10.1016/j.ccr.2009.12.048. View

De Cock J, Shibue T, Dongre A, Keckesova Z, Reinhardt F, Weinberg R . Inflammation Triggers Zeb1-Dependent Escape from Tumor Latency. Cancer Res. 2016; 76(23):6778-6784. PMC: 5135644. DOI: 10.1158/0008-5472.CAN-16-0608. View

Grivennikov S, Karin E, Terzic J, Mucida D, Yu G, Vallabhapurapu S . IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer. Cancer Cell. 2009; 15(2):103-13. PMC: 2667107. DOI: 10.1016/j.ccr.2009.01.001. View

McDonald O, Maitra A, Hruban R . Human correlates of provocative questions in pancreatic pathology. Adv Anat Pathol. 2012; 19(6):351-62. PMC: 3487591. DOI: 10.1097/PAP.0b013e318273f998. View

10.

Kandoth C, McLellan M, Vandin F, Ye K, Niu B, Lu C . Mutational landscape and significance across 12 major cancer types. Nature. 2013; 502(7471):333-339. PMC: 3927368. DOI: 10.1038/nature12634. View

11.

Lesina M, Kurkowski M, Ludes K, Rose-John S, Treiber M, Kloppel G . Stat3/Socs3 activation by IL-6 transsignaling promotes progression of pancreatic intraepithelial neoplasia and development of pancreatic cancer. Cancer Cell. 2011; 19(4):456-69. DOI: 10.1016/j.ccr.2011.03.009. View

12.

Ho P, Lay E, Jian W, Parra D, Chan K . Stat3 activation in urothelial stem cells leads to direct progression to invasive bladder cancer. Cancer Res. 2012; 72(13):3135-42. PMC: 3418917. DOI: 10.1158/0008-5472.CAN-11-3195. View

13.

Akbani R, Ng P, Werner H, Shahmoradgoli M, Zhang F, Ju Z . A pan-cancer proteomic perspective on The Cancer Genome Atlas. Nat Commun. 2014; 5:3887. PMC: 4109726. DOI: 10.1038/ncomms4887. View

14.

Jhan J, Andrechek E . Stat3 accelerates Myc induced tumor formation while reducing growth rate in a mouse model of breast cancer. Oncotarget. 2016; 7(40):65797-65807. PMC: 5323193. DOI: 10.18632/oncotarget.11667. View

15.

Fukuda A, Wang S, Morris 4th J, Folias A, Liou A, Kim G . Stat3 and MMP7 contribute to pancreatic ductal adenocarcinoma initiation and progression. Cancer Cell. 2011; 19(4):441-55. PMC: 3075548. DOI: 10.1016/j.ccr.2011.03.002. View

16.

Shen Y, Schlessinger K, Zhu X, Meffre E, Quimby F, Levy D . Essential role of STAT3 in postnatal survival and growth revealed by mice lacking STAT3 serine 727 phosphorylation. Mol Cell Biol. 2003; 24(1):407-19. PMC: 303338. DOI: 10.1128/MCB.24.1.407-419.2004. View

17.

Putoczki T, Thiem S, Loving A, Busuttil R, Wilson N, Ziegler P . Interleukin-11 is the dominant IL-6 family cytokine during gastrointestinal tumorigenesis and can be targeted therapeutically. Cancer Cell. 2013; 24(2):257-71. DOI: 10.1016/j.ccr.2013.06.017. View

18.

Guerra C, Schuhmacher A, Canamero M, Grippo P, Verdaguer L, Perez-Gallego L . Chronic pancreatitis is essential for induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes in adult mice. Cancer Cell. 2007; 11(3):291-302. DOI: 10.1016/j.ccr.2007.01.012. View

19.

Pilati C, Amessou M, Bihl M, Balabaud C, Tran Van Nhieu J, Paradis V . Somatic mutations activating STAT3 in human inflammatory hepatocellular adenomas. J Exp Med. 2011; 208(7):1359-66. PMC: 3135371. DOI: 10.1084/jem.20110283. View

20.

Ischenko I, Liu J, Petrenko O, Hayman M . Transforming growth factor-beta signaling network regulates plasticity and lineage commitment of lung cancer cells. Cell Death Differ. 2014; 21(8):1218-28. PMC: 4085528. DOI: 10.1038/cdd.2014.38. View