The loss of imprinting of MEST has been linked to certain types of cancer by promoter switching. However, MEST-mediated regulation of tumorigenicity and metastasis are yet to be understood. Herein, we reported that MEST is a key regulator of IL-6/JAK/STAT3/Twist-1 signal pathway-mediated tumor metastasis. Enhanced MEST expression is significantly associated with pathogenesis of breast cancer patients. Also, MEST induces metastatic potential of breast cancer through induction of the EMT-TFs-mediated EMT program. Moreover, MEST leads to Twist-1 induction by STAT3 activation and subsequently enables the induction of activation of the EMT program via the induction of STAT3 nuclear translocation. Furthermore, the c-terminal region of MEST was essential for STAT3 activation via the induction of JAK2/STAT3 complex formation. Finally, MEST is required for metastasis in an experimental metastasis model. These observations suggest that MEST is a promising target for intervention to prevent tumor metastasis.
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Conflict of interest
The authors declare that they have no conflict of interest.
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Edited by S. Fulda
Mayer W, Hemberger M, Frank HG, Grummer R, Winterhager E, Kaufmann P, et al. Expression of the imprinted genes MEST/Mest in human and murine placenta suggests a role in angiogenesis. Dev Dyn. 2000;217:1–10.
Lefebvre L, Viville S, Barton SC, Ishino F, Surani MA. Genomic structure and parent-of-origin-specific methylation of Peg1. Hum Mol Genet. 1997;6:1907–15.
Kosaki K, Kosaki R, Craigen WJ, Matsuo N. Isoform-specific imprinting of the human PEG1/MEST gene. Am J Hum Genet. 2000;66:309–12.
Pedersen IS, Dervan PA, Broderick D, Harrison M, Miller N, Delany E, et al. Frequent loss of imprinting of PEG1/MEST in invasive breast cancer. Cancer Res. 1999;59:5449–51.
Nakanishi H, Suda T, Katoh M, Watanabe A, Igishi T, Kodani M, et al. Loss of imprinting of PEG1/MEST in lung cancer cell lines. Oncol Rep. 2004;12:1273–8.
Moon YS, Park SK, Kim HT, Lee TS, Kim JH, Choi YS. Imprinting and expression status of isoforms 1 and 2 of PEG1/MEST gene in uterine leiomyoma. Gynecol Obstet Invest. 2010;70:120–5.
Nishihara S, Hayashida T, Mitsuya K, Schulz TC, Ikeguchi M, Kaibara N, et al. Multipoint imprinting analysis in sporadic colorectal cancers with and without microsatellite instability. Int J Oncol. 2000;17:317–22.
Jin W, Yun C, Kwak MK, Kim TA, Kim SJ. TrkC binds to the type II TGF-beta receptor to suppress TGF-beta signaling. Oncogene. 2007;26:7684–91.
Curtis C, Shah SP, Chin SF, Turashvili G, Rueda OM, Dunning MJ, et al. The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. Nature. 2012;486:346–52.
Harrell JC, Prat A, Parker JS, Fan C, He X, Carey L, et al. Genomic analysis identifies unique signatures predictive of brain, lung, and liver relapse. Breast Cancer Res Treat. 2012;132:523–35.
Valastyan S, Weinberg RA. Tumor metastasis: molecular insights and evolving paradigms. Cell. 2011;147:275–92.
Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.
Fidler IJ. The pathogenesis of cancer metastasis: the ‘seed and soil’ hypothesis revisited. Nat Rev Cancer. 2003;3:453–8.
Jin W, Kim GM, Kim MS, Lim MH, Yun C, Jeong J, et al. TrkC plays an essential role in breast tumor growth and metastasis. Carcinogenesis. 2010;31:1939–47.
Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY, et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell. 2008;133:704–15.
Cheng GZ, Zhang WZ, Sun M, Wang Q, Coppola D, Mansour M, et al. Twist is transcriptionally induced by activation of STAT3 and mediates STAT3 oncogenic function. J Biol Chem. 2008;283:14665–73.
Kim MS, Kim GM, Choi YJ, Kim HJ, Kim YJ, Jin W. TrkC promotes survival and growth of leukemia cells through Akt-mTOR-dependent up-regulation of PLK-1 and Twist-1. Mol Cells. 2013;36:177–84.
Ma XJ, Salunga R, Tuggle JT, Gaudet J, Enright E, McQuary P, et al. Gene expression profiles of human breast cancer progression. Proc Natl Acad Sci USA. 2003;100:5974–9.
Hartwell KA, Muir B, Reinhardt F, Carpenter AE, Sgroi DC, Weinberg RA. The Spemann organizer gene, Goosecoid, promotes tumor metastasis. Proc Natl Acad Sci USA. 2006;103:18969–74.
Kim MS, Kim GM, Choi YJ, Kim HJ, Kim YJ, Jin W. c-Src activation through a TrkA and c-Src interaction is essential for cell proliferation and hematological malignancies. Biochem Biophys Res Commun. 2013;441:431–7.
Mani SA, Yang J, Brooks M, Schwaninger G, Zhou A, Miura N, et al. Mesenchyme Forkhead 1 (FOXC2) plays a key role in metastasis and is associated with aggressive basal-like breast cancers. Proc Natl Acad Sci USA. 2007;104:10069–74.
Hennessy BT, Gonzalez-Angulo AM, Stemke-Hale K, Gilcrease MZ, Krishnamurthy S, Lee JS, et al. Characterization of a naturally occurring breast cancer subset enriched in epithelial-to-mesenchymal transition and stem cell characteristics. Cancer Res. 2009;69:4116–24.
Taube JH, Herschkowitz JI, Komurov K, Zhou AY, Gupta S, Yang J, et al. Core epithelial-to-mesenchymal transition interactome gene-expression signature is associated with claudin-low and metaplastic breast cancer subtypes. Proc Natl Acad Sci USA. 2010;107:15449–54.
Scheel C, Eaton EN, Li SH, Chaffer CL, Reinhardt F, Kah KJ, et al. Paracrine and autocrine signals induce and maintain mesenchymal and stem cell states in the breast. Cell. 2011;145:926–40.
Liu S, Wicha MS. Targeting breast cancer stem cells. J Clin Oncol. 2010;28:4006–12.
Rosen JM, Jordan CT. The increasing complexity of the cancer stem cell paradigm. Science. 2009;324:1670–3.
Frank NY, Schatton T, Frank MH. The therapeutic promise of the cancer stem cell concept. J Clin Invest. 2010;120:41–50.
Creighton CJ, Li X, Landis M, Dixon JM, Neumeister VM, Sjolund A, et al. Residual breast cancers after conventional therapy display mesenchymal as well as tumor-initiating features. Proc Natl Acad Sci USA. 2009;106:13820–5.
Li X, Lewis MT, Huang J, Gutierrez C, Osborne CK, Wu MF, et al. Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. J Natl Cancer Inst. 2008;100:672–9.
Marotta LL, Almendro V, Marusyk A, Shipitsin M, Schemme J, Walker SR, et al. The JAK2/STAT3 signaling pathway is required for growth of CD44(+)CD24(−) stem cell-like breast cancer cells in human tumors. J Clin Invest. 2011;121:2723–35.
Levy DE, Darnell JE Jr. Stats: transcriptional control and biological impact. Nat Rev Mol Cell Biol. 2002;3:651–62.
Buettner R, Mora LB, Jove R. Activated STAT signaling in human tumors provides novel molecular targets for therapeutic intervention. Clin Cancer Res. 2002;8:945–54.
Haura EB, Turkson J, Jove R. Mechanisms of disease: Insights into the emerging role of signal transducers and activators of transcription in cancer. Nat Clin Pract Oncol. 2005;2:315–24.
Yang J, Mani SA, Donaher JL, Ramaswamy S, Itzykson RA, Come C, et al. Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell. 2004;117:927–39.
Fillmore CM, Kuperwasser C. Human breast cancer cell lines contain stem-like cells that self-renew, give rise to phenotypically diverse progeny and survive chemotherapy. Breast Cancer Res. 2008;10:R25.
Kim MS, Lee WS, Jeong J, Kim SJ, Jin W. Induction of metastatic potential by TrkB via activation of IL6/JAK2/STAT3 and PI3K/AKT signaling in breast cancer. Oncotarget. 2015;6:40158–71.
Kwon MC, Koo BK, Moon JS, Kim YY, Park KC, Kim NS, et al. Crif1 is a novel transcriptional coactivator of STAT3. EMBO J. 2008;27:642–53.
Hong S, Song MR. STAT3 but not STAT1 is required for astrocyte differentiation. PLoS ONE. 2014;9:e86851.
This work was supported by a National Research Foundation of Korea grant (NRF-2012R1A2A2A01002728 to WJ and 2015R1D1A1A01059406, 2018R1C1B6008372 to MSK). This work was supported by the Cooperative Research Program for Agriculture Science & Technology Development (Project no. PJ0132772019 to WJ), Rural Development Administration. This research was a part of the project entitled ‘Development of Biomedical materials based on marine proteins’, funded by the Ministry of Oceans and Fisheries, Korea.