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Open Access 01-12-2019 | Colorectal Cancer | Research

RETRACTED ARTICLE: miR-195-5p/NOTCH2-mediated EMT modulates IL-4 secretion in colorectal cancer to affect M2-like TAM polarization

Published in: Journal of Hematology & Oncology | Issue 1/2019

Abstract

Background

Tumor microenvironment (TME) is a complex environment containing tumor cells, tumor-associated macrophages (TAMs), interstitial cells, and non-cellular components. Epithelial–mesenchymal transition (EMT), as a major actor in cancer tumorigenicity and metastasis, was involved in the interaction between TAMs and tumor cells. However, the potential mechanisms of EMT and how EMT-programmed tumor cells affect M2-like TAMs still need further exploration.

Methods

An integrated analysis of nine CRC miRNA expression datasets was performed. Functional assays, including the EdU, clone formation, wound healing, and transwell assays, were used to determine the anticancer role of miR-195-5p in human CRC progression. Furthermore, RNA immunoprecipitation, RNA decay, and dual-luciferase reporter assays were used to determine the mechanism of miR-195-p CRC progression. Then co-culture, migration, and ELISA assays were applied to determine the role of miR-195-5p in macrophage recruitment and alternative polarization. Xenograft mouse models were used to determine the role of miR-195-5p in CRC tumorigenicity and TAM polarization in vivo.

Results

An integrated analysis confirmed that miR-195-5p was significantly downregulated in CRC tissues, and patients with a low level of miR-195-5p had significantly shortened overall survival as revealed by the TCGA-COAD dataset. Altered miR-195-5p in colon cancer cells led to distinct changes of proliferation, migration, invasion, and EMT. Mechanistically, miR-195-5p regulated NOTCH2 expression in a post-transcriptional manner by directly binding to 3′-UTR of the Notch2 mRNA. Subsequently, miR-195-5p/NOTCH2 suppressed GATA3-mediated IL-4 secretion in CRC cells and ultimately inhibited M2-like TAM polarization.

Conclusions

miR-195-5p may play a vital role in regulating NOTCH2-mediated tumor cell EMT, thereby affecting IL-4-related M2-like TAM polarization in CRC.

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Smith RA, Andrews K, Brooks D, DeSantis CE, Fedewa SA, Lortet-Tieulent J, Manassaram-Baptiste D, Brawley OW, Wender RC. Cancer screening in the United States, 2016: a review of current American Cancer Society guidelines and current issues in cancer screening. CA Cancer J Clin. 2016;66(2):96–114.PubMedCrossRef

Suarez-Carmona M, Lesage J, Cataldo D, Gilles C. EMT and inflammation: inseparable actors of cancer progression. Mol Oncol. 2017;11(7):805–23.PubMedPubMedCentralCrossRef

Zheng X, Carstens J, Kim J, Scheible M, Kaye J, Sugimoto H, Wu C, LeBleu V, Kalluri R. Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer. Nature. 2015;527(7579):525–30.PubMedPubMedCentralCrossRef

Hsieh CH, Tai SK, Yang MH. Snail-overexpressing cancer cells promote M2-like polarization of tumor-associated macrophages by delivering MiR-21-abundant exosomes. Neoplasia. 2018;20(8):775–88.PubMedPubMedCentralCrossRef

Bates RC, DeLeo MJ 3rd, Mercurio AM. The epithelial-mesenchymal transition of colon carcinoma involves expression of IL-8 and CXCR-1-mediated chemotaxis. Exp Cell Res. 2004;299(2):315–24.PubMedCrossRef

Tazzyman S, Barry ST, Ashton S, Wood P, Blakey D, Lewis CE, Murdoch C. Inhibition of neutrophil infiltration into A549 lung tumors in vitro and in vivo using a CXCR2-specific antagonist is associated with reduced tumor growth. Int J Cancer. 2011;129(4):847–58.PubMedCrossRef

Kudo-Saito C, Shirako H, Takeuchi T, Kawakami Y. Cancer metastasis is accelerated through immunosuppression during Snail-induced EMT of cancer cells. Cancer Cell. 2009;15(3):195–206.PubMedCrossRef

Alfaro C, Teijeira A, Onate C, Perez G, Sanmamed MF, Andueza MP, Alignani D, Labiano S, Azpilikueta A, Rodriguez-Paulete A, Garasa S, Fusco JP, Aznar A, Inoges S, De Pizzol M, Allegretti M, Medina-Echeverz J, Berraondo P, Perez-Gracia JL, Melero I. Tumor-produced interleukin-8 attracts human myeloid-derived suppressor cells and elicits extrusion of neutrophil extracellular traps (NETs). Clin Cancer Res. 2016;22(15):3924–36.PubMedCrossRef

Baer C, Squadrito ML, Laoui D, Thompson D, Hansen SK, Kiialainen A, Hoves S, Ries CH, Ooi CH, De Palma M. Suppression of microRNA activity amplifies IFN-gamma-induced macrophage activation and promotes anti-tumour immunity. Nat Cell Biol. 2016;18(7):790–802.PubMedCrossRef

10.

Zhong X, Chen B, Yang Z. The role of tumor-associated macrophages in colorectal carcinoma progression. Cell Physiol Biochem. 2018;45(1):356–65.PubMedCrossRef

11.

Helm O, Held-Feindt J, Grage-Griebenow E, Reiling N, Ungefroren H, Vogel I, Kruger U, Becker T, Ebsen M, Rocken C, Kabelitz D, Schafer H, Sebens S. Tumor-associated macrophages exhibit pro- and anti-inflammatory properties by which they impact on pancreatic tumorigenesis. Int J Cancer. 2014;135(4):843–61.PubMedCrossRef

12.

Zhou S, Yu L, Xiong M, Dai G. LncRNA SNHG12 promotes tumorigenesis and metastasis in osteosarcoma by upregulating Notch2 by sponging miR-195-5p. Biochem Biophys Res Commun. 2018;495(2):1822–32.PubMedCrossRef

13.

Martinez VG, Rubio C, Martinez-Fernandez M, Segovia C, Lopez-Calderon F, Garin MI, Teijeira A, Munera-Maravilla E, Varas A, Sacedon R, Guerrero F, Villacampa F, de la Rosa F, Castellano D, Lopez-Collazo E, Paramio JM, Vicente A, Duenas M. BMP4 induces M2 macrophage polarization and favors tumor progression in bladder cancer. Clin Cancer Res. 2017;23(23):7388–99.PubMedCrossRef

14.

Su S, Liu Q, Chen J, Chen J, Chen F, He C, Huang D, Wu W, Lin L, Huang W, Zhang J, Cui X, Zheng F, Li H, Yao H, Su F, Song E. A positive feedback loop between mesenchymal-like cancer cells and macrophages is essential to breast cancer metastasis. Cancer Cell. 2014;25(5):605–20.PubMedCrossRef

15.

Lamouille S, Xu J, Derynck R. Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol. 2014;15(3):178–96.PubMedPubMedCentralCrossRef

16.

Nutter JM, Fitzgerald TL, Bertrand FE, Sigounas G. Notch-1 promotes stemness and epithelial to mesenchymal transition in colorectal cancer. J Cell Biochem. 2015;116(11):2517–27.PubMedCrossRef

17.

Cavnar MJ, Zeng S, Kim TS, Sorenson EC, Ocuin LM, Balachandran VP, Seifert AM, Greer JB, Popow R, Crawley MH, Cohen NA, Green BL, Rossi F, Besmer P, Antonescu CR, DeMatteo RP. KIT oncogene inhibition drives intratumoral macrophage M2 polarization. J Exp Med. 2013;210(13):2873–86.PubMedPubMedCentralCrossRef

18.

Maraver A, Fernandez-Marcos PJ, Cash TP, Mendez-Pertuz M, Duenas M, Maietta P, Martinelli P, Munoz-Martin M, Martinez-Fernandez M, Canamero M, Roncador G, Martinez-Torrecuadrada JL, Grivas D, de la Pompa JL, Valencia A, Paramio JM, Real FX, Serrano M. NOTCH pathway inactivation promotes bladder cancer progression. J Clin Invest. 2015;125(2):824–30.PubMedPubMedCentralCrossRef

19.

Yuan X, Wu H, Han N, Xu H, Chu Q, Yu S, Chen Y, Wu K. Notch signaling and EMT in non-small cell lung cancer: biological significance and therapeutic application. J Hematol Oncol. 2014;7:87.PubMedPubMedCentralCrossRef

20.

Tseng YC, Tsai YH, Tseng MJ, Hsu KW, Yang MC, Huang KH, Li AF, Chi CW, Hsieh RH, Ku HH, Yeh TS. Notch2-induced COX-2 expression enhancing gastric cancer progression. Mol Carcinog. 2012;51(12):939–51.PubMedCrossRef

21.

Peng H, Ning H, Wang Q, Lu W, Chang Y, Wang TT, Lai J, Kolattukudy PE, Hou R, Hoft DF, Dykewicz MS, Liu J. Monocyte chemotactic protein-induced protein 1 controls allergic airway inflammation by suppressing IL-5-producing TH2 cells through the Notch/Gata3 pathway. J Allergy Clin Immunol. 2018;142(2):582–594.e510.PubMedCrossRef

22.

Tanaka S, Motomura Y, Suzuki Y, Yagi R, Inoue H, Miyatake S, Kubo M. The enhancer HS2 critically regulates GATA-3-mediated Il4 transcription in T(H)2 cells. Nat Immunol. 2011;12(1):77–85.PubMedCrossRef

23.

Gordon S, Martinez FO. Alternative activation of macrophages: mechanism and functions. Immunity. 2010;32(5):593–604.PubMedCrossRef

24.

Zhang X, Xu J, Jiang T, Liu G, Wang D, Lu Y. MicroRNA-195 suppresses colorectal cancer cells proliferation via targeting FGF2 and regulating Wnt/beta-catenin pathway. Am J Cancer Res. 2016;6(11):2631–40.PubMedPubMedCentral

25.

Zheng L, Chen J, Zhou Z, He Z. miR-195 enhances the radiosensitivity of colorectal cancer cells by suppressing CARM1. Onco Targets Ther. 2017;10:1027–38.PubMedPubMedCentralCrossRef

26.

Jin Y, Wang M, Hu H, Huang Q, Chen Y, Wang G. Overcoming stemness and chemoresistance in colorectal cancer through miR-195-5p-modulated inhibition of notch signaling. Int J Biol Macromol. 2018;117:445–53.PubMedCrossRef

27.

Frid MG, Brunetti JA, Burke DL, Carpenter TC, Davie NJ, Reeves JT, Roedersheimer MT, van Rooijen N, Stenmark KR. Hypoxia-induced pulmonary vascular remodeling requires recruitment of circulating mesenchymal precursors of a monocyte/macrophage lineage. Am J Pathol. 2006;168(2):659–69.PubMedPubMedCentralCrossRef

28.

Chen F, Wang S, Fang Y, Zheng L, Zhi X, Cheng B, Chen Y, Zhang C, Shi D, Song H, Cai C, Zhou P, Xiong B. Feasibility of a novel one-stop ISET device to capture CTCs and its clinical application. Oncotarget. 2017;8(2):3029–41.

29.

Sun M, Song H, Wang S, Zhang C, Zheng L, Chen F, Shi D, Chen Y, Yang C, Xiang Z, Liu Q, Wei C, Xiong B. Integrated analysis identifies microRNA-195 as a suppressor of Hippo-YAP pathway in colorectal cancer. J Hematol Oncol. 2017;10(1):79.PubMedPubMedCentralCrossRef

30.

Slattery ML, Herrick JS, Pellatt DF, Stevens JR, Mullany LE, Wolff E, Hoffman MD, Samowitz WS, Wolff RK. MicroRNA profiles in colorectal carcinomas, adenomas and normal colonic mucosa: variations in miRNA expression and disease progression. Carcinogenesis. 2016;37(3):245–61.PubMedPubMedCentralCrossRef

31.

Burow DA, Umeh-Garcia MC, True MB, Bakhaj CD, Ardell DH, Cleary MD. Dynamic regulation of mRNA decay during neural development. Neural Dev. 2015;10:11.PubMedPubMedCentralCrossRef

32.

Sakata-Yanagimoto M, Nakagami-Yamaguchi E, Saito T, Kumano K, Yasutomo K, Ogawa S, Kurokawa M, Chiba S. Coordinated regulation of transcription factors through Notch2 is an important mediator of mast cell fate. Proc Natl Acad Sci U S A. 2008;105(22):7839–44.PubMedPubMedCentralCrossRef

33.

Furuya K, Sasaki A, Tsunoda Y, Tsuji M, Udaka Y, Oyamada H, Tsuchiya H, Oguchi K. Eribulin upregulates miR-195 expression and downregulates Wnt3a expression in non-basal-like type of triple-negative breast cancer cell MDA-MB-231. Hum Cell. 2016;29(2):76–82.PubMedCrossRef

34.

Wu J, Ji A, Wang X, Zhu Y, Yu Y, Lin Y, Liu Y, Li S, Liang Z, Xu X, Zheng X, Xie L. MicroRNA-195-5p, a new regulator of Fra-1, suppresses the migration and invasion of prostate cancer cells. J Transl Med. 2015;13:289.PubMedPubMedCentralCrossRef

35.

Cai C, Chen QB, Han ZD, Zhang YQ, He HC, Chen JH, Chen YR, Yang SB, Wu YD, Zeng YR, Qin GQ, Liang YX, Dai QS, Jiang FN, Wu SL, Zeng GH, Zhong WD, Wu CL. miR-195 inhibits tumor progression by targeting RPS6KB1 in human prostate cancer. Clin Cancer Res. 2015;21(21):4922–34.PubMedPubMedCentralCrossRef

36.

Li M, Ren CX, Zhang JM, Xin XY, Hua T, Wang HB, Wang HB. The effects of miR-195-5p/MMP14 on proliferation and invasion of cervical carcinoma cells through TNF signaling pathway based on bioinformatics analysis of microarray profiling. Cell Physiol Biochem. 2018;50(4):1398–413.PubMedCrossRef

37.

Hayashi T, Gust KM, Wyatt AW, Goriki A, Jager W, Awrey S, Li N, Oo HZ, Altamirano-Dimas M, Buttyan R, Fazli L, Matsubara A, Black PC. Not all NOTCH is created equal: the oncogenic role of NOTCH2 in bladder cancer and its implications for targeted therapy. Clin Cancer Res. 2016;22(12):2981–92.PubMedCrossRef

38.

Chu D, Zheng J, Wang W, Zhao Q, Li Y, Li J, Xie H, Zhang H, Dong G, Xu C, Li M, Chen D, Ji G. Notch2 expression is decreased in colorectal cancer and related to tumor differentiation status. Ann Surg Oncol. 2009;16(12):3259–66.PubMedCrossRef

39.

Nakano N, Nishiyama C, Yagita H, Hara M, Motomura Y, Kubo M, Okumura K, Ogawa H. Notch signaling enhances FcepsilonRI-mediated cytokine production by mast cells through direct and indirect mechanisms. J Immunol. 2015;194(9):4535–44.

40.

Zhu J, Min B, Hu-Li J, Watson CJ, Grinberg A, Wang Q, Killeen N, Urban JF Jr, Guo L, Paul WE. Conditional deletion of Gata3 shows its essential function in T(H)1-T(H)2 responses. Nat Immunol. 2004;5(11):1157–65.PubMedCrossRef

41.

Zhang Y, Selvanesan BC, Topi G, Salim T, Sand-Dejmek J, Jönsson G, Sjölander A. M2-like macrophages induce colon cancer cell invasion via matrix metalloproteinases. J Cell Physiol. 2017;232(12):3468–80.PubMedCrossRef

42.

Hamm A, Prenen H, Van Delm W, Di Matteo M, Wenes M, Delamarre E, Schmidt T, Weitz J, Sarmiento R, Dezi A, Gasparini G, Rothé F, Schmitz R, D'Hoore A, Iserentant H, Hendlisz A, Mazzone M. Tumour-educated circulating monocytes are powerful candidate biomarkers for diagnosis and disease follow-up of colorectal cancer. Gut. 2016;65(6):990–1000.PubMedCrossRef

43.

Badawi M, Abouelfadl D, El-Sharkawy S, El-Aal W, Abbas N. Tumor-associated macrophage (TAM) and angiogenesis in human colon carcinoma. Open Access Maced J Med Sci. 2015;3(2):209–14.PubMedPubMedCentralCrossRef

44.

Korehisa S, Oki E, Iimori M, Nakaji Y, Shimokawa M, Saeki H, Okano S, Oda Y, Maehara Y. Clinical significance of programmed cell death-ligand 1 expression and the immune microenvironment at the invasive front of colorectal cancers with high microsatellite instability. Int J Cancer. 2018;142(4):822–32.PubMedCrossRef

45.

Cortes M, Sanchez-Moral L, de Barrios O, Fernandez-Acenero MJ, Martinez-Campanario MC, Esteve-Codina A, Darling DS, Gyorffy B, Lawrence T, Dean DC, Postigo A. Tumor-associated macrophages (TAMs) depend on ZEB1 for their cancer-promoting roles. EMBO J. 2017;36(22):3336–55.PubMedPubMedCentralCrossRef

Title: RETRACTED ARTICLE: miR-195-5p/NOTCH2-mediated EMT modulates IL-4 secretion in colorectal cancer to affect M2-like TAM polarization
Publication date: 01-12-2019
Keywords: Colorectal Cancer
Colorectal Cancer
Published in: Journal of Hematology & Oncology / Issue 1/2019
Electronic ISSN: 1756-8722
DOI: https://doi.org/10.1186/s13045-019-0708-7

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