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Open Access 01-12-2017 | Research

Novel roles of DC-SIGNR in colon cancer cell adhesion, migration, invasion, and liver metastasis

Authors: Heya Na, Xiaoli Liu, Xiaomeng Li, Xinsheng Zhang, Yu Wang, Zhaohui Wang, Menglang Yuan, Yu Zhang, Shuangyi Ren, Yunfei Zuo

Published in: Journal of Hematology & Oncology | Issue 1/2017

Abstract

Background

Tumor metastasis is an essential cause of the poor prognosis of colon cancer. DC-SIGNR is a C-type lectin that is frequently found on human liver sinusoidal endothelial cells. LSECtin, which is a homologue of DC-SIGNR, has been demonstrated to participate in colon cancer liver metastasis. Due to the similarities in the expression pattern and structure of the two proteins, we speculated that DC-SIGNR could also be involved in this process.

Methods

Colon cancer cells were treated with the DC-SIGNR protein or control IgG, after which cell migration, invasion, and morphology were assayed. Xenograft mouse models were used to determine the role of DC-SIGNR in colon cancer liver metastasis in vivo. In addition, a human gene expression array was used to detect differential gene expression in colon cancer cells stimulated with the DC-SIGNR protein. The serum level of DC-SIGNR was examined in colon cancer patients by ELISA, and the significance of DC-SIGNR was determined.

Results

In our research, we investigated whether DC-SIGNR promotes colon cancer cell adhesion, migration, and invasion. Knocking down mouse DC-SIGNR decreased the liver metastatic potency of colon cancer cells and increased survival time. Expressing human DC-SIGNR enhanced colon cancer liver metastasis. Furthermore, DC-SIGNR conferred metastatic capability on cancer cells by upregulating various metallothionein isoforms. To validate the above results, we also found that the serum DC-SIGNR level was statistically higher in colon cancer patients with liver metastasis compared with those without metastasis.

Conclusions

These results imply that DC-SIGNR may promote colon carcinoma hepatic metastasis and could serve as a promising therapeutic target for anticancer treatment.

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Sosa MS, Bragado P, Aguirre-Ghiso JA. Mechanisms of disseminated cancer cell dormancy: an awakening field. Nat Rev Cancer. 2014;14:611–22.

Bouvet M, Tsuji K, Yang M, Jiang P, Moossa AR, Hoffman RM. In vivo color-coded imaging of the interaction of colon cancer cells and splenocytes in the formation of liver metastases. Cancer Res. 2006;66:11293–7.

Nguyen DX, Bos PD, Massague J. Metastasis: from dissemination to organ-specific colonization. Nat Rev Cancer. 2009;9:274–84.CrossRefPubMed

Irmisch A, Huelsken J. Metastasis: new insights into organ-specific extravasation and metastatic niches. Exp Cell Res. 2013;319:1604–10.CrossRefPubMed

Reymond N, d’Agua BB, Ridley AJ. Crossing the endothelial barrier during metastasis. Nat Rev Cancer. 2013;13:858–70.CrossRefPubMed

Chikina AS, Aleksandrova A. The cellular mechanisms and regulation of metastasis formation. Mol Biol (Mosk). 2014;48:195–213.CrossRef

Pohlmann S, Soilleux EJ, Baribaud F, Leslie GJ, Morris LS, Trowsdale J, Lee B, Coleman N, Doms RW. DC-SIGNR, a DC-SIGN homologue expressed in endothelial cells, binds to human and simian immunodeficiency viruses and activates infection in trans. Proc Natl Acad Sci U S A. 2001;98:2670–5.CrossRefPubMedPubMedCentral

Guo Y, Feinberg H, Conroy E, Mitchell DA, Alvarez R, Blixt O, Taylor ME, Weis WI, Drickamer K. Structural basis for distinct ligand-binding and targeting properties of the receptors DC-SIGN and DC-SIGNR. Nat Struct Mol Biol. 2004;11:591–8.CrossRefPubMed

Cormier EG, Durso RJ, Tsamis F, Boussemart L, Manix C, Olson WC, Gardner JP, Dragic T. L-SIGN (CD209L) and DC-SIGN (CD209) mediate transinfection of liver cells by hepatitis C virus. Proc Natl Acad Sci U S A. 2004;101:14067–72.CrossRefPubMedPubMedCentral

10.

Pohlmann S, Baribaud F, Doms RW. DC-SIGN and DC-SIGNR: helping hands for HIV. Trends Immunol. 2001;22:643–6.CrossRefPubMed

11.

Chan VS, Chan KY, Chen Y, Poon LL, Cheung AN, Zheng B, Chan KH, Mak W, Ngan HY, Xu X, et al. Homozygous L-SIGN (CLEC4M) plays a protective role in SARS coronavirus infection. Nat Genet. 2006;38:38–46.CrossRefPubMed

12.

Zuo Y, Ren S, Wang M, Liu B, Yang J, Kuai X, Lin C, Zhao D, Tang L, He F. Novel roles of liver sinusoidal endothelial cell lectin in colon carcinoma cell adhesion, migration and in-vivo metastasis to the liver. Gut. 2013;62:1169–78.CrossRefPubMed

13.

Jiang Y, Zhang C, Chen K, Chen Z, Sun Z, Zhang Z, Ding D, Ren S, Zuo Y. The clinical significance of DC-SIGN and DC-SIGNR, which are novel markers expressed in human colon cancer. PLoS One. 2014;9, e114748.CrossRefPubMedPubMedCentral

14.

Coupland LA, Chong BH, Parish CR. Platelets and P-selectin control tumor cell metastasis in an organ-specific manner and independently of NK cells. Cancer Res. 2012;72:4662–71.CrossRefPubMed

15.

Yasmin-Karim S, King MR, Messing EM, Lee YF. E-selectin ligand-1 controls circulating prostate cancer cell rolling/adhesion and metastasis. Oncotarget. 2014;5:12097–110.CrossRefPubMedPubMedCentral

16.

Arteta B, Lasuen N, Lopategi A, Sveinbjornsson B, Smedsrod B, Vidal-Vanaclocha F. Colon carcinoma cell interaction with liver sinusoidal endothelium inhibits organ-specific antitumor immunity through interleukin-1-induced mannose receptor in mice. Hepatology. 2010;51:2172–82.CrossRefPubMed

17.

Raudenska M, Gumulec J, Podlaha O, Sztalmachova M, Babula P, Eckschlager T, Adam V, Kizek R, Masarik M. Metallothionein polymorphisms in pathological processes. Metallomics. 2014;6:55–68.CrossRefPubMed

18.

Mehus AA, Muhonen WW, Garrett SH, Somji S, Sens DA, Shabb JB. Quantitation of human metallothionein isoforms: a family of small, highly conserved, cysteine-rich proteins. Mol Cell Proteomics. 2014;13:1020–33.CrossRefPubMedPubMedCentral

19.

Sun X, Niu X, Chen R, He W, Chen, Kang R, Tang D. Metallothionein-1G facilitates sorafenib resistance through inhibition of ferroptosis. Hepatology. 2016.

20.

Chun JH, Kim HK, Kim E, Kim IH, Kim JH, Chang HJ, Choi IJ, Lim HS, Kim IJ, Kang HC, et al. Increased expression of metallothionein is associated with irinotecan resistance in gastric cancer. Cancer Res. 2004;64:4703–6.CrossRefPubMed

21.

Pedersen MO, Larsen A, Stoltenberg M, Penkowa M. The role of metallothionein in oncogenesis and cancer prognosis. Prog Histochem Cytochem. 2009;44:29–64.CrossRefPubMed

22.

Johnson TR, McLellan JS, Graham BS. Respiratory syncytial virus glycoprotein G interacts with DC-SIGN and L-SIGN to activate ERK1 and ERK2. J Virol. 2012;86:1339–47.CrossRefPubMedPubMedCentral

23.

Auwerx J, Francois KO, Vanstreels E, Van Laethem K, Daelemans D, Schols D, Balzarini J. Capture and transmission of HIV-1 by the C-type lectin L-SIGN (DC-SIGNR) is inhibited by carbohydrate-binding agents and polyanions. Antiviral Res. 2009;83:61–70.CrossRefPubMed

24.

Drickamer K. C-type lectin-like domains. Curr Opin Struct Biol. 1999;9:585–90.CrossRefPubMed

25.

Mitchell DA, Fadden AJ, Drickamer K. A novel mechanism of carbohydrate recognition by the C-type lectins DC-SIGN and DC-SIGNR. Subunit organization and binding to multivalent ligands. J Biol Chem. 2001;276:28939–45.CrossRefPubMed

26.

Mogilner A. On the edge: modeling protrusion. Curr Opin Cell Biol. 2006;18:32–9.CrossRefPubMed

27.

Pantaloni D, Le Clainche C, Carlier MF. Mechanism of actin-based motility. Science. 2001;292:1502–6.CrossRefPubMed

28.

Wolff JA, Budker V. The mechanism of naked DNA uptake and expression. Adv Genet. 2005;54:3–20.PubMed

29.

Zitka O, Krizkova S, Huska D, Adam V, Hubalek J, Eckschlager T, Kizek R. Chip gel electrophoresis as a tool for study of matrix metalloproteinase 9 interaction with metallothionein. Electrophoresis. 2011;32:857–60.CrossRefPubMed

30.

Kim HG, Kim JY, Han EH, Hwang YP, Choi JH, Park BH, Jeong HG. Metallothionein-2A overexpression increases the expression of matrix metalloproteinase-9 and invasion of breast cancer cells. FEBS Lett. 2011;585:421–8.CrossRefPubMed

31.

Ryu HH, Jung S, Jung TY, Moon KS, Kim IY, Jeong YI, Jin SG, Pei J, Wen M, Jang WY. Role of metallothionein 1E in the migration and invasion of human glioma cell lines. Int J Oncol. 2012;41:1305–13.PubMed

32.

Paschos KA, Canovas D, Bird NC. The role of cell adhesion molecules in the progression of colorectal cancer and the development of liver metastasis. Cell Signal. 2009;21:665–74.CrossRefPubMed

33.

Powlesland AS, Ward EM, Sadhu SK, Guo Y, Taylor ME, Drickamer K. Widely divergent biochemical properties of the complete set of mouse DC-SIGN-related proteins. J Biol Chem. 2006;281:20440–9.CrossRefPubMed

34.

Geijtenbeek TB, Groot PC, Nolte MA, van Vliet SJ, Gangaram-Panday ST, van Duijnhoven GC, Kraal G, van Oosterhout AJ, van Kooyk Y. Marginal zone macrophages express a murine homologue of DC-SIGN that captures blood-borne antigens in vivo. Blood. 2002;100:2908–16.CrossRefPubMed

35.

Park CG, Takahara K, Umemoto E, Yashima Y, Matsubara K, Matsuda Y, Clausen BE, Inaba K, Steinman RM. Five mouse homologues of the human dendritic cell C-type lectin, DC-SIGN. Int Immunol. 2001;13:1283–90.CrossRefPubMed

36.

Kang YS, Yamazaki S, Iyoda T, Pack M, Bruening SA, Kim JY, Takahara K, Inaba K, Steinman RM, Park CG. SIGN-R1, a novel C-type lectin expressed by marginal zone macrophages in spleen, mediates uptake of the polysaccharide dextran. Int Immunol. 2003;15:177–86.CrossRefPubMed

37.

Koppel EA, van Gisbergen KP, Geijtenbeek TB, van Kooyk Y. Distinct functions of DC-SIGN and its homologues L-SIGN (DC-SIGNR) and mSIGNR1 in pathogen recognition and immune regulation. Cell Microbiol. 2005;7:157–65.CrossRefPubMed

38.

Kasahara K, Fujiwara Y, Nishio K, Ohmori T, Sugimoto Y, Komiya K, Matsuda T, Saijo N. Metallothionein content correlates with the sensitivity of human small cell lung cancer cell lines to cisplatin. Cancer Res. 1991;51:3237–42.PubMed

39.

Yap X, Tan HY, Huang J, Lai Y, Yip GW, Tan PH, Bay BH. Over-expression of metallothionein predicts chemoresistance in breast cancer. J Pathol. 2009;217:563–70.CrossRefPubMed

40.

Hishikawa Y, Koji T, Dhar DK, Kinugasa S, Yamaguchi M, Nagasue N. Metallothionein expression correlates with metastatic and proliferative potential in squamous cell carcinoma of the oesophagus. Br J Cancer. 1999;81:712–20.CrossRefPubMedPubMedCentral

41.

Emri E, Egervari K, Varvolgyi T, Rozsa D, Miko E, Dezso B, Veres I, Mehes G, Emri G, Remenyik E. Correlation among metallothionein expression, intratumoural macrophage infiltration and the risk of metastasis in human cutaneous malignant melanoma. J Eur Acad Dermatol Venereol. 2013;27:e320–7.CrossRefPubMed

42.

Janssen AM, van Duijn W, Kubben FJ, Griffioen G, Lamers CB, van Krieken JH, van de Velde CJ, Verspaget HW. Prognostic significance of metallothionein in human gastrointestinal cancer. Clin Cancer Res. 2002;8:1889–96.PubMed

43.

Nemec AA, Leikauf GD, Pitt BR, Wasserloos KJ, Barchowsky A. Nickel mobilizes intracellular zinc to induce metallothionein in human airway epithelial cells. Am J Respir Cell Mol Biol. 2009;41:69–75.CrossRefPubMed

44.

Ren XY, Zhou Y, Zhang JP, Feng WH, Jiao BH. Metallothionein gene expression under different time in testicular Sertoli and spermatogenic cells of rats treated with cadmium. Reprod Toxicol. 2003;17:219–27.CrossRefPubMed

45.

Wakida K, Shimazawa M, Hozumi I, Satoh M, Nagase H, Inuzuka T, Hara H. Neuroprotective effect of erythropoietin, and role of metallothionein-1 and -2, in permanent focal cerebral ischemia. Neuroscience. 2007;148:105–14.CrossRefPubMed

46.

Goos JA, Coupe VM, van de Wiel MA, Diosdado B, Delis-Van Diemen PM, Hiemstra AC, de Cuba EM, Belien JA, Menke-van der Houven van Oordt CW, Geldof AA, et al. A prognostic classifier for patients with colorectal cancer liver metastasis, based on AURKA, PTGS2 and MMP9. Oncotarget. 2016;7:2123–34.PubMed

47.

Waas ET, Wobbes T, Lomme RM, DeGroot J, Ruers T, Hendriks T. Matrix metalloproteinase 2 and 9 activity in patients with colorectal cancer liver metastasis. Br J Surg. 2003;90:1556–64.CrossRefPubMed

48.

Nothnick WB. Regulation of uterine matrix metalloproteinase-9 and the role of microRNAs. Semin Reprod Med. 2008;26:494–9.CrossRefPubMedPubMedCentral

49.

Gilet A, Zou F, Boumenir M, Frippiat JP, Thornton SN, Lacolley P, Ropars A. Aldosterone up-regulates MMP-9 and MMP-9/NGAL expression in human neutrophils through p38, ERK1/2 and PI3K pathways. Exp Cell Res. 2015;331:152–63.CrossRefPubMed

50.

Zhang Z, Amorosa LF, Coyle SM, Macor MA, Lubitz SE, Carson JL, Birnbaum MJ, Lee LY, Haimovich B. Proteolytic Cleavage of AMPKalpha and intracellular MMP9 expression are both required for TLR4-mediated mTORC1 activation and HIF-1alpha expression in leukocytes. J Immunol. 2015;195:2452–60.CrossRefPubMedPubMedCentral

51.

Bashirova AA, Geijtenbeek TB, van Duijnhoven GC, van Vliet SJ, Eilering JB, Martin MP, Wu L, Martin TD, Viebig N, Knolle PA, et al. A dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin (DC-SIGN)-related protein is highly expressed on human liver sinusoidal endothelial cells and promotes HIV-1 infection. J Exp Med. 2001;193:671–8.CrossRefPubMedPubMedCentral

52.

Engering A, van Vliet SJ, Hebeda K, Jackson DG, Prevo R, Singh SK, Geijtenbeek TB, van Krieken H, van Kooyk Y. Dynamic populations of dendritic cell-specific ICAM-3 grabbing nonintegrin-positive immature dendritic cells and liver/lymph node-specific ICAM-3 grabbing nonintegrin-positive endothelial cells in the outer zones of the paracortex of human lymph nodes. Am J Pathol. 2004;164:1587–95.CrossRefPubMedPubMedCentral

53.

Wu Y, Siadaty MS, Berens ME, Hampton GM, Theodorescu D. Overlapping gene expression profiles of cell migration and tumor invasion in human bladder cancer identify metallothionein 1E and nicotinamide N-methyltransferase as novel regulators of cell migration. Oncogene. 2008;27:6679–89.CrossRefPubMed

54.

Kmiecik AM, Pula B, Suchanski J, Olbromski M, Gomulkiewicz A, Owczarek T, Kruczak A, Ambicka A, Rys J, Ugorski M, et al. Metallothionein-3 increases triple-negative breast cancer cell invasiveness via induction of metalloproteinase expression. PLoS One. 2015;10, e0124865.CrossRefPubMedPubMedCentral

55.

Kessenbrock K, Plaks V, Werb Z. Matrix metalloproteinases: regulators of the tumor microenvironment. Cell. 2010;141:52–67.CrossRefPubMedPubMedCentral

56.

Sanceau J, Truchet S, Bauvois B. Matrix metalloproteinase-9 silencing by RNA interference triggers the migratory-adhesive switch in Ewing’s sarcoma cells. J Biol Chem. 2003;278:36537–46.CrossRefPubMed

57.

Chen X, Su Y, Fingleton B, Acuff H, Matrisian LM, Zent R, Pozzi A. Increased plasma MMP9 in integrin alpha1-null mice enhances lung metastasis of colon carcinoma cells. Int J Cancer. 2005;116:52–61.CrossRefPubMed

Title: Novel roles of DC-SIGNR in colon cancer cell adhesion, migration, invasion, and liver metastasis
Authors: Heya Na
Xiaoli Liu
Xiaomeng Li
Xinsheng Zhang
Yu Wang
Zhaohui Wang
Menglang Yuan
Yu Zhang
Shuangyi Ren
Yunfei Zuo
Publication date: 01-12-2017
Publisher: BioMed Central
Published in: Journal of Hematology & Oncology / Issue 1/2017
Electronic ISSN: 1756-8722
DOI: https://doi.org/10.1186/s13045-016-0383-x

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