Expression analysis of Dickkopf-related protein 3 (Dkk3) suggests its pleiotropic roles for a secretory glycoprotein in adult mouse

Journal of Molecular Histology - Tập 48 - Trang 29-39 - 2016
Junji Inoue1, Hirofumi Fujita1, Tetsuya Bando1, Yoichi Kondo1,2, Hiromi Kumon3,4, Hideyo Ohuchi1
1Department of Cytology and Histology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
2Department of Anatomy and Cell Biology, Osaka Medical College, Takatsuki, Japan
3Innovation Center Okayama for Nanobio-targeted Therapy (ICONT), Okayama University, Okayama, Japan
4Niimi College, Niimi, Japan

Tóm tắt

Dickkopf-related protein 3 (Dkk3) is the third member of the Dkk gene family and identical to the gene, whose expression was reduced in immortalized cells. Therefore, its another name is reduced expression in immortalized cells. Since the intratumoral introduction of Dkk3 inhibits tumor growth in mouse models of cancers, Dkk3 is likely a tumor suppressor gene. However, the functions of Dkk3 in vivo remain unclear. As the first step to decipher the physiological roles of this gene, we examined the expression pattern of Dkk3 in various tissues from adult mice. In situ hybridization showed that Dkk3 mRNA was detected in the brain, retina, heart, gastrointestinal tract, adrenal glands, thymus, prostate glands, seminal vesicles, testes, and ovaries in a regionally specific manner. Furthermore, we raised anti-mouse Dkk3 antibody and performed immunohistochemistry. Cytoplasmic localization of Dkk3 protein was observed in the cells of the adrenal medulla, while Dkk3 immunoreactivity was observed in the lumen of the stomach and intestine, implying that the Dkk3 protein may be secreted into the lumen of the gastrointestinal tract. These results suggest that Dkk3 has pleiotropic roles for a secretory glycoprotein that acts primarily in the gastrointestinal tract, thymus, endocrine and reproductive organs of the mouse.

Tài liệu tham khảo

Abarzua F, Sakaguchi M, Takaishi M, Nasu Y, Kurose K, Ebara S, Miyazaki M, Namba M, Kumon H, Huh NH (2005) Adenovirus-mediated overexpression of REIC/Dkk-3 selectively induces apoptosis in human prostate cancer cells through activation of c-Jun-NH2-kinase. Cancer Res 65:9617–9622 Bafico A, Liu G, Yaniv A, Gazit A, Aaronson SA (2001) Novel mechanism of Wnt signalling inhibition mediated by Dickkopf-1 interaction with LRP6/Arrow. Nat Cell Biol 7:683–686 Bamberger C, Hafner A, Schmale H, Werner S (2005) Expression of different p63 variants in healing skin wounds suggests a role of p63 in reepithelialization and muscle repair. Wound Repair Regen 13:41–50 Barrantes IB, Montero-Pedrazuela A, Guadaño-Ferraz A, Obregon MJ, de Martinez MR, Gailus-Durner V, Fuchs H, Franz TJ, Kalaydjiev S, Klempt M, Hölter S, Rathkolb B, Reinhard C, de Morreale EG, Bernal J, Busch DH, Wurst W, Wolf E, Schulz H, Shtrom S, Greiner E, de Hrabé AM, Westphal H, Niehrs C (2006) Generation and characterization of dickkopf3 mutant mice. Mol Cell Biol 26:2317–2326 Byun T, Karimi M, Marsh JL, Milovanovic T, Lin F, Holcombe RF (2005) Expression of secreted Wnt antagonists in gastrointestinal tissues: potential role in stem cell homeostasis. J Clin Pathol 58:515–519 Das DS, Wadhwa N, Kunj N, Sarda K, Pradhan BS, Majumdar SS (2013) Dickkopf homolog 3 (DKK3) plays a crucial role upstream of Wnt/b-catenin signaling for Sertoli cell mediated regulation of spermatogenesis. PLoS ONE 8:e63603. doi:10.1371/journal.pone.0063603 Du G, Kataoka K, Sakaguchi M, Abarzua F, Than SS, Sonegawa H, Makino T, Shimizu T, Huh NH (2011) Expression of REIC/Dkk3 in normal and hyperproliferative epidermis. Exp Dermatol 20:273–277 Fujii M, Katase N, Lefeuvre M, Gunduz M, Buery RR, Tamamura R, Tsujigiwa H, Nagatsuka H (2011) Dickkopf (Dkk)-3 and β-catenin expressions increased in the transition from normal oral mucosal to oral squamous cell carcinoma. J Mol Histol 42:499–504 Fujii Y, Hoshino T, Kumon H (2014) Molecular simulation analysis of the structure complex of C2 domains of DKK family members and β-propeller domains of LRP5/6: explaining why DKK3 does not bind to LRP5/6. Acta Med Okayama 68:63–78 Glinka A, Wu W, Delius H, Monaghan AP, Blumenstock C, Niehrs C (1998) Dickkopf-1 is a member of a new family of secreted proteins and functions in head induction. Nature 391:357–362 Hara K, Kageji T, Mizobuchi Y, Kitazato KT, Okazaki T, Fujihara T, Nakajima K, Mure H, Kuwayama K, Hara T, Nagahiro S (2015) Blocking of the interaction between Wnt proteins and their co-receptors contributes to the anti-tumor effects of adenovirus-mediated Dkk3 in glioblastoma. Cancer Lett 356:496–505 Kataoka K, Du G, Maehara N, Murata H, Sakaguchi M, Huh N (2012) Expression pattern of REIC/Dkk3 in mouse squamous epithelia. Clin Exp Dermatol 37:428–431 Krupnik VE, Sharp JD, Jiang C, Robison K, Chickering TW, Amaravadi L, Brown DE, Guyot D, Mays G, Leiby K, Chang B, Duong T, Goodearl AD, Gearing DP, Sokol SY, McCarthy SA (1999) Functional and structural diversity of the human Dickkopf gene family. Gene 238:301–313 Lee EJ, Jo M, Rho SB, Park K, Yoo YN, Park J, Chae M, Zhang W, Lee JH (2009) Dkk3, downregulated in cervical cancer, functions as a negative regulator of beta-catenin. Int J Cancer 124:287–297 Li S, Qin X, Liu B, Sun L, Zhang X, Li Z, Shan B, You J, Zhou Q (2011) Dickkopf-1 is involved in invasive growth of esophageal cancer cells. J Mol Histol 42:491–498 Mao B, Niehrs C (2003) Kremen2 modulates Dickkopf2 activity during Wnt/LRP6 signaling. Gene 302:179–183 Monaghan AP, Kioschis P, Wu W, Zuniga A, Bock D, Poustka A, Delius H, Niehrs C (1999) Dickkopf genes are co-ordinately expressed in mesodermal lineages. Mech Dev 87:45–56 Niehrs C (2006) Function and biological roles of the Dickkopf family of Wnt modulators. Oncogene 57:7469–7481 Ochiai K, Watanabe M, Ueki H, Huang P, Fujii Y, Nasu Y, Noguchi H, Hirata T, Sakaguchi M, Huh NH, Kashiwakura Y, Kaku H, Kumon H (2011) Tumor suppressor REIC/Dkk3 interacts with the dynein light chain, Tctex-1. Biochem Biophys Res Commun 412:391–395 Papatriantafyllou M, Moldenhauer G, Ludwig J, Tafuri A, Garbi N, Hollmann G, Küblbeck G, Klevenz A, Schmitt S, Pougialis G, Niehrs C, Gröne HJ, Hämmerling GJ, Arnold B, Oelert T (2012) Dickkopf-3, an immune modulator in peripheral CD8 T-cell tolerance. Proc Natl Acad Sci USA 109:1631–1636 Ryu SW, Kim JH, Kim MK, Lee YJ, Park JS, Park HM, Kim DH, Lee SH, Lee EJ (2013) Reduced expression of DKK3 is associated with adverse clinical outcomes of uterine cervical squamous cell carcinoma. Int J Gynecol Cancer 23:134–140 Schaeren-Wiemers N, Gerfin-Moser A (1993) A single protocol to detect transcripts of various types and expression levels in neural tissue and cultured cells: in situ hybridization using digoxigenin-labelled cRNA probes. Histochemistry 100:431–440 Suwa T, Chen M, Hawks CL, Hornsby PJ (2003) Zonal expression of dickkopf-3 and components of the Wnt signalling pathways in the human adrenal cortex. J Endocrinol 178:149–158 Tanimoto R, Abarzua F, Sakaguchi M, Takaishi M, Nasu Y, Kumon H, Huh NH (2007) REIC/Dkk3 as a potential gene therapeutic agent against human testicular cancer. Int J Mol Med 19:363–368 Tanimoto R, Sakaguchi M, Abarzua F, Kataoka K, Kurose K, Murata H, Nasu Y, Kumon H, Huh NH (2010) Down-regulation of BiP/GRP78 sensitizes resistant prostate cancer cells to gene-therapeutic overexpression of REIC/Dkk3. Int J Cancer 126:1562–1569 Tsuji T, Miyazaki M, Sakaguchi M, Inoue Y, Namba M (2000) A REIC gene shows down-regulation in human immortalized cells and human tumor-derived cell lines. Biochem Biophys Res Commun 268:20–24 Veeck J, Dahl E (2012) Targeting the Wnt pathway in cancer: the emerging role of Dickkopf-3. Biochim Biophys Acta 1825:18–28 Veeck J, Wild PJ, Fuchs T, Schüffler PJ, Hartmann A, Knüchel R, Dahl E (2009) Prognostic relevance of Wnt-inhibitory factor-1 (WIF1) and Dickkopf-3 (DKK3) promoter methylation in human breast cancer. BMC Cancer 9:217. doi:10.1186/1471-2407-9-217 Wang Z, Ma LJ, Kang Y, Li X, Zhang XJ (2015) Dickkopf-3 (Dkk3) induces apoptosis in cisplatin-resistant lung adenocarcinoma cells via the Wnt/β-catenin pathway. Oncol Rep 33:1097–1106 Watanabe M, Kashiwakura Y, Huang P, Ochiai K, Futami J, Li SA, Takaoka M, Nasu Y, Sakaguchi M, Huh NH, Kumon H (2009) Immunological aspects of REIC/Dkk3 in monocyte differentiation and tumor regression. Int J Oncol 34:657–663 Xiang T, Li L, Yin X, Zhong L, Peng W, Qiu Z, Ren G, Tao Q (2013) Epigenetic silencing of the WNT antagonist Dickkopf 3 disrupts normal Wnt/β-catenin signalling and apoptosis regulation in breast cancer cells. J Cell Mol Med 10:1236–1246 Zhou G, Ye J, Sun L, Zhang Z, Feng J (2016) Overexpression of Dishevelled-2 contributes to proliferation and migration of human esophageal squamous cell carcinoma. J Mol Histol 47:287–295