The microRNA miR-516a-3p regulates the Wnt pathway by targeting extracellular sulfatase 1 in human scirrhous gastric cancers: Anti-metastatic therapy via miRNA-based medicine
Main Article Content
Abstract
The mechanism and function of cancer metastasis-associated microRNAs (miRNAs) have not been completely examined. Using a miRNA array, we previously determined that a significantly decreased level of miR-516a-3p was closely associated with the peritoneal dissemination of scirrhous gastric cancers. We previously established HSC-58 cells from a scirrhous gastric cancer patient, and we further isolated metastatic cells (58As9) from ascites in nude mice upon repeated orthotopic transplantation of HSC-58. In our previous report (Takei Y, et al. Cancer Res, 2011), we showed that the miR-516a-3p expression was significantly low and the peritoneal dissemination was significantly high in 58As9 compared with HSC-58. To augment the decreased expression of miR-516a-3p in 58As9 cells, we successfully prepared a cell line (58As9-miR-516a-3p) that stably overexpressed the miRNA. In the present study, we showed that orthotopic transplantation of 58As9-miR-516a-3p into nude mice resulted in significantly decreased primary tumor growth, ascites, and peritoneal dissemination. Moreover, the transplanted nude mice showed long survival time, probably due to the small amount of ascitic fluids pooled. The miRNA directly targeted sulfatase 1, which works to remove a sulfate group from heparan sulfate proteoglycans on the cell surface, and promotes the release of membrane-bound Wnt ligands into medium. Significantly increased concentrations of Wnt3a, Wnt5a, and nuclear-accumulated b-catenin were observed in 58As9 cells, and in 58As9-miR-516a-3p, all of the levels were attenuated. Anti-metastatic therapy via injection of the miR-516a-3p expression vector/atelocollagen mixture into 58As9 orthotopic tumors in nude mice resulted in significantly prolonged survival along with the inhibition of ascites and peritoneal dissemination. Our findings thus indicate that the miR-516a-3p-sulfatase 1-Wnt b-catenin route can be targeted to block the peritoneal dissemination of scirrhous gastric cancers.
Article Details
How to Cite
TAKEI, Yoshifumi et al.
The microRNA miR-516a-3p regulates the Wnt pathway by targeting extracellular sulfatase 1 in human scirrhous gastric cancers: Anti-metastatic therapy via miRNA-based medicine.
Medical Research Archives, [S.l.], v. 5, n. 7, july 2017.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/1379>. Date accessed: 16 apr. 2024.
Keywords
microRNA (miRNA), scirrhous gastric cancer, peritoneal dissemination, Wnt pathway, β-catenin, anti-metastatic therapy
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
References
1 Anderson C, Nijagal A, Kim J. Molecular markers for gastric adenocarcinoma: an update. Mol Diagn Ther 2006;10:345-52.
2 Takahashi I, Matsusaka T, Onohara T, Nishizaki T, Ishikawa T, Tashiro H, Wakasugi K, Kume K, Maehara Y, Sugimachi K. Clinicopathological features of long-term survivors of scirrhous gastric cancer. Hepatogastroenterology 2000;47:1485-8.
3 Nakazawa K, Yashiro M, Hirakawa K. Keratinocyte growth factor produced by gastric fibroblasts specifically stimulates proliferation of cancer cells from scirrhous gastric carcinoma. Cancer Res 2003;63:8848-52.
4 Liu Y, Yoshimura K, Yamaguchi N, Shinmura K, Yokota J, Katai H. Causation of Borrmann type 4 gastric cancer: heritable factors or environmental factors? Gastric Cancer 2003;6:17-23.
5 Hippo Y, Yashiro M, Ishii M, Taniguchi H, Tsutsumi S, Hirakawa K, Kodama T, Aburatani H. Differential gene expression profiles of scirrhous gastric cancer cells with high metastatic potential to peritoneum or lymph nodes. Cancer Res 2001;61:889-95.
6 Jass JR, Sobin LH, Watanabe H. The World Health Organization’s histologic classification of gastrointestinal tumors. A commentary on the second edition. Cancer 1990;66:2162-7.
7 Samel S, Singal A, Becker H, Post S. Problems with intraoperative hyperthermic peritoneal chemotherapy for advanced gastric cancer. Eur J Surg Oncol 2000;26:222-6.
8 Calin GA, Croce CM. MicroRNA signatures in human cancers. Nat Rev Cancer 2006;6:857-66.
9 Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 2004;116:281-97.
10 Hurst DR, Edmonds MD, Welch DR. Metastamir: the field of metastasis-regulatory microRNA is spreading. Cancer Res 2009;69:7495-8.
11 Ma L, Teruya-Feldstein J, Weinberg RA. Tumour invasion and metastasis initiated by microRNA-10b in breast cancer. Nature 2007;449:682-8.
12 Takei Y, Takigahira M, Mihara K, Tarumi Y, Yanagihara K. The metastasis-associated microRNA miR-516a-3p is a novel therapeutic target for inhibiting peritoneal dissemination of human scirrhous gastric cancer. Cancer Res 2011;71:1442-53.
13 Yanagihara K, Tanaka H, Takigahira M, Ino Y, Yamaguchi Y, Toge T, Sugano K, Hirohashi S. Establishment of two cell lines from human gastric scirrhous carcinoma that possess the potential to metastasize spontaneously in nude mice. Cancer Sci 2004;95:575-82.
14 Yanagihara K, Takigahira M, Tanaka H, Komatsu T, Fukumoto H, Koizumi F, Nishio K, Ochiya T, Ino Y, Hirohashi S. Development and biological analysis of peritoneal metastasis mouse models for human scirrhous stomach cancer. Cancer Sci 2005;96:323-32.
15 Morimoto-Tomita M, Uchimura K, Werb Z, Hemmerich S, Rosen SD. Cloning and characterization of two extracellular heparin-degrading endosulfatases in mice and humans. J Biol Chem 2002;277:49175-85.
16 Ai X, Do AT, Lozynska O, Kusche-Gullberg M, Lindahl U, Emerson CP Jr. QSulf1 remodels the 6-O sulfation states of cell surface heparan sulfate proteoglycans to promote Wnt signaling. J Cell Biol 2003;162:341-51.
17 Reinhart BJ, Slack FJ, Basson M, Pasquinelli AE, Bettinger JC, Rougvie AE, Horvitz HR, Ruvkun G. The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans. Nature 2000;403:901-6.
18 Mu P, Nagahara S, Makita N, Tarumi Y, Kadomatsu K, Takei Y. Systemic delivery of siRNA specific to tumor mediated by atelocollagen: Combined therapy using siRNA targeting Bcl-xL and cisplatin against prostate cancer. Int J Cancer 2009;125:2978-90.
19 Takei Y, Kadomatsu K, Yuzawa Y, Matsuo S, Muramatsu T. A small interfering RNA targeting vascular endothelial growth factor as cancer therapeutics. Cancer Res 2004;64:3365-70.
20 Sherf BA., Navarro SL, Hannah RR, Waod KV. Dual-Luciferase® reporter assay: an advanced coreporter technology integrating firefly and Renilla luciferase assays. Promega Notes 1996;57:2-9.
21 Takei Y, Kadomatsu K, Matsuo S, Itoh H, Nakazawa K, Kubota S, Muramatsu T. Antisense oligodeoxynucleotide targeted to Midkine, a heparin-binding growth factor, suppresses tumorigenicity of mouse rectal carcinoma cells. Cancer Res 2001;61:8486-91.
22 Takei Y, Kadomatsu K, Itoh H, Sato W, Nakazawa K, Kubota S, Muramatsu T. 5'-, 3'-inverted thymidine-modified antisense oligodeoxynucleotide targeting midkine. Its design and application for cancer therapy. J Biol Chem 2002;277:23800-6.
23 Takei Y, Kadomatsu K, Goto T, Muramatsu T. Combinational antitumor effect of siRNA against midkine and paclitaxel on growth of human prostate cancer xenografts. Cancer 2006;107:864-73.
24 Takei Y, Kadomatsu K. In vivo delivery technique of nucleic acid compounds using atelocollagen: Its use in cancer therapeutics targeted at the heparin-binding growth factor midkine. Gene Ther Mol Biol;9:257-64.
25 Ochiya T, Takahama Y, Nagahara S, Sumita Y, Hisada A, Itoh H, Nagai Y, Terada M. New delivery system for plasmid DNA in vivo using atelocollagen as a carrier material: the Minipellet. Nat Med 1999;5:707-10.
26 Bafico A, Liu G, Goldin L, Harris V, Aaronson SA. An autocrine mechanism for constitutive Wnt pathway activation in human cancer cells. Cancer Cell 2004;6:497-506.
27 Nawroth R, van Zante A, Cervantes S, McManus M, Hebrok M, Rosen SD. Extracellular sulfatases, elements of the Wnt signaling pathway, positively regulate growth and tumorigenicity of human pancreatic cancer cells. PLoS One 2007;2:e392.
28 Wielenga VJ, Smits R, Korinek V, Smit L, Kielman M, Fodde R, Clevers H, Pals ST. Expression of CD44 in Apc and Tcf mutant mice implies regulation by the WNT pathway. Am J Pathol. 1999;154:515-23.
29 Tetsu O, McCormick F. Beta-catenin regulates expression of cyclin D1 in colon carcinoma cells. Nature 1999;398:422-6.
30 Shtutman M, Zhurinsky J, Simcha I, Albanese C, D'Amico M, Pestell R, Ben-Ze'ev A. The cyclin D1 gene is a target of the beta-catenin/LEF-1 pathway. Proc Natl Acad Sci U S A. 1999;96:5522-7.
31 Sleeman J, Steeg PS. Cancer metastasis as a therapeutic target. Eur J Cancer 2010;46:1177-80.
32 Steeg PS, Theodorescu D. Metastasis: a therapeutic target for cancer. Nat Clin Pract Oncol 2008;5:206-19.
33 Tavazoie SF, Alarcón C, Oskarsson T, Padua D, Wang Q, Bos PD, Gerald WL, Massagué J. Endogenous human microRNAs that suppress breast cancer metastasis. Nature 2008;451:147-52.
34 Honma K, Iwao-Koizumi K, Takeshita F, Yamamoto Y, Yoshida T, Nishio K, Nagahara S, Kato K, Ochiya T. RPN2 gene confers docetaxel resistance in breast cancer. Nat Med. 2008;14:939-48.
35 Zöller M. CD44: can a cancer-initiating cell profit from an abundantly expressed molecule? Nat Rev Cancer 2011;11:254-67.
36 Ishimoto T, Nagano O, Yae T, Tamada M, Motohara T, Oshima H, Oshima M, Ikeda T, Asaba R, Yagi H, Masuko T, Shimizu T, et al. CD44 Variant Regulates Redox Status in Cancer Cells by Stabilizing the xCT Subunit of System xc(-) and Thereby Promotes Tumor Growth. Cancer Cell 2011;19:387-400.
37 Takaishi S, Okumura T, Tu S, Wang SS, Shibata W, Vigneshwaran R, Gordon SA, Shimada Y, Wang TC. Identification of gastric cancer stem cells using the cell surface marker CD44. Stem Cells 2009;27:1006-20.
1 Anderson C, Nijagal A, Kim J. Molecular markers for gastric adenocarcinoma: an update. Mol Diagn Ther 2006;10:345-52.
2 Takahashi I, Matsusaka T, Onohara T, Nishizaki T, Ishikawa T, Tashiro H, Wakasugi K, Kume K, Maehara Y, Sugimachi K. Clinicopathological features of long-term survivors of scirrhous gastric cancer. Hepatogastroenterology 2000;47:1485-8.
3 Nakazawa K, Yashiro M, Hirakawa K. Keratinocyte growth factor produced by gastric fibroblasts specifically stimulates proliferation of cancer cells from scirrhous gastric carcinoma. Cancer Res 2003;63:8848-52.
4 Liu Y, Yoshimura K, Yamaguchi N, Shinmura K, Yokota J, Katai H. Causation of Borrmann type 4 gastric cancer: heritable factors or environmental factors? Gastric Cancer 2003;6:17-23.
5 Hippo Y, Yashiro M, Ishii M, Taniguchi H, Tsutsumi S, Hirakawa K, Kodama T, Aburatani H. Differential gene expression profiles of scirrhous gastric cancer cells with high metastatic potential to peritoneum or lymph nodes. Cancer Res 2001;61:889-95.
6 Jass JR, Sobin LH, Watanabe H. The World Health Organization’s histologic classification of gastrointestinal tumors. A commentary on the second edition. Cancer 1990;66:2162-7.
7 Samel S, Singal A, Becker H, Post S. Problems with intraoperative hyperthermic peritoneal chemotherapy for advanced gastric cancer. Eur J Surg Oncol 2000;26:222-6.
8 Calin GA, Croce CM. MicroRNA signatures in human cancers. Nat Rev Cancer 2006;6:857-66.
9 Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 2004;116:281-97.
10 Hurst DR, Edmonds MD, Welch DR. Metastamir: the field of metastasis-regulatory microRNA is spreading. Cancer Res 2009;69:7495-8.
11 Ma L, Teruya-Feldstein J, Weinberg RA. Tumour invasion and metastasis initiated by microRNA-10b in breast cancer. Nature 2007;449:682-8.
12 Takei Y, Takigahira M, Mihara K, Tarumi Y, Yanagihara K. The metastasis-associated microRNA miR-516a-3p is a novel therapeutic target for inhibiting peritoneal dissemination of human scirrhous gastric cancer. Cancer Res 2011;71:1442-53.
13 Yanagihara K, Tanaka H, Takigahira M, Ino Y, Yamaguchi Y, Toge T, Sugano K, Hirohashi S. Establishment of two cell lines from human gastric scirrhous carcinoma that possess the potential to metastasize spontaneously in nude mice. Cancer Sci 2004;95:575-82.
14 Yanagihara K, Takigahira M, Tanaka H, Komatsu T, Fukumoto H, Koizumi F, Nishio K, Ochiya T, Ino Y, Hirohashi S. Development and biological analysis of peritoneal metastasis mouse models for human scirrhous stomach cancer. Cancer Sci 2005;96:323-32.
15 Morimoto-Tomita M, Uchimura K, Werb Z, Hemmerich S, Rosen SD. Cloning and characterization of two extracellular heparin-degrading endosulfatases in mice and humans. J Biol Chem 2002;277:49175-85.
16 Ai X, Do AT, Lozynska O, Kusche-Gullberg M, Lindahl U, Emerson CP Jr. QSulf1 remodels the 6-O sulfation states of cell surface heparan sulfate proteoglycans to promote Wnt signaling. J Cell Biol 2003;162:341-51.
17 Reinhart BJ, Slack FJ, Basson M, Pasquinelli AE, Bettinger JC, Rougvie AE, Horvitz HR, Ruvkun G. The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans. Nature 2000;403:901-6.
18 Mu P, Nagahara S, Makita N, Tarumi Y, Kadomatsu K, Takei Y. Systemic delivery of siRNA specific to tumor mediated by atelocollagen: Combined therapy using siRNA targeting Bcl-xL and cisplatin against prostate cancer. Int J Cancer 2009;125:2978-90.
19 Takei Y, Kadomatsu K, Yuzawa Y, Matsuo S, Muramatsu T. A small interfering RNA targeting vascular endothelial growth factor as cancer therapeutics. Cancer Res 2004;64:3365-70.
20 Sherf BA., Navarro SL, Hannah RR, Waod KV. Dual-Luciferase® reporter assay: an advanced coreporter technology integrating firefly and Renilla luciferase assays. Promega Notes 1996;57:2-9.
21 Takei Y, Kadomatsu K, Matsuo S, Itoh H, Nakazawa K, Kubota S, Muramatsu T. Antisense oligodeoxynucleotide targeted to Midkine, a heparin-binding growth factor, suppresses tumorigenicity of mouse rectal carcinoma cells. Cancer Res 2001;61:8486-91.
22 Takei Y, Kadomatsu K, Itoh H, Sato W, Nakazawa K, Kubota S, Muramatsu T. 5'-, 3'-inverted thymidine-modified antisense oligodeoxynucleotide targeting midkine. Its design and application for cancer therapy. J Biol Chem 2002;277:23800-6.
23 Takei Y, Kadomatsu K, Goto T, Muramatsu T. Combinational antitumor effect of siRNA against midkine and paclitaxel on growth of human prostate cancer xenografts. Cancer 2006;107:864-73.
24 Takei Y, Kadomatsu K. In vivo delivery technique of nucleic acid compounds using atelocollagen: Its use in cancer therapeutics targeted at the heparin-binding growth factor midkine. Gene Ther Mol Biol;9:257-64.
25 Ochiya T, Takahama Y, Nagahara S, Sumita Y, Hisada A, Itoh H, Nagai Y, Terada M. New delivery system for plasmid DNA in vivo using atelocollagen as a carrier material: the Minipellet. Nat Med 1999;5:707-10.
26 Bafico A, Liu G, Goldin L, Harris V, Aaronson SA. An autocrine mechanism for constitutive Wnt pathway activation in human cancer cells. Cancer Cell 2004;6:497-506.
27 Nawroth R, van Zante A, Cervantes S, McManus M, Hebrok M, Rosen SD. Extracellular sulfatases, elements of the Wnt signaling pathway, positively regulate growth and tumorigenicity of human pancreatic cancer cells. PLoS One 2007;2:e392.
28 Wielenga VJ, Smits R, Korinek V, Smit L, Kielman M, Fodde R, Clevers H, Pals ST. Expression of CD44 in Apc and Tcf mutant mice implies regulation by the WNT pathway. Am J Pathol. 1999;154:515-23.
29 Tetsu O, McCormick F. Beta-catenin regulates expression of cyclin D1 in colon carcinoma cells. Nature 1999;398:422-6.
30 Shtutman M, Zhurinsky J, Simcha I, Albanese C, D'Amico M, Pestell R, Ben-Ze'ev A. The cyclin D1 gene is a target of the beta-catenin/LEF-1 pathway. Proc Natl Acad Sci U S A. 1999;96:5522-7.
31 Sleeman J, Steeg PS. Cancer metastasis as a therapeutic target. Eur J Cancer 2010;46:1177-80.
32 Steeg PS, Theodorescu D. Metastasis: a therapeutic target for cancer. Nat Clin Pract Oncol 2008;5:206-19.
33 Tavazoie SF, Alarcón C, Oskarsson T, Padua D, Wang Q, Bos PD, Gerald WL, Massagué J. Endogenous human microRNAs that suppress breast cancer metastasis. Nature 2008;451:147-52.
34 Honma K, Iwao-Koizumi K, Takeshita F, Yamamoto Y, Yoshida T, Nishio K, Nagahara S, Kato K, Ochiya T. RPN2 gene confers docetaxel resistance in breast cancer. Nat Med. 2008;14:939-48.
35 Zöller M. CD44: can a cancer-initiating cell profit from an abundantly expressed molecule? Nat Rev Cancer 2011;11:254-67.
36 Ishimoto T, Nagano O, Yae T, Tamada M, Motohara T, Oshima H, Oshima M, Ikeda T, Asaba R, Yagi H, Masuko T, Shimizu T, et al. CD44 Variant Regulates Redox Status in Cancer Cells by Stabilizing the xCT Subunit of System xc(-) and Thereby Promotes Tumor Growth. Cancer Cell 2011;19:387-400.
37 Takaishi S, Okumura T, Tu S, Wang SS, Shibata W, Vigneshwaran R, Gordon SA, Shimada Y, Wang TC. Identification of gastric cancer stem cells using the cell surface marker CD44. Stem Cells 2009;27:1006-20.