Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Journal of Hematology & Oncology
Published in: Journal of Hematology & Oncology 1/2017

Open Access 01-12-2017 | Research

Thrombospondin-2 promotes prostate cancer bone metastasis by the up-regulation of matrix metalloproteinase-2 through down-regulating miR-376c expression

Authors: Po-Chun Chen, Chih-Hsin Tang, Liang-Wei Lin, Chun-Hao Tsai, Cheng-Ying Chu, Tien-Huang Lin, Yuan-Li Huang

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

Login to get access

Abstract

Background

Thrombospondin-2 (TSP-2) is a secreted matricellular glycoprotein that is found to mediate cell-to-extracellular matrix attachment and participates in many physiological and pathological processes. The expression profile of TSP-2 on tumors is controversial, and it up-regulates in some cancers, whereas it down-regulates in others, suggesting that the functional role of TSP-2 on tumors is still uncertain.

Methods

The expression of TSP-2 on prostate cancer progression was determined in the tissue array by the immunohistochemistry. The molecular mechanism of TSP-2 on prostate cancer (PCa) metastasis was investigated through pharmaceutical inhibitors, siRNAs, and miRNAs analyses. The role of TSP-2 on PCa metastasis in vivo was verified through xenograft in vivo imaging system.

Results

Based on the gene expression omnibus database and immunohistochemistry, we found that TSP-2 increased with the progression of PCa, especially in metastatic PCa and is correlated with the matrix metalloproteinase-2 (MMP-2) expression. Additionally, through binding to CD36 and integrin ανβ3, TSP-2 increased cell migration and MMP-2 expression. With inhibition of p38, ERK, and JNK, the TSP-2-induced cell migration and MMP-2 expression were abolished, indicating that the TSP-2’s effect on PCa is MAPK dependent. Moreover, the microRNA-376c (miR-376c) was significantly decreased by the TSP-2 treatment. Furthermore, the TSP-2-induced MMP-2 expression and the subsequent cell motility were suppressed upon miR-376c mimic stimulation. On the other hand, the animal studies revealed that the bone metastasis was abolished when TSP-2 was stably knocked down in PCa cells.

Conclusions

Taken together, our results indicate that TSP-2 enhances the migration of PCa cells by increasing MMP-2 expression through down-regulation of miR-376c expression. Therefore, TSP-2 may represent a promising new target for treating PCa.
Appendix
Available only for authorised users
Literature
1.
2.
3.
Ganguly SS, Li X, Miranti CK. The host microenvironment influences prostate cancer invasion, systemic spread, bone colonization, and osteoblastic metastasis. Front Oncol. 2014;4:364.CrossRefPubMedPubMedCentral
4.
Deng X, He G, Liu J, Luo F, Peng X, Tang S, Gao Z, Lin Q, Keller JM, Yang T, Keller ET. Recent advances in bone-targeted therapies of metastatic prostate cancer. Cancer Treat Rev. 2014;40:730–8.CrossRefPubMedPubMedCentral
5.
John A, Tuszynski G. The role of matrix metalloproteinases in tumor angiogenesis and tumor metastasis. Pathol Oncol Res. 2001;7:14–23.CrossRefPubMed
6.
Morgia G, Falsaperla M, Malaponte G, Madonia M, Indelicato M, Travali S, Mazzarino MC. Matrix metalloproteinases as diagnostic (MMP-13) and prognostic (MMP-2, MMP-9) markers of prostate cancer. Urol Res. 2005;33:44–50.CrossRefPubMed
7.
8.
Bornstein P, Armstrong LC, Hankenson KD, Kyriakides TR, Yang Z. Thrombospondin 2, a matricellular protein with diverse functions. Matrix Biol. 2000;19:557–68.CrossRefPubMed
9.
Kodama J, Hashimoto I, Seki N, Hongo A, Yoshinouchi M, Okuda H, Kudo T. Thrombospondin-1 and -2 messenger RNA expression in invasive cervical cancer: correlation with angiogenesis and prognosis. Clin Cancer Res. 2001;7:2826–31.PubMed
10.
Kyriakides TR, Zhu YH, Smith LT, Bain SD, Yang Z, Lin MT, Danielson KG, Iozzo RV, LaMarca M, McKinney CE, et al. Mice that lack thrombospondin 2 display connective tissue abnormalities that are associated with disordered collagen fibrillogenesis, an increased vascular density, and a bleeding diathesis. J Cell Biol. 1998;140:419–30.CrossRefPubMedPubMedCentral
11.
12.
Chen H, Strickland DK, Mosher DF. Metabolism of thrombospondin 2. Binding and degradation by 3 t3 cells and glycosaminoglycan-variant Chinese hamster ovary cells. J Biol Chem. 1996;271:15993–9.CrossRefPubMed
13.
Yang Z, Strickland DK, Bornstein P. Extracellular matrix metalloproteinase 2 levels are regulated by the low density lipoprotein-related scavenger receptor and thrombospondin 2. J Biol Chem. 2001;276:8403–8.CrossRefPubMed
14.
Hornebeck W, Emonard H, Monboisse JC, Bellon G. Matrix-directed regulation of pericellular proteolysis and tumor progression. Semin Cancer Biol. 2002;12:231–41.CrossRefPubMed
15.
Kunstfeld R, Hawighorst T, Streit M, Hong YK, Nguyen L, Brown LF, Detmar M. Thrombospondin-2 overexpression in the skin of transgenic mice reduces the susceptibility to chemically induced multistep skin carcinogenesis. J Dermatol Sci. 2014;74:106–15.CrossRefPubMedPubMedCentral
16.
Santin AD, Zhan F, Bellone S, Palmieri M, Cane S, Bignotti E, Anfossi S, Gokden M, Dunn D, Roman JJ, et al. Gene expression profiles in primary ovarian serous papillary tumors and normal ovarian epithelium: identification of candidate molecular markers for ovarian cancer diagnosis and therapy. Int J Cancer. 2004;112:14–25.CrossRefPubMed
17.
Hsu CW, Yu JS, Peng PH, Liu SC, Chang YS, Chang KP, Wu CC. Secretome profiling of primary cells reveals that THBS2 is a salivary biomarker of oral cavity squamous cell carcinoma. J Proteome Res. 2014;13:4796–807.CrossRefPubMed
18.
Chijiwa T, Abe Y, Inoue Y, Matsumoto H, Kawai K, Matsuyama M, Miyazaki N, Inoue H, Mukai M, Ueyama Y, Nakamura M. Cancerous, but not stromal, thrombospondin-2 contributes prognosis in pulmonary adenocarcinoma. Oncol Rep. 2009;22:279–83.PubMed
19.
Matos AR, Coutinho-Camillo CM, Thuler LC, Fonseca FP, Soares FA, Silva EA, Gimba ER. Expression analysis of thrombospondin 2 in prostate cancer and benign prostatic hyperplasia. Exp Mol Pathol. 2013;94:438–44.CrossRefPubMed
20.
Fang YX, Gao WQ. Roles of microRNAs during prostatic tumorigenesis and tumor progression. Oncogene. 2014;33:135–47.CrossRefPubMed
21.
Wilczynska A, Bushell M. The complexity of miRNA-mediated repression. Cell Death Differ. 2015;22:22–33.CrossRefPubMed
22.
Ayub SG, Kaul D, Ayub T. Microdissecting the role of microRNAs in the pathogenesis of prostate cancer. Cancer Genet. 2015;208:289–302.CrossRefPubMed
23.
Formosa A, Markert EK, Lena AM, Italiano D, Finazzi-Agro E, Levine AJ, Bernardini S, Garabadgiu AV, Melino G, Candi E. MicroRNAs, miR-154, miR-299-5p, miR-376a, miR-376c, miR-377, miR-381, miR-487b, miR-485-3p, miR-495 and miR-654-3p, mapped to the 14q32.31 locus, regulate proliferation, apoptosis, migration and invasion in metastatic prostate cancer cells. Oncogene. 2014;33:5173–82.CrossRefPubMed
24.
Ye G, Fu G, Cui S, Zhao S, Bernaudo S, Bai Y, Ding Y, Zhang Y, Yang BB, Peng C. MicroRNA 376c enhances ovarian cancer cell survival by targeting activin receptor-like kinase 7: implications for chemoresistance. J Cell Sci. 2011;124:359–68.CrossRefPubMed
25.
Jin Y, Peng D, Shen Y, Xu M, Liang Y, Xiao B, Lu J. MicroRNA-376c inhibits cell proliferation and invasion in osteosarcoma by targeting to transforming growth factor-alpha. DNA Cell Biol. 2013;32:302–9.CrossRefPubMed
26.
Tsai CH, Tsai HC, Huang HN, Hung CH, Hsu CJ, Fong YC, Hsu HC, Huang YL, Tang CH. Resistin promotes tumor metastasis by down-regulation of miR-519d through the AMPK/p38 signaling pathway in human chondrosarcoma cells. Oncotarget. 2015;6:258–70.PubMed
27.
Huang YL, Chang CL, Tang CH, Lin YC, Ju TK, Huang WP, Lee H. Extrinsic sphingosine 1-phosphate activates S1P5 and induces autophagy through generating endoplasmic reticulum stress in human prostate cancer PC-3 cells. Cell Signal. 2014;26:611–8.CrossRefPubMed
28.
Ross JS, Kaur P, Sheehan CE, Fisher HA, Kaufman Jr RA, Kallakury BV. Prognostic significance of matrix metalloproteinase 2 and tissue inhibitor of metalloproteinase 2 expression in prostate cancer. Mod Pathol. 2003;16:198–205.CrossRefPubMed
29.
Lovaas JD, Zhu L, Chiao CY, Byles V, Faller DV, Dai Y. SIRT1 enhances matrix metalloproteinase-2 expression and tumor cell invasion in prostate cancer cells. Prostate. 2013;73:522–30.CrossRefPubMed
30.
Simantov R, Febbraio M, Silverstein RL. The antiangiogenic effect of thrombospondin-2 is mediated by CD36 and modulated by histidine-rich glycoprotein. Matrix Biol. 2005;24:27–34.CrossRefPubMed
31.
Calzada MJ, Zhou L, Sipes JM, Zhang J, Krutzsch HC, Iruela-Arispe ML, Annis DS, Mosher DF, Roberts DD. Alpha4beta1 integrin mediates selective endothelial cell responses to thrombospondins 1 and 2 in vitro and modulates angiogenesis in vivo. Circ Res. 2004;94:462–70.CrossRefPubMed
32.
Chen H, Sottile J, O’Rourke KM, Dixit VM, Mosher DF. Properties of recombinant mouse thrombospondin 2 expressed in Spodoptera cells. J Biol Chem. 1994;269:32226–32.PubMed
33.
Javelaud D, Mauviel A. Crosstalk mechanisms between the mitogen-activated protein kinase pathways and Smad signaling downstream of TGF-beta: implications for carcinogenesis. Oncogene. 2005;24:5742–50.CrossRefPubMed
34.
Dutta A, Li J, Lu H, Akech J, Pratap J, Wang T, Zerlanko BJ, FitzGerald TJ, Jiang Z, Birbe R, et al. Integrin alphavbeta6 promotes an osteolytic program in cancer cells by upregulating MMP2. Cancer Res. 2014;74:1598–608.CrossRefPubMedPubMedCentral
35.
Liu B, Cui J, Sun J, Li J, Han X, Guo J, Yi M, Amizuka N, Xu X, Li M. Immunolocalization of MMP9 and MMP2 in osteolytic metastasis originating from MDA-MB-231 human breast cancer cells. Mol Med Rep. 2016;14:1099–106.PubMedPubMedCentral
36.
Ni X, Xia T, Zhao Y, Zhou W, Wu N, Liu X, Ding Q, Zha X, Sha J, Wang S. Downregulation of miR-106b induced breast cancer cell invasion and motility in association with overexpression of matrix metalloproteinase 2. Cancer Sci. 2014;105:18–25.CrossRefPubMed
37.
Wang J, Ren Y, Guo X, Cheng H, Ye Y, Qi J, Yang C, You H. Alterations in enhancer of zeste homolog 2, matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-2 expression are associated with ex vivo and in vitro bone metastasis in renal cell carcinoma. Mol Med Rep. 2015;11:3585–92.PubMed
38.
Pulukuri SM, Gondi CS, Lakka SS, Jutla A, Estes N, Gujrati M, Rao JS. RNA interference-directed knockdown of urokinase plasminogen activator and urokinase plasminogen activator receptor inhibits prostate cancer cell invasion, survival, and tumorigenicity in vivo. J Biol Chem. 2005;280:36529–40.CrossRefPubMed
39.
40.
Ebos JM, Lee CR, Cruz-Munoz W, Bjarnason GA, Christensen JG, Kerbel RS. Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. Cancer Cell. 2009;15:232–9.CrossRefPubMedPubMedCentral
41.
Koch M, Hussein F, Woeste A, Grundker C, Frontzek K, Emons G, Hawighorst T. CD36-mediated activation of endothelial cell apoptosis by an N-terminal recombinant fragment of thrombospondin-2 inhibits breast cancer growth and metastasis in vivo. Breast Cancer Res Treat. 2011;128:337–46.CrossRefPubMed
42.
Slavin S, Yeh CR, Da J, Yu S, Miyamoto H, Messing EM, Guancial E, Yeh S. Estrogen receptor alpha in cancer-associated fibroblasts suppresses prostate cancer invasion via modulation of thrombospondin 2 and matrix metalloproteinase 3. Carcinogenesis. 2014;35:1301–9.CrossRefPubMed
43.
Firlej V, Mathieu JR, Gilbert C, Lemonnier L, Nakhle J, Gallou-Kabani C, Guarmit B, Morin A, Prevarskaya N, Delongchamps NB, Cabon F. Thrombospondin-1 triggers cell migration and development of advanced prostate tumors. Cancer Res. 2011;71:7649–58.CrossRefPubMed
44.
Sargiannidou I, Qiu C, Tuszynski GP. Mechanisms of thrombospondin-1-mediated metastasis and angiogenesis. Semin Thromb Hemost. 2004;30:127–36.CrossRefPubMed
45.
Lin TH, Liu HH, Tsai TH, Chen CC, Hsieh TF, Lee SS, Lee YJ, Chen WC, Tang CH. CCL2 increases alphavbeta3 integrin expression and subsequently promotes prostate cancer migration. Biochim Biophys Acta. 1830;2013:4917–27.
46.
Teti A, Migliaccio S, Baron R. The role of the alphaVbeta3 integrin in the development of osteolytic bone metastases: a pharmacological target for alternative therapy? Calcif Tissue Int. 2002;71:293–9.CrossRefPubMed
47.
Wijayakumara DD, Hu DG, Meech R, McKinnon RA, Mackenzie PI. Regulation of human UGT2B15 and UGT2B17 by miR-376c in prostate cancer cell lines. J Pharmacol Exp Ther. 2015;354:417–25.CrossRefPubMed
48.
Gartrell BA, Saad F. Managing bone metastases and reducing skeletal related events in prostate cancer. Nat Rev Clin Oncol. 2014;11:335–45.CrossRefPubMed
49.
Lynch CC. Matrix metalloproteinases as master regulators of the vicious cycle of bone metastasis. Bone. 2011;48:44–53.CrossRefPubMed
Metadata
Title
Thrombospondin-2 promotes prostate cancer bone metastasis by the up-regulation of matrix metalloproteinase-2 through down-regulating miR-376c expression
Authors
Po-Chun Chen
Chih-Hsin Tang
Liang-Wei Lin
Chun-Hao Tsai
Cheng-Ying Chu
Tien-Huang Lin
Yuan-Li Huang
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/s13045-017-0390-6

Other articles of this Issue 1/2017

Journal of Hematology & Oncology 1/2017 Go to the issue

Letter to the Editor

Can pegylated interferon improve the outcome of polycythemia vera patients?

Case report

Severe nivolumab-induced pneumonitis preceding durable clinical remission in a patient with refractory, metastatic lung squamous cell cancer: a case report

Review

Immunotherapy in hematologic malignancies: past, present, and future

Research

SIX3, a tumor suppressor, inhibits astrocytoma tumorigenesis by transcriptional repression of AURKA/B

Review

The crosstalk between autophagic and endo-/exosomal pathways in antigen processing for MHC presentation in anticancer T cell immune responses

Research

Targeting the CXCR4 pathway using a novel anti-CXCR4 IgG1 antibody (PF-06747143) in chronic lymphocytic leukemia
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits