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

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

Research output: Contribution to journalArticle

18 Citations (Scopus)

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.

Original languageEnglish
Article number33
JournalJournal of Hematology and Oncology
Volume10
Issue number1
DOIs
Publication statusPublished - Jan 25 2017

Fingerprint

Bone Neoplasms
Matrix Metalloproteinase 2
MicroRNAs
Prostatic Neoplasms
Up-Regulation
Neoplasm Metastasis
Cell Movement
thrombospondin 2
Down-Regulation
Immunohistochemistry
Physiological Phenomena
Neoplasms
Pathologic Processes
Heterografts
Integrins

Keywords

  • Matrix metalloproteinase-2
  • Metastasis
  • microRNA
  • Prostate cancer
  • Thrombospondin-2

ASJC Scopus subject areas

  • Hematology
  • Molecular Biology
  • Oncology
  • Cancer Research

Cite this

Thrombospondin-2 promotes prostate cancer bone metastasis by the up-regulation of matrix metalloproteinase-2 through down-regulating miR-376c expression. / Chen, Po Chun; Tang, Chih Hsin; Lin, Liang Wei; Tsai, Chun Hao; Chu, Cheng Ying; Lin, Tien Huang; Huang, Yuan Li.

In: Journal of Hematology and Oncology, Vol. 10, No. 1, 33, 25.01.2017.

Research output: Contribution to journalArticle

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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.",
keywords = "Matrix metalloproteinase-2, Metastasis, microRNA, Prostate cancer, Thrombospondin-2",
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T1 - Thrombospondin-2 promotes prostate cancer bone metastasis by the up-regulation of matrix metalloproteinase-2 through down-regulating miR-376c expression

AU - Chen, Po Chun

AU - Tang, Chih Hsin

AU - Lin, Liang Wei

AU - Tsai, Chun Hao

AU - Chu, Cheng Ying

AU - Lin, Tien Huang

AU - Huang, Yuan Li

PY - 2017/1/25

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N2 - 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.

AB - 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.

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KW - Metastasis

KW - microRNA

KW - Prostate cancer

KW - Thrombospondin-2

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