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 language | English |
|---|---|
| Article number | 33 |
| Journal | Journal of Hematology and Oncology |
| Volume | 10 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - Jan 25 2017 |
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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 journal › Article
}
TY - JOUR
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
Y1 - 2017/1/25
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.
KW - Matrix metalloproteinase-2
KW - Metastasis
KW - microRNA
KW - Prostate cancer
KW - Thrombospondin-2
UR - http://www.scopus.com/inward/record.url?scp=85010754305&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85010754305&partnerID=8YFLogxK
U2 - 10.1186/s13045-017-0390-6
DO - 10.1186/s13045-017-0390-6
M3 - Article
VL - 10
JO - Journal of Hematology and Oncology
JF - Journal of Hematology and Oncology
SN - 1756-8722
IS - 1
M1 - 33
ER -