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

Abstract

BackgroundThrombospondin-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.MethodsThe 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.ResultsBased 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.ConclusionsTaken 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-017-0390-6) contains supplementary material, which is available to authorized users.

Association of HMGB1 Gene Polymorphisms with Lung Cancer Susceptibility and Clinical Aspects

“…Notably, the rs1045411 polymorphism resides in the 3ʹ-flanking region and may therefore affect HMGB1 gene expression. Previous studies have also indicated that the rs1045411 polymorphism reduces the risk of oral squamous cell carcinoma and gastric cancer development 31 , 32 . Findings from the GTEx database in the current study confirm that variant T at rs1045411 shows a reduced trend in HMGB1 expression, compared with the wild-type C homozygous genotypes.…”

Estrogen promotes tumor metastasis via estrogen receptor beta-mediated regulation of matrix-metalloproteinase-2 in non-small cell lung cancer

“…Extranuclear signaling has been linked to rapid responses to E2 via stimulation of mitogen-activated protein kinase (MAPK), especially p38MAPK, protein kinase B (AKT), phosphatidylinositol-3-kinase (PI3K) in the cytosol [ 18 , 19 ]. Mechanistically, considering the fact that a key biological function of MAPK/AKT is regulation of the expression of MMPs [ 36 – 39 ], we found that MMP-2 activation induced by ERβ were significantly associated with p38MAPK and AKT phosphorylation in vitro and in vivo . Taken together, these results demonstrated that estrogen regulates MMP-2 expression via ERβ and may promote metastasis through the p38MAPK and PI3K/AKT signaling pathway.…”

THBS2, a microRNA‑744‑5p target, modulates MMP9 expression through CUX1 in pancreatic neuroendocrine tumors

“…MMP2/9 forms complexes with THBS2 to interact with LRP1 and gets degraded; however, THBS2 could also regulate MMPs indirectly (26). The results from the present study demonstrated that CUX1 mediated the effect of THBS2 on MMP9.…”

“…Deregulation of THBS2 induces adhesion, apoptosis, migration and cytoskeletal organization of cancer cells (25). Chen et al (26) reported that THBS2 promoted prostate cancer bone metastasis by inducing miR-376c-mediated MMP2 upregulation. Cancer-associated fibroblasts also suppressed prostate cancer invasion via modulation of the ERα/THBS2/MMP3 axis (27).…”