Abstract
BackgroundOsteosarcoma is the most common primary malignant tumor in children and young adults, and its treatment requires effective therapeutic approaches because of a high mortality rate for lung metastasis. Epithelial to mesenchymal transition (EMT) has received considerable attention as a conceptual paradigm for explaining the invasive and metastatic behavior during cancer progression. The cysteine-rich angiogenic inducer 61 (Cyr61) gene, a member of the CCN gene family, is responsible for the secretion of Cyr61, a matrix-associated protein that is involved in several cellular functions. A previous study showed that Cyr61 expression is related to osteosarcoma progression. In addition, Cyr61 could promote cell migration and metastasis in osteosarcoma. However, discussions on the molecular mechanism involved in Cyr61-regulated metastasis in osteosarcoma is poorly discussed.ResultsWe determined that the expression level of Cyr61 induced cell migration ability in osteosarcoma cells. The Cyr61 protein promoted the mesenchymal transition of osteosarcoma cells by upregulating mesenchymal markers (TWIST-1 and N-cadherin) and inhibiting the epithelial marker (E-cadherin). Moreover, the Cyr61-induced cell migration was mediated by EMT. The Cyr61 protein elicited a signaling cascade that included αvβ5 integrin, Raf-1, mitogen-activated protein kinase (MEK), extracellular signal-regulated kinase (ERK), and Elk-1. The reagent or gene knockdown of these signaling proteins could inhibit Cyr61-promoted EMT in osteosarcoma. Finally, the knockdown of Cyr61 expression obviously inhibited cell migration and repressed mesenchymal phenotypes, reducing lung metastasis.ConclusionOur results indicate that Cyr61 promotes the EMT of osteosarcoma cells by regulating EMT markers via a signal transduction pathway that involves αvβ5 integrin, Raf-1, MEK, ERK, and Elk-1.Electronic supplementary materialThe online version of this article (doi:10.1186/1476-4598-13-236) contains supplementary material, which is available to authorized users.
Highlights
Osteosarcoma is the most common primary malignant tumor in children and young adults, and its treatment requires effective therapeutic approaches because of a high mortality rate for lung metastasis
We selected the high-migration-ability MG63 cell sublines by using the Transwell assay, and our results revealed that the mRNA and protein expression levels of cysteine-rich angiogenic inducer 61 (Cyr61) increased in the high-migration-prone subline (MG63, M7, and M10) (Figure 1A-C, respectively)
Pretreating MG63 cells with a Cyr61-neutralized antibody abolished Cyr61-induced cell migration (Figure 1F). These results indicate that Cyr61 plays a pivotal role in osteosarcoma migration ability
Summary
Osteosarcoma is the most common primary malignant tumor in children and young adults, and its treatment requires effective therapeutic approaches because of a high mortality rate for lung metastasis. EMT-related transcription factors such as TWIST-1, snail, slug, ZEB1, and ZEB2 orchestrate the EMT, and enable the early steps of metastasis, which consist primarily of local invasion and the subsequent dissemination of tumor cells to distant sites [8] These transcription factors repress E-cadherin expression by binding to the E-box in the E-cadherin gene promoter, and promote EMT [9,10,11,12,13]. Substantial evidence has indicated that osteosarcoma exhibits EMTlike states, characterized by changes in the expression of EMT-related transcription factors, such as TWIST-1, snail, and ZEBs, which are involved in the complex pathogenesis of osteosarcoma [14] Targeting these transcription factors may provide a novel opportunity in osteosarcoma treatment by controlling metastasis
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