Abstract
Background: Dysregulation of the receptor tyrosine kinase Axl and its ligand Gas6 has been shown to promote the progression of osteosarcoma and correlates with poor prognosis. This study aimed to identify the role of Gas6/ Axl for anti-apoptosis as induced by cisplatin (DDP) and methotrexate (MTX) chemotherapy and to analyze the relationship between P-Axl and apoptosis-related proteins in osteosarcoma. Method: Cultured osteosarcoma cell lines MG63, 143B and U2OS were used for apoptosis assays, Axl siRNA transfection, cytotoxicity assays, cell cycle analysis, and other assessment methods. A total of 41 cases of osteosarcoma patients were included for immunohistochemistry staining and clinicopathological relative analysis. TUNEL assay was performed in ten pair’s cases for apoptosis detection and relative analysis of P-Axl. Results: Among the osteosarcoma cell lines, Gas6 could obviously protect tumor cells from apoptosis induced by DDP and MTX by binding to Axl (P<0.05). Axl siRNA transfection enhanced cell apoptosis, whereas Gas6 was unable to function upon previous knockdown of Axl. Among the 41 osteosarcoma cases, the positive rate of Bcl-2, Bax, and P-Axl was 70.7%, 36.6%, and 85.4%, respectively. In osteofibrous dysplasia, the positive rate of them was 22.2%, 11.1%, and 14.6%, respectively. The expression levels of these apoptosis-related factors were significantly higher in osteosarcoma than in osteofibrous dysplasia (P<0.05). Through clinico-pathological analysis, there were significant relationships between the survival status and Bcl-2 or Bax expression (P<0.05). TUNEL assay also demonstrated that P-Axl high expression inhibited apoptosis in osteosarcoma tissues. By Cox univariate analysis, Bcl-2 or Bax was correlated with the patients’ prognosis. Importantly, Pearson correlation analysis demonstrated that Bcl-2 was positively correlated to P-Axl with statistical significance (r=0.842, P<0.0001). Conclusion: Gas6/Axl protects osteosarcoma cells from the apoptosis induced by DDP and MTX chemotherapy and inhibits apoptosis in osteosarcoma tissue, possibly through the regulation of apoptosis-related protein Bcl-2.
Highlights
The 5-year survival of osteosarcoma patients has been improved since the 1980s, further improvement in survival has not been achieved owing to a lack of well-validated prognostic markers and the problem of non-response to chemotherapy [1].Axl was first isolated in chronic myelogenous leukemia, and was characterized and given the name “Axl,” derived from Greek term “anexelekto,” or uncontrolled function [2,3]
Gas6/Axl protects osteosarcoma cells from the apoptosis induced by DDP and MTX chemotherapy and inhibits apoptosis in osteosarcoma tissue, possibly through the regulation of apoptosis-related protein Bcl-2
Gas6 protected osteosarcoma cells from cell death through ligand binding to its target receptor Axl
Summary
The 5-year survival of osteosarcoma patients has been improved since the 1980s, further improvement in survival has not been achieved owing to a lack of well-validated prognostic markers and the problem of non-response to chemotherapy [1].Axl was first isolated in chronic myelogenous leukemia, and was characterized and given the name “Axl,” derived from Greek term “anexelekto,” or uncontrolled function [2,3]. Axl was cloned as the first TAM family tyrosine kinase receptor, and subsequent cloning of both Tyro and Mer in 1994 revealed the existence of similar domains in this family [3,4]. The TAM receptors are grouped based on their common ligands, Gas and protein S. The Gas gene named from “growth arrest-specific” factors was cloned in 1988 [5]. Dysregulation of the receptor tyrosine kinase Axl and its ligand Gas has been shown to promote the progression of osteosarcoma and correlates with poor prognosis. This study aimed to identify the role of Gas6/ Axl for anti-apoptosis as induced by cisplatin (DDP) and methotrexate (MTX) chemotherapy and to analyze the relationship between P-Axl and apoptosis-related proteins in osteosarcoma
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