Targeting programmed cell death ligand 1 by CRISPR/Cas9 in osteosarcoma cells
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Yunfei Liao1,2, Lulu Chen1, Yong Feng2,3, Jacson Shen2, Yan Gao2, Gregory Cote4, Edwin Choy4, David Harmon4, Henry Mankin2, Francis Hornicek2, Zhenfeng Duan2
1Department of Endocrinology, Wuhan Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
2Sarcoma Biology Laboratory, Department of Orthopaedic Surgery, Massachusetts General Hospital and Harvard Medical School, Boston 02114, Massachusetts, USA
3Department of Orthopaedic Surgery, Wuhan Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
4Division of Hematology and Oncology, Massachusetts General Hospital and Harvard Medical School, Boston 02114, Massachusetts, USA
Zhenfeng Duan, email: [email protected]
Keywords: programmed cell death ligand 1, osteosarcoma, CRISPR/Cas9, metastasis
Received: January 04, 2017 Accepted: March 09, 2017 Published: March 17, 2017
Programmed cell death ligand 1 (PD-L1) is a transmembrane protein that is expressed on tumor cells that suppresses the T cell-mediated immune response. Therapies targeting the PD-L1 pathway promote anti-tumor immunity and have shown promising results in some types of cancers. However, the functional and therapeutic roles of PD-L1 in osteosarcoma remain largely unknown. In this study, we found that PD-L1 protein was expressed in osteosarcoma cell lines and tissue microarray of patient tumors. Tissue microarray immunohistochemistry analysis showed that the overall and five-year survival rates of patients with high levels of PD-L1 expression were significantly shorter than patients with low levels. High levels of PD-L1 expression were also associated with metastasis in osteosarcoma patients. Furthermore, we applied the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 system to target PD-L1 gene at the DNA level in osteosarcoma cell lines. We found that the expression of PD-L1 could be efficiently disrupted by CRISPR/Cas9 system and PD-L1 knockdown increased drug sensitivities for doxorubicin and paclitaxel. These results suggest that PD-L1 is an independent prognostic factor in osteosarcoma and that PD-L1 knockout by CRISPR/Cas9 may be a therapeutic approach for the treatment of osteosarcoma.
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