Yanqin Zhang1,2,3, Qianghua Hu3, Guixin Li4, Lili Li1,2, Shoulei Liang1,2, Yun Zhang5, Jiayong Liu6, Zhengfu Fan6, Lin Li3, Bingzheng Zhou3, Yongxin Ruan3, Xueli Yang3, She'an Chen3, Tianyang Mu3, Guowen Wang1,2, Shunbin Xiong1,2,7. 1. Department of Bone and Soft Tissue Tumors, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China. 2. National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center of Cancer, Tianjin, China. 3. Department of Cancer Stem Cell, Dalian Medical University, Dalian, China. 4. Department of Laboratory Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, China. 5. College of Pharmacy and Health Sciences, Texas Southern University, Houston, Texas, USA. 6. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Bone and Soft Tissue Tumor, Peking University Cancer Hospital & Institute, Beijing, China. 7. Department of Genetics, M.D. Anderson Cancer Center, The University of Texas, Houston, Texas, USA.
Abstract
BACKGROUND/AIMS: Gain-of-function of mutant p53 is associated with a high rate of lung metastasis in osteosarcoma. To investigate the mechanism of mutant p53-induced osteosarcoma metastasis, expression array analysis was performed, comparing non-metastatic osteosarcomas from p53+/- mice with metastatic osteosarcomas from p53R172H/+ mice. Onzin (Plac8) was identified as one of the genes upregulated in p53R172H/+ mouse metastatic osteosarcomas. Accordingly, we investigated the role of ONZIN in human osteosarcoma metastasis. METHODS: ONZIN function and its downstream targets were examined in osteosarcoma cell lines. Assays related to tumorigenesis and metastasis, including cell migration, invasion, clonogenic survival, and soft agar colony formation, were performed in osteosarcoma cells. Additionally, mouse xenograft models were used to examine the role of ONZIN overpression in tumorigenesis in vivo. Lastly, 87 osteosarcoma patients were recruited to investigate the clinical relevance of ONZIN overexpression in metastasis and prognosis. RESULTS: ONZIN overexpression enhanced osteosarcoma cell proliferation, clonogenic survival, migration, and invasion independent of p53 status. Furthermore, ONZIN overexpression induced CXCL5 upregulation and resulted in increased ERK phosphorylation, which contributed to more aggressive osteosarcoma metastatic phenotypes. More importantly, overexpression of ONZIN in human osteosarcoma patients was closely associated with lung metastasis, poor prognoses, and survival. CONCLUSIONS: Overexpression of ONZIN promotes osteosarcoma progression and metastasis, and can serve as a clinical biomarker for osteosarcoma metastasis and prognosis.
BACKGROUND/AIMS: Gain-of-function of mutant p53 is associated with a high rate of lung metastasis in osteosarcoma. To investigate the mechanism of mutant p53-induced osteosarcoma metastasis, expression array analysis was performed, comparing non-metastatic osteosarcomas from p53+/- mice with metastatic osteosarcomas from p53R172H/+ mice. Onzin (Plac8) was identified as one of the genes upregulated in p53R172H/+ mouse metastatic osteosarcomas. Accordingly, we investigated the role of ONZIN in humanosteosarcoma metastasis. METHODS:ONZIN function and its downstream targets were examined in osteosarcoma cell lines. Assays related to tumorigenesis and metastasis, including cell migration, invasion, clonogenic survival, and soft agar colony formation, were performed in osteosarcoma cells. Additionally, mouse xenograft models were used to examine the role of ONZIN overpression in tumorigenesis in vivo. Lastly, 87 osteosarcomapatients were recruited to investigate the clinical relevance of ONZIN overexpression in metastasis and prognosis. RESULTS:ONZIN overexpression enhanced osteosarcoma cell proliferation, clonogenic survival, migration, and invasion independent of p53 status. Furthermore, ONZIN overexpression induced CXCL5 upregulation and resulted in increased ERK phosphorylation, which contributed to more aggressive osteosarcoma metastatic phenotypes. More importantly, overexpression of ONZIN in humanosteosarcomapatients was closely associated with lung metastasis, poor prognoses, and survival. CONCLUSIONS: Overexpression of ONZIN promotes osteosarcoma progression and metastasis, and can serve as a clinical biomarker for osteosarcoma metastasis and prognosis.
Authors: Katarzyna A Roszkowska; Slawomir Gizinski; Maria Sady; Zdzislaw Gajewski; Maciej B Olszewski Journal: Int J Mol Sci Date: 2020-02-17 Impact factor: 5.923