Oncotarget

Research Papers:

PLA2G16 promotes osteosarcoma metastasis and drug resistance via the MAPK pathway

Lin Li, Shoulei Liang, Amanda R. Wasylishen, Yanqin Zhang, Xueli Yang, Bingzheng Zhou, Luling Shan, Xiuxin Han, Tianyang Mu _, Guowen Wang and Shunbin Xiong

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Oncotarget. 2016; 7:18021-18035. https://doi.org/10.18632/oncotarget.7694

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Abstract

Lin Li1, Shoulei Liang2, Amanda R. Wasylishen3, Yanqin Zhang1, Xueli Yang1, Bingzheng Zhou1, Luling Shan2, Xiuxin Han2, Tianyang Mu1, Guowen Wang2, Shunbin Xiong1,3

1Institute of Cancer Stem Cell, Dalian Medical University Cancer Center, Dalian, China

2Department of Bone and Soft Tissue Tumors, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China

3Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America

Correspondence to:

Tianyang Mu, e-mail: muty@dmu.edu.cn

Guowen Wang, e-mail: wangguowendr@163.com

Shunbin Xiong, e-mail: sxiong@mdanderson.org

Keywords: PLA2G16, osteosarcoma, metastasis, drug sensitivity, MAPK

Received: November 16, 2015     Accepted: February 11, 2016     Published: February 25, 2016

ABSTRACT

The prognosis of metastatic osteosarcoma is dismal and a better understanding of the mechanisms underlying disease progression is essential to improve treatment options and patient outcomes. We previously demonstrated Pla2g16 overexpression in mouse osteosarcoma contributes to metastasis phenotypes and increased expression of PLA2G16 is associated with metastasis and poor prognosis in human tumors. To further examine the mechanisms through which PLA2G16 contributes to human osteosarcoma metastasis and explore the potential of PLA2G16 as a therapeutic target in osteosarcoma, we generated a panel of human osteosarcoma cell lines expressing different levels of PLA2G16. The functional analyses of these cell lines demonstrated high levels of PLA2G16 expression increased osteosarcoma cell migration, invasion, clonogenic survival, and anchorage-independent colony formation. Importantly, this activity was dependent on the phospholipase activity of PLA2G16. Additionally, PLA2G16 overexpression decreased the sensitivity of cells to a panel of chemotherapeutic agents. Analysis of downstream pathways revealed the pro-metastasis functions of PLA2G16 were mediated through the MAPK pathway, as knockdown of PLA2G16 decreased ERK1/2 phosphorylation and pharmacological inhibition of MEK significantly repressed PLA2G16 mediated cell migration and clonogenic survival. Furthermore, PLA2G16 overexpression promoted xenograft tumor growth in vivo, and these tumors exhibit increased ERK1/2 phosphorylation. Lastly, the expression of PLA2G16 is strongly correlated with the increased ERK1/2 phosphorylation in human osteosarcoma samples, and the combined lesions are associated with reduced overall and metastasis-free survival. Collectively, these results demonstrate increased PLA2G16 expression activates the MAPK pathway to enhance osteosarcoma metastasis and may be a novel therapeutic target for these cancers.


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