title: PLA2G16 promotes osteosarcoma metastasis and drug resistance via the MAPK pathway.
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.
authors.affiliation: Institute of Cancer Stem Cell, Dalian Medical University Cancer Center, Dalian, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.affiliation: Department 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.
authors.forename: Shoulei
authors.initials: S
authors.lastname: Liang
authors.affiliation: Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Amanda R
authors.initials: AR
authors.lastname: Wasylishen
authors.affiliation: Institute of Cancer Stem Cell, Dalian Medical University Cancer Center, Dalian, China.
authors.forename: Yanqin
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Institute of Cancer Stem Cell, Dalian Medical University Cancer Center, Dalian, China.
authors.forename: Xueli
authors.initials: X
authors.lastname: Yang
authors.affiliation: Institute of Cancer Stem Cell, Dalian Medical University Cancer Center, Dalian, China.
authors.forename: Bingzheng
authors.initials: B
authors.lastname: Zhou
authors.affiliation: Department 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.
authors.forename: Luling
authors.initials: L
authors.lastname: Shan
authors.affiliation: Department 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.
authors.forename: Xiuxin
authors.initials: X
authors.lastname: Han
authors.affiliation: Institute of Cancer Stem Cell, Dalian Medical University Cancer Center, Dalian, China.
authors.forename: Tianyang
authors.initials: T
authors.lastname: Mu
authors.affiliation: Department 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.
authors.forename: Guowen
authors.initials: G
authors.lastname: Wang
authors.affiliation: Institute of Cancer Stem Cell, Dalian Medical University Cancer Center, Dalian, China.|Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Shunbin
authors.initials: S
authors.lastname: Xiong
mesh_terms: D000328:Adult; D000818:Animals; D001859:Bone Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology; D019008:Drug Resistance, Neoplasm; D005260:Female; D057809:HEK293 Cells; D064593:Heterografts; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D012516:Osteosarcoma / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D054512:Phospholipases A2, Calcium-Independent / Q000235:genetics / Q000378:metabolism*; D011379:Prognosis; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D055815:Young Adult
chemical_list: D025521:Tumor Suppressor Proteins; C490065:PLAAT3 protein, human; D054512:Phospholipases A2, Calcium-Independent
keywords: MAPK; PLA2G16; drug sensitivity; metastasis; osteosarcoma