Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0029463 (osteosarcoma)
 16,637 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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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PMID:PLA2G16 promotes osteosarcoma metastasis and drug resistance via the MAPK pathway. 2693 4

Previous studies have revealed that miR-142-5p serves a critical role in human cancer progression. However, the biological function of miR-142-5p in osteosarcoma (OS) development remains unclear. In the present study, the role of miR-142-5p in human OS HOS cells was determined, and the underlying mechanism involved was examined. Compared with the adjacent healthy tissues, the expression level of miR-142-5p was downregulated and the expression level of group XVI phospholipase A2 (PLA2G16) protein was upregulated in human OS tissues. The aforementioned results were also indicated in human OS HOS cells when compared with human fetal osteoblastic hFOB1.19 cells. Additionally, the results demonstrated that PLA2G16 was a direct target of miR-142-5p. miR-142-5p transfection upregulated the expression level of miR-142-5p and suppressed the expression level of PLA2G16 protein in HOS cells. MTT assays indicated a time-dependent decrease by miR-142-5p transfection in the proliferation of HOS cells. 5-bromo-2'-deoxyuridine incorporation assays confirmed that miR-142-5p transfection inhibited DNA synthesis in HOS cells. In addition, miR-142-5p transfection increased the Caspase-3 (CASP3) activity and apoptotic rate. Western blot analysis indicated that miR-142-5p transfection reduced BCL2, apoptosis regulator expression and upregulated the expression of CASP3 and BCL2 associated X, apoptosis regulator in HOS cells. Furthermore, miR-142-5p transfection decreased the expression levels of phosphorylated (p)-proto-oncogene, serine/threonine kinase, p-mitogen-activated protein kinase kinase, and p-extracellular signal-regulated kinase (ERK) 1/2 proteins in HOS cells. PLA2G16 overexpression restored the expression level of p-ERK 1/2 protein, which was reduced by miR-142-5p overexpression. MTT and CASP3 activity assays indicated that restoration of PLA2G16 reversed the tumour-suppressive role of miR-142-5p transfection in HOS cells. In conclusion, the results of the present study indicated that miR-142-5p suppressed proliferation and promoted apoptosis in human OS HOS cells by targeting PLA2G16 through ERK1/2 signaling pathway.
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PMID:miR-142-5p suppresses proliferation and promotes apoptosis of human osteosarcoma cell line, HOS, by targeting PLA2G16 through the ERK1/2 signaling pathway. 3065 7