Abstract
BackgroundIncreasing evidence has indicated parathyroid hormone type 1 receptor (PTHR1) plays important roles for the development and progression of osteosarcoma (OS). However, its function mechanisms remain unclear. The goal of this study was to further illuminate the roles of PTHR1 in OS using microarray data.MethodsMicroarray data were available from the Gene Expression Omnibus database under the accession number GSE46861, including six tumors from mice with PTHR1 knockdown (PTHR1.358) and six tumors from mice with control knockdown (Ren.1309). Differentially expressed genes (DEGs) between PTHR1.358 and Ren.1309 were identified using the LIMMA method, and then, protein–protein interaction (PPI) network was constructed using data from STRING database to screen crucial genes associated with PTHR1. KEGG pathway enrichment analysis was performed to investigate the underlying functions of DEGs using DAVID tool.ResultsA total of 1163 genes were identified as DEGs, including 617 downregulated (Lef1, lymphoid enhancer-binding factor 1) and 546 upregulated genes (Dkk1, Dickkopf-related protein 1). KEGG enrichment analysis indicated upregulated DEGs were involved in Renin-angiotensin system (e.g., Agt, angiotensinogen) and Wnt signaling pathway (e.g., Dkk1), while downregulated DEGs participated in Basal cell carcinoma (e.g., Lef1). A PPI network (534 nodes and 2830 edges) was constructed, in which Agt gene was demonstrated to be the hub gene and its interactive genes (e.g., CCR3, CC chemokine receptor 3; and CCL9, chemokine CC chemokine ligand 9) were inflammation related.ConclusionsOur present study preliminarily reveals the pro-malignant effects of PTHR1 in OS cells may be mediated by activating Wnt, angiogenesis, and inflammation pathways via changing the expressions of the crucial enriched genes (Dkk1, Lef1, Agt-CCR3, and Agt-CCL9).
Highlights
Increasing evidence has indicated parathyroid hormone type 1 receptor (PTHR1) plays important roles for the development and progression of osteosarcoma (OS)
Upon activation by PTH/parathyroid hormone-related peptide (PTHrP), PTHR1 induces the generation of cyclic AMP from ATP through adenylyl cyclase followed by the release of cAMP-dependent protein kinases [9,10,11]
Identification of Differentially expressed genes (DEGs) After data normalization, 1163 genes were identified as DEGs between PTHR1.358 and Ren.13096 cell samples based on the threshold of adjusted p < 0.05 and |logFC| > 0.5, including 617 downregulated and 546 upregulated genes (Table 1)
Summary
Increasing evidence has indicated parathyroid hormone type 1 receptor (PTHR1) plays important roles for the development and progression of osteosarcoma (OS). Accumulating evidence has indicated parathyroid hormone type 1 receptor (PTHR1), a G-proteincoupled receptor, may play important roles in the pathogenesis of OS. Further studies suggest PHTR1 may exert the tumorpromoting effects through being activated by its ligands, including parathyroid hormone (PTH) and parathyroid hormone-related peptide (PTHrP) [9, 10]. Active protein kinases (PKA, PKC, or ERK) move to the nucleus and phosphorylates transcription factors, such as cAMP-response element-binding protein (CREB) and runt-related transcription factor 2 (Runx-2) which lead to the development of OS through regulating the expression their target genes (TGF-b1, transforming growth factor b1; CTGF, connective tissue growth factor; FGF-2, fibroblast growth factor; HAS2, HA-synthase-2 [3, 12, 13]). The functions of PTHR1 in OS remain not fully understood
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