| Cancer cells are characterized by deregulated proliferation which not only plays an important role in early tumorigenesis,but is also critical in tumor progression.It is manifested that overexpression and/or excessive activation of cell cycle activators such as E2F1 can stimulate unlimited proliferation of tumor cells.PIR(Pirin)protein belongs to the cupin superfamily and is highly conserved between eukaryotes and prokaryotes.We analyzed the Oncomine database and found that PIR had been up-regulated in various tumors,especially in breast cancer,implying the possible involvement of PIR in tumorigenesis.However,it is unclear whether and how PIR participates in promoting formation and progression of breast cancer.In this study,we found that knock-down of PIR in MCF-7 and MDA-MB-231 cell lines results in a dramatic decrease of cell proliferation in vitro and xenograf tumor growth in mice.Mechanistically,the cell cycle activator E2F1 and its target genes cdk4,cdk6,cycE,cycD and DDR1 are significantly down-regulated in PIR-silenced cells,resulting in G1/S phase arrest of cell cycle.Luciferase reporter gene assay and chromatin immunoprecipitation assay show that PIR can bind to the promoter region of E2F1,leading to E2F1 transcription and subsequent G1/S phase transition,and finally cause abnormal proliferation of tumor cells.Consistent with the observation in PIR-silenced cells,PIR inhibitors significantly inhibited the proliferation of both MCF-7 and MDA-MB-231 cell lines.In addition,knocking down PIR significantly reduced migration and invasion of MCF-7 cell in vitro and their metastasis in xenograf mice,which may be attributed to the reduction in DDR1.Taken together,our study reveals the mechanism by which PIR stimulates tumorigenesis and progression of breast cancer by activating E2F1 and its target genes.Therefore,our research suggests that PIR might be a potential drug target for treating cancers with high levels of PIR expression. |
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