PIR promotes tumorigenesis of breast cancer by upregulating cell cycle activator E2F1
PIR promotes tumorigenesis of breast cancer by upregulating cell cycle activator E2F1
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PIR通过上调细胞周期激活剂E2F1促进乳腺癌的肿瘤发生
DOI：
10.1080/15384101.2019.1662259
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发表时间：
2019
期刊：
影响因子：
4.3
通讯作者：
Li Qinxi
中科院分区：
文献类型：
--
作者：
Suleman Muhammad;Chen Ai;Ma Huanhuan;Wen Shixiong;Zhao Wentao;Lin Donghai;Wu Guode;Li Qinxi
摘要海鞘蛋白(PIR)属于Cupin超家族，在真核生物和原核生物中高度保守。据报道，PIR在多种肿瘤中表达上调，并参与肿瘤的发生。然而，到目前为止，它的生物学功能，特别是在促进肿瘤发生方面的作用，还没有得到很好的描述。在这里，我们报告了在MCF7和MDA-MB-231细胞系中PIR的敲除导致细胞增殖和小鼠异种移植瘤生长的急剧下降。在机制上，细胞周期激活剂E2F1及其靶基因CDK4、CDK6、CycE、CycD和DDR1在PIR耗竭细胞中显著下调，导致G1/S期停滞。荧光素酶报告实验和染色质免疫沉淀实验表明，PIR通过与E2F1启动子区域结合而激活E2F1转录。与在PIR基因敲除细胞中观察到的一致，PIR抑制剂显著抑制这两种细胞系的增殖。此外，PIR基因的敲除显著降低了MCF7细胞的体外迁移和侵袭能力以及在小鼠体内的转移能力，这可能是由于DDR1的减少所致。总之，PIR通过激活E2F1及其靶基因来刺激肿瘤的发生和发展。因此，我们的发现表明，PIR是治疗PIR高表达的癌症的潜在药物靶点。
ABSTRACT Pirin (PIR) protein belongs to the superfamily of cupin and is highly conserved between eukaryotic and prokaryotic organisms. It has been reported that PIR is upregulated in various tumors and involved in tumorigenesis. However, its biological functions particularly in promoting tumorigenesis are, to date, poorly characterized. Here we report that knockdown of PIR in MCF7 and MDA-MB-231 cell lines causes a dramatic decrease in cell proliferation and xenograft tumor growth in mice. Mechanistically, the cell cycle activator E2F1 and its target genes cdk4, cdk6, cycE, cycD and DDR1 are remarkably downregulated in PIR depleted cells, leading to G1/S phase arrest. Luciferase reporter assay and chromatin immunoprecipitation assay indicate that PIR can activate E2F1 transcription by binding to its promoter region. Consistent with the observation in PIR knockdown cells, PIR inhibitors markedly inhibit the proliferation of both cell lines. Furthermore, knockdown of PIR significantly decreases the abilities of MCF7 cells for mobility and invasion in vitro and their metastasis in mice, which may be attributed to the decrease of DDR1. In conclusion, PIR stimulates tumorigenesis and progression by activating E2F1 and its target genes. Our finding thus suggests PIR as a potential druggable target for the therapy of cancers with high expression level of PIR.