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Oncogene:成骨转录因子RUNX2可促进前列腺癌转移

来源:生物谷 2015-04-20 09:14

                                                    

2015年4月20日讯 /生物谷BIOON/ --近日,国际学术期刊oncogene在线发表了美国科学家关于成骨转录因子RUNx2在前列腺癌转移过程中发挥重要作用的最新研究进展。

有研究发现,成骨转录因子Runx2在前列腺癌中具有异常表达,并与转移性肿瘤发生有关。在骨发育过程中,Runx2会受到RAS/MAP激酶途径激活,该信号途径能够对Runx2的多个丝氨酸位点进行磷酸化从而实现对Runx2的激活,而RAS/MAP信号途径通常在前列腺癌中也会出现较高活性。
 
在该研究中,研究人员对Runx2的两个丝氨酸位点在前列腺癌中的作用进行了研究。他们发现Runx2倾向于表达在侵袭性更强的前列腺癌细胞系中,通过进一步分析证实,Runx2以及ERK的磷酸化水平在PC3细胞系中最高,其次是C4-2B和LNcaP细胞系,这些结果同时得到了免疫荧光共聚焦实验的验证。磷酸化的Runx2会发生核定位。当野生型Runx2表达在前列腺癌细胞系中,其能够增强癌细胞转移相关的基因表达,促进细胞迁移和侵袭活性。与之相比,对Runx2的磷酸化位点进行突变则会大大降低癌细胞的转移侵袭能力。
 
随后,研究人员对前列腺癌病人的组织进行了分析,发现磷酸化的Runx2具有很强的核定位,同时在其他一些转移性疾病如淋巴结转移也存在磷酸化Runx2的核定位。
 
这项研究表明Runx2的磷酸化对于前列腺癌及其他一些转移性疾病的发生具有重要作用,或可作为靶点用于转移性疾病的诊断和治疗。(生物谷Bioon.com)
 
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Role of Runx2 phosphorylation in prostate cancer and association with metastatic disease
 
C Ge1, G Zhao, Y Li1, H Li, X Zhao, G Pannone, P Bufo, A Santoro, F Sanguedolce, S Tortorella, M Mattoni, S Papagerakis, E T Keller and R T Franceschi
 
The osteogenic transcription factor, Runx2, is abnormally expressed in prostate cancer (PCa) and associated with metastatic disease. During bone development, Runx2 is activated by signals known to be hyperactive in PCa including the RAS/MAP kinase pathway, which phosphorylates Runx2 on multiple serine residues including S301 and S319 (equivalent to S294 and S312 in human Runx2). This study examines the role of these phosphorylation sites in PCa. Runx2 was preferentially expressed in more invasive PCa cell lines (PC3>C4-2B>LNCaP). Furthermore, analysis using a P-S319-Runx2-specific antibody revealed that the ratio of P-S319-Runx2/total Runx2 as well as P-ERK/total ERK was highest in PC3 followed by C4-2B and LNCaP cells. These results were confirmed by immunofluorescence confocal microscopy, which showed a higher percentage of PC3 cells staining positive for P-S319-Runx2 relative to C4-2B and LNCaP cells. Phosphorylated Runx2 had an exclusively nuclear localization. When expressed in prostate cell lines, wild-type Runx2 increased metastasis-associated gene expression, in vitro migratory and invasive activity as well as in vivo growth of tumor cell xenografts. In contrast, S301A/S319A phosphorylation site mutations greatly attenuated these Runx2 responses. Analysis of tissue microarrays from 129 patients revealed strong nuclear staining with the P-S319-Runx2 antibody in primary PCas and metastases. P-S319-Runx2 staining was positively correlated with Gleason score and occurrence of lymph node metastases while little or no Runx2 phosphorylation was seen in normal prostate, benign prostate hyperplasia or prostatitis indicating that Runx2 S319 phosphorylation is closely associated with PCa induction and progression towards an aggressive phenotype. These studies establish the importance of Runx2 phosphorylation in prostate tumor growth and highlight its value as a potential diagnostic marker and therapeutic target.
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