PSF1, a DNA Replication Factor Expressed Widely in Stem and Progenitor Cells, Drives Tumorigenic and Metastatic Properties
PSF1, a DNA Replication Factor Expressed Widely in Stem and Progenitor Cells, Drives Tumorigenic and Metastatic Properties
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DOI：
10.1158/0008-5472.can-09-3662
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发表时间：
2010-02-01
期刊：
影响因子：
11.2
通讯作者：
Takakura, Nobuyuki
中科院分区：
文献类型：
--
作者：
Nagahama, Yumi;Ueno, Masaya;Takakura, Nobuyuki
PSF 1（partner of sld five 1）是一种进化上保守的DNA复制因子，参与低等物种的DNA复制，在广泛的正常干细胞群和祖细胞群中强烈表达。由于干细胞和祖细胞具有高增殖能力，我们推测PSF 1可能在肿瘤生长中起重要作用。为了开始研究PSF 1在癌细胞中的功能，我们克隆了小鼠PSF 1启动子，并产生了稳定表达PSF 1启动子报告基因的肺和结肠癌细胞。细胞中的报告基因表达与内源性PSF 1 mRNA表达相关。在肿瘤细胞异种移植模型中，高水平的报告基因表达与高增殖活性、连续移植潜力和转移能力相关。值得注意的是，表达报告水平的癌细胞定位于肿瘤中的血管周围区域，并显示出与胚胎干细胞相关的表达特征。RNAi介导的内源性PSF 1沉默通过破坏DNA合成和染色体分离来抑制癌细胞生长。这些发现暗示了PSF 1在肿瘤发生中的作用，并提供了其作为治疗诊断靶点的潜力的初步证据。Cancer Res; 70（3）; 1215-24. (C)2010年AACR。
PSF1 (partner of sld five 1) is an evolutionarily conserved DNA replication factor implicated in DNA replication in lower species that is strongly expressed in a wide range of normal stem cell populations and progenitor cell populations. Because stem and progenitor cells possess high proliferative capacity, we hypothesized that PSF1 may play an important role in tumor growth. To begin to investigate PSF1 function in cancer cells, we cloned the mouse PSF1 promoter and generated lung and colon carcinoma cells that stably express a PSF1 promoter-reporter gene. Reporter expression in cells correlated with endogenous PSF1 mRNA expression. In a tumor cell xenograft model, high levels of reporter expression correlated with high proliferative activity, serial transplantation potential, and metastatic capability. Notably, cancer cells expressing reporter levels localized to perivascular regions in tumors and displayed expression signatures related to embryonic stem cells. RNAi-mediated silencing of endogenous PSF1 inhibited cancer cell growth by disrupting DNA synthesis and chromosomal segregation. These findings implicate PSF1 in tumorigenesis and offer initial evidence of its potential as a theranostic target. Cancer Res; 70(3); 1215-24. (C) 2010 AACR.