PAQR3 Plays a Suppressive Role in the Tumorigenesis of Colorectal Cancers
PAQR3 Plays a Suppressive Role in the Tumorigenesis of Colorectal Cancers
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PAQR3 在结直肠癌的肿瘤发生中发挥抑制作用
DOI：
10.1093/carcin/bgs245
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发表时间：
2012-11-01
期刊：
影响因子：
4.7
通讯作者：
Chen, Yan
中科院分区：
文献类型：
--
作者：
Wang, Xiao;Li, Xuebing;Chen, Yan
PAQR 3是一个蛋白质和脂肪Q受体（PAQR）家族的成员，最近被鉴定为负调节Ras/Raf/MEK/ERK信号级联的空间调节因子。然而，PAQR 3在结直肠癌发生中的生理功能知之甚少。通过将Paqr 3缺失的小鼠与具有编码肿瘤抑制性腺瘤性息肉病（APC）的基因的种系突变的Apc（Min/+）小鼠杂交来分析PAQR 3在小鼠中结肠直肠癌发展中的功能。Paqr 3基因缺失可显著延长Apc（Min/+）小鼠的生存时间，增加肿瘤面积。在SW-480结直肠癌细胞中，PAQR 3过表达可抑制细胞增殖率、非锚定依赖性生长、EGF刺激的ERK磷酸化和EGF诱导的β-catenin核积聚，而PAQR 3敲低可增强细胞增殖率、非锚定依赖性生长、ERK磷酸化和β-catenin核积聚。在人类中，与邻近的正常组织相比，PAQR 3的表达水平在结直肠癌样品中显著降低。此外，PAQR 3的表达水平与结直肠癌样品中的肿瘤分级呈负相关。总的来说，我们的数据首次揭示了PAQR 3在结直肠癌的发展中具有肿瘤抑制活性。
PAQR3 is a member of the progestin and adipoQ receptor (PAQR) family and was recently characterized as a spatial regulator that negatively modulates Ras/Raf/MEK/ERK signaling cascade. However, little is known about the physiological functions of PAQR3 in the tumorigenesis of colorectal cancers. The function of PAQR3 in colorectal cancer development in mice was analyzed by crossing Paqr3-depleted mice with Apc(Min/+) mice that have a germline mutation of the gene-encoding tumor suppressor adenomatous polyposis coli (APC). The survival time and tumor area in the small intestine of the Apc(Min/+) mice was significantly aggravated by Paqr3 deletion. The cell proliferation rate, anchorage-independent growth, EGF-stimulated ERK phosphorylation and EGF-induced nuclear accumulation of beta-catenin were inhibited by PAQR3 overexpression and enhanced by PAQR3 knockdown in SW-480 colorectal cancer cells. In humans, the expression level of PAQR3 was significantly decreased in colorectal cancer samples in comparison with adjacent normal tissues. In addition, the expression level of PAQR3 was inversely associated with tumor grade in the colorectal cancer samples. Collectively, our data reveal for the first time that PAQR3 has a tumor suppressor activity in the development of colorectal cancers.