Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Graduate School of the Chinese Academy of Sciences, Shanghai China.
Carcinogenesis. 2012 Nov;33(11):2228-35. doi: 10.1093/carcin/bgs245. Epub 2012 Jul 24.
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 β-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.
PAQR3 是孕激素和脂联素受体（PAQR）家族的成员，最近被确定为一种空间调节剂，可负向调节 Ras/Raf/MEK/ERK 信号级联。然而，PAQR3 在结直肠癌发生中的生理功能知之甚少。通过将 Paqr3 缺失小鼠与具有腺瘤性结肠息肉病基因编码肿瘤抑制因子 APC 种系突变的 Apc(Min/+) 小鼠杂交，分析了 PAQR3 在结直肠癌发展中的功能。Apc(Min/+) 小鼠的 Paqr3 缺失显著加重了其小肠中的存活时间和肿瘤面积。PAQR3 过表达可抑制 SW-480 结直肠癌细胞的细胞增殖率、无锚定生长、EGF 刺激的 ERK 磷酸化和 EGF 诱导的 β-连环蛋白核积累，而 PAQR3 敲低则增强了这些作用。在人类中，与相邻正常组织相比，结直肠癌样本中的 PAQR3 表达水平显著降低。此外，PAQR3 的表达水平与结直肠癌样本中的肿瘤分级呈负相关。综上所述，我们的数据首次揭示了 PAQR3 在结直肠癌发生发展中具有肿瘤抑制活性。
