CD44-Positive Cancer Stem Cells Expressing Cellular Prion Protein Contribute to Metastatic Capacity in Colorectal Cancer
CD44-Positive Cancer Stem Cells Expressing Cellular Prion Protein Contribute to Metastatic Capacity in Colorectal Cancer
复制标题
表达细胞朊病毒蛋白的 CD44 阳性癌症干细胞有助于结直肠癌的转移能力
DOI：
10.1158/0008-5472.can-12-3759
复制
发表时间：
2013-04-15
期刊：
影响因子：
11.2
通讯作者：
Chen, Quan
中科院分区：
文献类型：
--
作者：
Du, Lei;Rao, Guanhua;Chen, Quan
癌症干细胞与肿瘤进展、转移和复发有关，但其确切机制仍知之甚少。在这里，我们发现细胞朊病毒蛋白（PrPc、PRNP）的表达与结直肠癌转移风险增加呈正相关。 PrPc 定义了有助于转移能力的 CD44 阳性癌症干细胞亚群。 PrPc(+)CD44(+)结直肠癌干细胞表现出较高的肝转移能力，与PrPc(-)CD44(+)干细胞不同，PrPc(-)CD44(+)干细胞受到RNAi介导的PrPc减弱的抑制。值得注意的是，在原位转移小鼠模型中，给予 PrPc 单克隆抗体可显着抑制结直肠癌干细胞的致瘤性和转移。 PrPc 通过 ERK2 (MAPK1) 途径促进上皮细胞向间质细胞转化 (EMT)，从而赋予高转移能力。我们的研究结果揭示了 PrPc 在调节癌症干细胞 EMT 中的功能，并将 PrPc 确定为转移性结直肠癌的候选治疗靶点。癌症研究； 73（8）； 2682-94。 (C)2013 AACR。
Cancer stem cells are implicated in tumor progression, metastasis, and recurrence, although the exact mechanisms remain poorly understood. Here, we show that the expression of cellular prion protein (PrPc, PRNP) is positively correlated with an increased risk of metastasis in colorectal cancer. PrPc defines a subpopulation of CD44-positive cancer stem cells that contributes to metastatic capacity. PrPc(+)CD44(+) colorectal cancer stem cells displayed high liver metastatic capability, unlike PrPc(-)CD44(+) stem cells, that was inhibited by RNAi-mediated attenuation of PrPc. Notably, administration of PrPc monoclonal antibodies significantly inhibited tumorigenicity and metastasis of colorectal cancer stem cells in mouse models of orthotopic metastasis. PrPc promoted epithelial to mesenchymal transition (EMT) via the ERK2 (MAPK1) pathway, thereby conferring high metastatic capacity. Our findings reveal the function of PrPc in regulating EMT in cancer stem cells, and they identify PrPc as candidate therapeutic target in metastatic colorectal cancer. Cancer Res; 73(8); 2682-94. (C)2013 AACR.