细胞型朊蛋白调控肿瘤干细胞转移的分子机制

Cancer is a major cause of mortality, and most human cancer deaths are related to metastasis. Accumulating evidence suggests that cancer stem cells are essential in tumor progression and metastasis, although the exact mechanisms remain poorly understood. Our recent study revealed that cellular prion protein (PrPc, PRNP), co-expressing with CD44, identifies a functionally distinct subpopulation of CD44+ cancer stem cell, which contributes to drug resistance, cancer initiation and metastasis. In this application, we would identify proteins that play roles in cancer metastasis, especially those interact with PrPc via gene arry analysis. Co-immunoprecipitation assay was used to confirm the interaction. EMT and metastasis related genes such as Twist, ERK2, and MMP are also detected. We would investigate the expression profile of these metastasis related proteins in PrPc overexpressed or PrPc knocked down cancer stem cells so that we can identify the signaling pathway of metastasis in cancer stem cells. We have generated specific anti-PrPc antibodies that could inhibit tumor growth and metastasis in NOD/SCID mice. In this study, we would apply these monoclonal anti-PrPc antibodies to investigating metastatic signaling pathway of cancer stem cells. The humanized anti-PrPc antibodies would shed a light in cancer therapy.

肿瘤转移是恶性肿瘤致死最重要的原因，肿瘤干细胞调控肿瘤的发生、生长和转移。我们最近的工作表明细胞型朊蛋白参与调控结直肠癌干细胞的耐药性、克隆形成和肿瘤形成能力，促进肿瘤干细胞从肠壁转移到肝脏，引起肿瘤干细胞发生上皮-间充质转化，但具体机制还不十分清楚。在本项申请中，我们将通过基因芯片的方法寻找肿瘤干细胞转移相关蛋白，从中发现PrPc的相互作用蛋白及上下游调控分子，重点关注EMT和转移相关Twist, ERK2, MMP蛋白，研究PrPc调控肿瘤干细胞转移的信号通路。同时我们将应用自制的PrPc单克隆抗体，在体外和体内转移模型中验证PrPc单克隆抗体对肿瘤干细胞转移信号通路的作用，确认肿瘤转移的具体机制和明确的信号通路，为治疗肿瘤转移提供新的思路。

肿瘤的复发和转移是恶性肿瘤致死最重要的原因，而肿瘤干细胞调控肿瘤的发生、生长、耐药和转移。我们发现细胞型朊蛋白参与调控结直肠癌干细胞的耐药性、克隆形成和肿瘤形成能力，促进肿瘤干细胞从肠壁转移到肝脏，引起肿瘤干细胞发生上皮-间充质转化。在本课题执行过程中，我们通过基因芯片的方法寻找肿瘤干细胞转移相关蛋白，通过比较PrPc阳性和阴性肿瘤干细胞亚群的cDNA表达谱差异，发现了一些与PrPc的相互作用蛋白及上下游调控分子。我们关注EMT相关蛋白和细胞膜蛋白MPx，从分子水平研究了PrPc调控肿瘤干细胞转移的信号通路。同时应用实验室制备的具有中和活性的PrPc单克隆抗体，我们在小鼠体外和体内转移模型中验证了PrPc单克隆抗体和MPx单克隆抗体对肿瘤干细胞生长和转移的作用，发现了与肿瘤转移相关的关键蛋白及其调控机制以及明确的信号通路，为治疗肿瘤转移提供新的思路。