中国科学家破解三阴性乳腺癌细胞多信号传导通路关键

　　蛋白质C受体（PROCR）作为若干正常组织干细胞标志物，还影响肿瘤生长。不过，PROCR的实际作用及其下游信号传导机制尚不明确。

蛋白质C：由肝合成的维生素K依赖因子，又称自体凝血酶原IIA、凝血因子XIV，可以灭活凝血因子Va、VIII，阻碍因子Xa与血小板磷脂结合，削弱因子Xa对凝血酶原的激活作用，刺激纤溶酶原激活物释放，增强纤溶酶活性，促进纤维蛋白溶解。

　　2017年12月，美国生物化学与分子生物学会《生物化学杂志》在线发表中国科学院生物化学与细胞生物学研究所曾艺、复旦大学附属肿瘤医院邵志敏等学者的研究报告，发现PROCR可以刺激三阴性乳腺癌细胞多种信号传导通路。

　　该研究深入剖析了乳腺癌细胞的PROCR信号通路，通过蛋白质芯片结合敲低和过度表达的方法，发现PROCR能够同时激活多种通路。

　　此外，依赖于PROCR的细胞外调节蛋白激酶（ERK）和磷脂酰肌醇3激酶→蛋白激酶B→哺乳动物雷帕霉素靶蛋白（PI3k-Akt-mTOR）信号通路通过原癌基因酪氨酸蛋白激酶（Src）和胰岛素样生长因子1受体（IGF-1R）反式激活作用进行信号传导。

反式激活：激活因子（如转录、翻译激活因子等）调控基因表达时，由于蛋白质直接结合或间接作用，引起基因表达激活或增强的调控作用。

　　上述通路活动导致原癌基因（c-Myc）和细胞周期蛋白D1的聚集。

　　另一方面，依赖于PROCR的Ras同源基因家族成员A→Rho相关卷曲螺旋蛋白激酶→p38丝裂原活化蛋白激酶（RhoA-ROCK-p38）信号又依赖于凝血因子II凝血酶受体（F2R）。

　　该研究通过PROCR高表达三阴性乳腺癌异种移植肿瘤原代细胞证实了上述发现。

　　据悉，该研究为全世界第一项对于乳腺癌细胞PROCR信号传导的全面研究，该研究结果还揭示了正常组织PROCR的分子机制。

　　因此，该研究为三阴性乳腺癌又发现了一个新的靶点，为针对该靶点的三阴性乳腺癌靶向治疗奠定了基础。

J Biol Chem. 2017 Dec 7. [Epub ahead of print]

Protein C receptor stimulates multiple signaling pathways in breast cancer cells.

Wang D, Liu C, Wang J, Jia Y, Hu X, Jiang H, Shao ZM, Zeng YA.

Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, China; Fudan University Shanghai Cancer Center, China.

The protein C receptor (PROCR) has emerged as a stem cell marker in several normal tissues and has also been implicated in tumor progression. However, the functional role of PROCR and the signaling mechanisms downstream of PROCR remain poorly understood. Here, we dissected the PROCR signaling pathways in breast cancer cells. Combining protein array, knockdown, and overexpression methods, we found that PROCR concomitantly activates multiple pathways. We also noted that PROCR-dependent ERK and PI3k-Akt-mTOR signaling pathways proceed through Src kinase and trans-activation of insulin-like growth factor 1 receptor (IGF-1R). These pathway activities led to the accumulation of c-Myc and Cyclin D1. On the other hand, PROCR-dependent RhoA-ROCK-p38 signaling relied on coagulation factor II thrombin receptor (F2R). We confirmed these findings in primary cells isolated from triple negative breast cancer-derived xenografts (PDX) that have high expression of PROCR. To the best our knowledge, this is the first comprehensive study of PROCR signaling in breast cancer cells, and its findings also shed light on the molecular mechanisms of PROCR in stem cells in normal tissue.

KEYWORDS: PROCR, breast cancer, TNBC, ERK, Akt, RhoA; breast cancer; cell signaling; mammary gland; signal transduction; stem cells

PMID: 29217770

PII: jbc.M117.814046

DOI: 10.1074/jbc.M117.814046