A feed-forward loop involving protein kinase Calpha and microRNAs regulates tumor cell cycle.
A feed-forward loop involving protein kinase Calpha and microRNAs regulates tumor cell cycle.
复制标题
DOI：
10.1158/0008-5472.can-08-0377
复制
发表时间：
2009-01-01
期刊：
影响因子：
11.2
通讯作者：
Rosner MR
中科院分区：
文献类型：
--
作者：
Cohen EE;Zhu H;Lingen MW;Martin LE;Kuo WL;Choi EA;Kocherginsky M;Parker JS;Chung CH;Rosner MR
蛋白激酶C α（PKCα）与癌症有关，但其机制在很大程度上尚不清楚。在这里，我们表明，PKCα促进头颈部鳞状细胞癌（SCCHN）的前馈网络，导致细胞周期失调。PKCα抑制剂降低SCCHN细胞系和异种移植肿瘤的增殖。肿瘤细胞中PKCα的抑制或耗竭通过抑制ERK磷酸化和细胞周期蛋白E的合成来降低DNA合成。此外，PKCα下调miR-15 a，一种直接抑制细胞周期蛋白E以及其他细胞周期调节因子的蛋白质合成的microRNA。此外，原发性肿瘤中PKCα和细胞周期蛋白E蛋白表达均增加，且PKCα与原发性肿瘤中miR 15 a表达呈负相关。最后，PKCα与SCCHN的不良预后相关。这些结果确定PKCα是HNSCC肿瘤细胞生长的关键调节因子，其机制涉及激活MAP激酶（细胞周期的启动子）和抑制miR-15 a（DNA合成的抑制剂）。虽然具体的组件可能是不同的，这种类型的前馈环路网络，由一个刺激，激活一个积极的信号，并删除一个负刹车，很可能是一个通用的一个，使诱导DNA合成的各种生长或致癌刺激。
Protein Kinase C alpha (PKCα) has been implicated in cancer but the mechanism is largely unknown. Here we show that PKCα promotes head and neck squamous cell carcinoma (SCCHN) by a feed forward network leading to cell cycle deregulation. PKCα inhibitors decrease proliferation in SCCHN cell lines and xenografted tumors. PKCα inhibition or depletion in tumor cells decreases DNA synthesis by suppressing ERK phosphorylation and cyclin E synthesis. Additionally, PKCα down-regulates miR-15a, a microRNA that directly inhibits protein synthesis of cyclin E as well as other cell cycle regulators. Furthermore, both PKCα and cyclin E protein expression are increased in primary tumors, and PKCα inversely correlates with miR15a expression in primary tumors. Finally, PKCα is associated with poor prognosis in SCCHN. These results identify PKCα as a key regulator of HNSCC tumor cell growth by a mechanism involving activation of MAP kinase, an initiator of the cell cycle, and suppression of miR-15a, an inhibitor of DNA synthesis. Although the specific components may be different, this type of feed forward loop network, consisting of a stimulus that activates a positive signal and removes a negative brake, is likely to be a general one that enables induction of DNA synthesis by a variety of growth or oncogenic stimuli.