Zhang Shihu, Zhang Yiyang, Cheng Qing, Ma Zhaoqun, Gong Guanwen, Deng Zhengming, Xu Kun, Wang Gaoyuan, Wei Yousong, Zou Xiaoping
Department of General Surgery, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China.
Digestive Department, Affiliated Drum Tower Clinical Medical School of Nanjing Medical University, Nanjing, China.
Oncotarget. 2017 Jun 27;8(39):65329-65338. doi: 10.18632/oncotarget.18649. eCollection 2017 Sep 12.
Developing novel strategies against human colorectal cancer (CRC) cells is needed. Activation of AMP-activated protein kinase (AMPK) could possibly inhibit CRC cells. Protein kinase C ζ (PKCζ) is an AMPK negative regulator. Here we found that PKCζ expression was significantly elevated in human colon cancer tissues and CRC cells. PKCζ upregulation was correlated with AMPK in-activation and mTOR complex 1 (mTORC1) over-activation. Reversely, PKCζ shRNA knockdown activated AMPK signaling and inhibited HT-29 cell proliferation. Significantly, downregulation of microRNA-25-5p (miR-25-5p), a PKCζ-targeting miRNA, could be the cause of PKCζ upregulation. Exogenous expression of miR-25-5p silenced PKCζ to activate AMPK signaling, which inhibited HT-29 cell proliferation. studies showed that HT-29 xenograft growth in mice was inhibited after expressing PKCζ shRNA or miR-25-5p. Collectively, PKCζ could be a novel oncogenic protein of human CRC. PKCζ silence, by targeted-shRNA or miR-25-5p expression, activates AMPK and inhibits HT-29 cell proliferation.
需要开发针对人类结肠直肠癌（CRC）细胞的新策略。激活AMP活化蛋白激酶（AMPK）可能会抑制CRC细胞。蛋白激酶Cζ（PKCζ）是一种AMPK负调节因子。在这里，我们发现PKCζ在人类结肠癌组织和CRC细胞中的表达显著升高。PKCζ上调与AMPK失活和mTOR复合物1（mTORC1）过度激活相关。相反，PKCζ shRNA敲低激活了AMPK信号并抑制了HT-29细胞增殖。重要的是，作为PKCζ靶向miRNA的微小RNA-25-5p（miR-25-5p）下调可能是PKCζ上调的原因。miR-25-5p的外源性表达使PKCζ沉默以激活AMPK信号，从而抑制HT-29细胞增殖。研究表明，在表达PKCζ shRNA或miR-25-5p后，小鼠体内HT-29异种移植瘤的生长受到抑制。总体而言，PKCζ可能是人类CRC的一种新型致癌蛋白。通过靶向shRNA或miR-25-5p表达使PKCζ沉默，可激活AMPK并抑制HT-29细胞增殖。
