PKCα promotes generation of reactive oxygen species via DUOX2 in hepatocellular carcinoma
PKCα promotes generation of reactive oxygen species via DUOX2 in hepatocellular carcinoma
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PKCα 通过 DUOX2 促进肝细胞癌中活性氧的产生
DOI：
10.1016/j.bbrc.2015.06.021
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发表时间：
2015
影响因子：
3.1
通讯作者：
Gu Jianxin
中科院分区：
文献类型：
--
作者：
Wang Jiajun;Shao Miaomiao;Liu Min;Peng Peike;Li Lili;Wu Weicheng;Wang Lan;Duan Fangfang;Zhang Mingming;Song Shushu;Jia Dongwei;Ruan Yuanyuan;Gu Jianxin
肝细胞癌（HCC）仍然是全球癌症相关死亡的第二大原因，活性氧（ROS）的升高一直被认为是几乎所有类型癌症（包括HCC）的标志。蛋白激酶C α（Protein Kinase C alpha，PKCα）是一种丝氨酸/苏氨酸蛋白激酶，在信号转导和肿瘤发生发展中起重要作用。PKCα的过度表达在人HCC中常见，并与其不良预后相关。然而，PKCα如何参与肝细胞癌的发生仍不完全清楚。在本研究中，我们发现在传统的PKC家族成员中，PKCα而不是PKCβI或βII促进了HCC细胞中ROS的产生。PKCα通过在转录后水平上调DUOX 2的表达，促进ROS的产生。DUOX 2的缺失消除了PKCα诱导的AKT/MAPK通路的激活以及HCC细胞中的细胞增殖、迁移和侵袭。此外，DUOX 2和PKCα的表达在HCC细胞系和患者样本中均呈正相关。总的来说，我们的研究结果表明，PKCα通过诱导DUOX 2表达和ROS产生在HCC的发展中起着关键作用，并提出了一种靶向PKCα/DUOX 2作为HCC治疗的潜在辅助疗法的策略。
Hepatocellular carcinoma (HCC) remains the second leading cause of cancer-related death worldwide, and elevated rates of reactive oxygen species (ROS) have long been considered as a hallmark of almost all types of cancer including HCC. Protein kinase C alpha (PKCα), a serine/threonine kinase among conventional PKC family, is recognized as a major player in signal transduction and tumor progression. Overexpression of PKCα is commonly observed in human HCC and associated with its poor prognosis. However, how PKCα is involved in hepatocellular carcinogenesis remains not fully understood. In this study, we found that among the members of conventional PKC family, PKCα, but not PKCβI or βII, promoted ROS production in HCC cells. PKCα stimulated generation of ROS by up-regulating DUOX2 at post-transcriptional level. Depletion of DUOX2 abrogated PKCα-induced activation of AKT/MAPK pathways as well as cell proliferation, migration and invasion in HCC cells. Moreover, the expression of DUOX2 and PKCα was well positively correlated in both HCC cell lines and patient samples. Collectively, our findings demonstrate that PKCα plays a critical role in HCC development by inducing DUOX2 expression and ROS generation, and propose a strategy to target PKCα/DUOX2 as a potential adjuvant therapy for HCC treatment.