Paradoxical role of autophagy in the dysplastic and tumor-forming stages of hepatocarcinoma development in rats.
Paradoxical role of autophagy in the dysplastic and tumor-forming stages of hepatocarcinoma development in rats.
复制标题
自噬在大鼠肝癌发展的发育不良和肿瘤形成阶段中的矛盾作用
DOI：
10.1038/cddis.2013.35
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发表时间：
2013-02-21
影响因子：
9
通讯作者：
Wei, L-x
中科院分区：
文献类型：
--
作者：
Sun, K.;Guo, X-l;Zhao, Q-d;Jing, Y-y;Kou, X-r;Xie, X-q;Zhou, Y.;Cai, N.;Gao, L.;Zhao, X.;Zhang, S-s;Song, J-r;Li, D.;Deng, W-j;Li, R.;Wu, M-c;Wei, L-x
许多研究表明，自噬在肿瘤发生发展中既有促进作用，又有抑制作用。然而，这种悖论的机制是未知的。肿瘤的发展是一个多步骤的过程。因此，我们研究了自噬在肝癌形成中的作用是否取决于肿瘤发展的阶段。根据我们的研究结果，氯喹抑制自噬在N-二乙基亚硝胺诱导的肝癌发生的大鼠模型中具有促癌作用，在其发育异常阶段（Ds）和肿瘤形成阶段（Ts）具有抑瘤作用。在Ds中，自噬抑制增强肝细胞增殖、DNA损伤和炎性细胞因子表达。这些变化依赖于自噬抑制导致活性氧（ROS）的上调，最终加速了肝癌的发生。然而，在Ts中，自噬抑制通过降低肿瘤细胞存活和增殖来抑制肿瘤形成。在此阶段，自噬抑制导致肿瘤内ROS过度积聚，促进细胞凋亡，并显著抑制肿瘤细胞代谢。综上所述，我们的数据表明，自噬抑制肝癌发生在Ds通过保护正常细胞的稳定性和促进肝癌发生在Ts通过支持肿瘤细胞的生长。自噬在肝癌发生发展的整个过程中始终扮演着保护者的角色。
Many reports have shown that autophagy has a role as both a promoter and inhibitor in tumor development. However, the mechanism of this paradox is unknown. Tumor development is a multistep process. Therefore, we investigated whether the role of autophagy in hepatocarcinoma formation depended on the stage of tumor development. Based on our results, autophagy inhibition by chloroquine had a tumor-promotive effect in the rat model with N-diethylnitrosamine-induced hepatocarcinogenesis in its dysplastic stage (Ds) and a tumor-suppressive effect in its tumor-forming stage (Ts). In the Ds, autophagy inhibition enhanced cell proliferation, DNA damage and inflammatory cytokines expression in liver. These changes were dependent on the upregulation of reactive oxygen species (ROS) that was resulted from autophagy inhibition, and ultimately accelerated the process of hepatocarcinogenesis. However, in the Ts, autophagy inhibition restrained tumor formation by decreasing tumor cell survival and proliferation. In this stage, autophagy inhibition led to excessive ROS accumulation in the tumor, which promoted cell apoptosis, and prominently suppressed tumor cell metabolism. Taken together, our data suggested that autophagy suppressed hepatocarcinogenesis in the Ds by protecting normal cell stability and promoted hepatocarcinogenesis in the Ts by supporting tumor cells growth. Autophagy always had a role as a protector throughout the process of hepatocarcinoma development.