Modulation of the Unfolded Protein Response Is the Core of MicroRNA-122-Involved Sensitivity to Chemotherapy in Hepatocellular Carcinoma
Modulation of the Unfolded Protein Response Is the Core of MicroRNA-122-Involved Sensitivity to Chemotherapy in Hepatocellular Carcinoma
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DOI：
10.1593/neo.11422
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发表时间：
2011-07-01
期刊：
影响因子：
4.8
通讯作者：
Sun, Shu-han
中科院分区：
文献类型：
--
作者：
Yang, Fu;Zhang, Ling;Sun, Shu-han
microRNA-122 (miR-122) 表达的丧失与肝细胞癌细胞 (HCC) 细胞的许多特征相关，包括克隆形成存活、贴壁依赖性生长、迁移、侵袭、上皮间质转化和肿瘤发生。然而，所有这些发现并不能充分解释 miR-122 的致癌潜力。在当前的研究中，我们使用二维差异凝胶电泳来测量人肝癌细胞中数千种蛋白质因抑制 miR-122 而表达的变化。 miR-122 抑制上调的几种蛋白参与未折叠蛋白反应 (UPR) 途径。 miR-122 的过度表达导致 UPR 通路激活受到抑制。因此，miR-122可能作为伴侣基因表达的抑制剂，负向调节HCC中的UPR通路。我们进一步表明，miR-122抑制剂通过上调其靶基因细胞周期蛋白依赖性激酶4（CDK4）来增强26S蛋白酶体非ATP酶调节亚基10（PSMD10）的稳定性。这一过程可能会激活 UPR 途径，以防止化疗介导的肿瘤细胞凋亡。目前的研究表明，miR-122通过CDK4-PSMD10途径负向调节UPR。 miR-122的下调激活CDK4-PSMD10-UPR通路以减少肿瘤细胞抗癌药物介导的细胞凋亡。我们确定了一个新的 HCC 治疗靶点，并宣布了 miR-122 沉默治疗用途的潜在风险。
The loss of microRNA-122 (miR-122) expression correlates to many characteristic properties of hepatocellular carcinoma (HCC) cells, including clonogenic survival, anchorage-independent growth, migration, invasion, epithelial-mesenchymal transition, and tumorigenesis. However, all of these findings do not sufficiently explain the oncogenic potential of miR-122. In the current study, we used two-dimensional differential in-gel electrophoresis to measure changes in the expression of thousands of proteins in response to the inhibition of miR-122 in human hepatoma cells. Several proteins that were upregulated on miR-122 inhibition were involved in the unfolded protein response (UPR) pathway. The overexpression of miR-122 resulted in the repression of UPR pathway activation. Therefore, miR-122 may act as an inhibitor of the chaperone gene expression and negatively regulate the UPR pathway in HCC. We further showed that the miR-122 inhibitor enhanced the stability of the 26S proteasome non-ATPase regulatory subunit 10 (PSMD10) through the up-regulation of its target gene cyclin-dependent kinase 4 (CDK4). This process may activate the UPR pathway to prevent chemotherapy-mediated tumor cell apoptosis. The current study suggests that miR-122 negatively regulates the UPR through the CDK4-PSMD10 pathway. The down-regulation of miR-122 activated the CDK4-PSMD10-UPR pathway to decrease tumor cell anticancer drug-mediated apoptosis. We identified a new HCC therapeutic target and proclaimed the potential risk of the therapeutic use of miR-122 silencing.