Modulation of the Unfolded Protein Response Is the Core of MicroRNA-122-Involved Sensitivity to Chemotherapy in Hepatocellular Carcinoma

• Published in: Neoplasia (New York, N.Y.) N.Y.), 2011-07, Vol.13 (7), p.590-IN4
• Main Authors: Yang, Fu, Zhang, Ling, Wang, Fang, Wang, Yue, Huo, Xi-song, Yin, Yi-xuan, Wang, Yu-qi, Zhang, Lin, Sun, Shu-han
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Apoptosis; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Cells, Cultured; Drug Resistance, Neoplasm - genetics; Gene Expression Regulation, Neoplastic - drug effects; Hep G2 Cells; Humans; Liver Neoplasms - drug therapy; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Mice; Mice, Nude; MicroRNAs - genetics; MicroRNAs - metabolism; MicroRNAs - physiology; Oncology; Transfection; Unfolded Protein Response - physiology; Xenograft Model Antitumor Assays
• ISSN: 1476-5586; 1522-8002; 1476-5586; 1522-8002
• DOI: 10.1593/neo.11422

Abstract 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.