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

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.

MicroRNA-1291-mediated silencing of IRE1α enhances Glypican-3 expression

“…In the same way, ATF6 signaling down-regulates the expression of miR-455 (Belmont et al 2012), and IRE1α signaling increases that of miR-346 (Bartoszewski et al 2011). Recently, miR-122, the most abundant miRNA in the liver, whose expression is repressed in HCC, was found to inhibit CDK4, which interacts and induces accumulation of PSMD10, a proteasome component and an enhancer of the UPR (Yang et al 2011). Herein, we describe for the first time a miRNA acting as an upstream inhibitor of the UPR pathway by directly targeting IRE1α expression.…”

Antitumor function of microRNA-122 against hepatocellular carcinoma

“…Intratumor injection of miR-122 encapsulated in cationic lipid nanoparticles suppressed the growth of HCC xenograft by 50 %, which was correlated with repression of target genes and impairment of angiogenesis [42]. In addition, miR-122 sensitizes HCC cells to antitumor agents including doxorubicin [27,43,44], vincristine [43], cisplatin [44], and sorafenib [12] by modulating the expression of multidrug resistance genes [43] and the unfolded protein response [44].…”

MiR-122 in hepatic function and liver diseases

“…Currently, several target genes of miR-122 have been identified to be involved in hepatocarcinogenesis, such as ADAM10 (a distintegrin and metalloprotease family 10), serum response factor (SRF) (Bai et al, 2009), insulin-like growth factor 1 receptor (Igf1R) (Zeng et al, 2010), cyclin G1 (Fornari et al, 2009), and Wnt1 (Xu et al, 2012). In addition, overexpression and restoration of miR-122 in HCC cells has been shown to sensitize HCC cells to chemotherapeutic agents (Bai et al, 2009;Xu et al, 2011;Yang et al, 2011). Owing to its remarkable tumor inhibitory activity, increasing miR-122 levels may be a promising strategy for HCC treatment .…”