Secretory clusterin promotes hepatocellular carcinoma progression by facilitating cancer stem cell properties via AKT/GSK-3β/β-catenin axis

Abstract

Background: To explore the modulatory effects and mechanism of secretory clusterin (sCLU) on cancer stem cell (CSC) properties in hepatocellular carcinoma (HCC). Methods: The effects of sCLU repression or overexpression on chemoresistance, migration, invasion, and tumor growth were detected by MTT, wound healing, transwell assays, and xenograft assay, respectively. The tumor sphere assay was performed to evaluate the self-renewal ability of HCC cells. In addition, the molecular regulation between sCLU and AKT/GSK-3β/β-catenin axis in HCC cells were discovered by western blotting, quantitative real-time PCR (qRT-PCR), and immunofluorescence. The expression status of sCLU and β-catenin in HCC tissues were investigated by immunohistochemistry. Results: Knockdown or overexpressing sCLU remarkably inhibited or promoted the chemoresistance against sorafenib/doxorubicin, metastasis, and tumor growth of HCC cells, respectively. HepG2 and HCCLM3-derived spheroids showed higher expression of sCLU than that in attached cells. Additionally, repressing sCLU impaired the self-renewal capacity of HCC cells and CSC-related chemoresistance while overexpression of sCLU enhanced these CSC properties. Knockdown or overexpression of sCLU inhibited or increased the expressions of β-catenin, cyclinD1, MMP-2 and MMP-9, and the phosphorylation of AKT or GSK3β signaling, respectively. However, LiCl or LY294002 abrogated the effects mediated by sCLU silencing or overexpression on chemoresistance, metastasis, and CSC phenotype. Furthermore, co-expression of sCLU and β-catenin in HCC tissues indicated poor prognosis of HCC patients. Conclusions: Taken together, the oncogenic sCLU might promote CSC phenotype via activating AKT/GSK3β/βcatenin axis, suggesting that sCLU was a potential molecular-target for HCC therapy.

Overexpression of secretory clusterin (sCLU) induces chemotherapy resistance in human gastric cancer cells by targeting miR-195-5p

“…For instance, various other studies have reported that sCLU was associated with drug resistance of osteosarcoma cells [11] and prostate cancer cells [40]. Furthermore, the increased resistance to drugs was not entirely due to the elevation of sCLU, and is probably regulated by additional signaling pathways, including the activating AKT/GSK3β/β-catenin axis [41] and Wnt/β-catenin and IGF-I signaling [40]. All of the above suggested that the mechanism of drug resistance was highly complex, while it is indicated that sCLU may have an important role in the multidrug resistance of cancer cells.…”

Wnt/β-Catenin Signaling as a Driver of Hepatocellular Carcinoma Progression: An Emphasis on Molecular Pathways

“…Finally, this axis results in nuclear translocation of β-catenin and subsequent increase in stemness and CSC features of HCC that are of importance for mediating drug resistance (sorafenib resistance). 103 The diterpenoid ovatodiolide as anti-cancer agent, inhibits Wnt/β-catenin axis to impair CSC features of HCC cells and disrupt their progression. 104 Therefore, β-catenin signaling can be considered a novel target in HCC therapy and for reducing its stemness.…”

Inflammation, Extracellular Matrix Remodeling, and Proteostasis in Tumor Microenvironment

“…Disappointingly, so far only a limited number of studies have specifically addressed this issue. In vitro studies conducted in breast, renal, nasopharyngeal, and hepatocellular cancer cell lines found that MMP-9 and MMP-2 expression is reduced following CLU silencing, concomitantly with a decrease in cell motility and invasion [ 155 , 156 , 157 , 158 ].…”