Oncogenic secretory clusterin in hepatocellular carcinoma: Expression at early staging and emerging molecular target

Zheng, Wenjie; Yao, Min; Qin, Qian; Wang, Sai; Qiu, Liwei; Yang, Junling; Wu, Wei; Dong, Zhizhen; Yao, Dengfu

doi:10.18632/oncotarget.13674

Cited by 19 publications

(23 citation statements)

References 39 publications

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“…It subsequently stimulates the downstream oncogenes to induce more aggressive phenotypes, including proliferation, metastasis and CSC phenotypes [28]. Our previous work and other studies demonstrated that sCLU could activate AKT and subsequently inactive GSK3β via phosphorylation in ser9 [17,29]. It has been investigated that GSK3β, a join-point between PI3K/AKT pathway and Wnt/βcatenin pathway, is essential for the stability of β-catenin in cytoplasm [30,31].…”

Section: Discussionmentioning

confidence: 99%

“…For sCLU silencing, the pRNAT-U6.1/Neo vector was generated previously by Biomics Company (Nantong, China) [17]. The sequences of shRNAs in this study were listed as follows: shRNA-1, 5′-GTA AGT ACG TCA ATA AGG A-3′;…”

Section: Plasmids and Transfectionmentioning

confidence: 99%

“…Cell viability was detected by the MTT assay as described previously [17]. In brief, HepG2 and HCCLM3 (1 × 10 3 / well) were seeded in 96-well plates.…”

Section: Mtt Assaymentioning

confidence: 99%

“…1. Our previous work demonstrated that HCCLM3 and HepG2 had relatively higher and lower expression levels of sCLU in HCC cell lines, respectively [17]. Thus, the two cell lines were chosen for further function assays.…”

Section: Knockdown Of Sclu Inhibited Malignant Behaviors Of Hcc Cellsmentioning

confidence: 99%

“…In addition, given its excellent performance in diagnosis and prognosis, sCLU has been recommended as a biomarker for HCC [15,16]. Our previous study showed that sCLU acted as a regulator of AKT/GSK-3β signaling, thereby directing chemoresistance and tumor growth of HCC cells [17]. Hyperactivation of Wnt/β-catenin signaling pathway, the downstream of AKT/GSK-3β, has been frequently associated with CSCs [18].…”

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confidence: 99%

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

Zheng

Yao

et al. 2020

J Transl Med

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Plasmids and Transfectionmentioning

confidence: 99%

“…Cell viability was detected by the MTT assay as described previously [17]. In brief, HepG2 and HCCLM3 (1 × 10 3 / well) were seeded in 96-well plates.…”

Section: Mtt Assaymentioning

confidence: 99%

Section: Knockdown Of Sclu Inhibited Malignant Behaviors Of Hcc Cellsmentioning

confidence: 99%

mentioning

confidence: 99%

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

Zheng

Yao

et al. 2020

J Transl Med

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Clusterin and Related Scoring Index as Potential Early Predictors of Response to Sorafenib in Hepatocellular Carcinoma

et al. 2021

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Advanced hepatocellular carcinoma (HCC) remains a highly lethal malignancy, although several systemic therapeutic options are available, including sorafenib (SFN), which has been one of the standard treatment agents for almost a decade. As early prediction of response to SFN remains challenging, biomarkers that enable early prediction using a clinically feasible method are needed. Here, we report that the serum secretory form of clusterin (sCLU) protein and its related predictive index are potential beneficial biomarkers for early prediction of SFN response. Using high‐throughput screening and subsequent multivariate analysis in the derivation cohort, we found that changes in the concentrations of CLU, vascular cell adhesion molecule‐1 (VCAM1), and α‐fetoprotein were significantly associated with response to SFN. Furthermore, we confirmed that an increase in CLU serum level 1 month after treatment initiation was significantly associated with shorter progression‐free survival. In addition, “NR‐index,” which comprises these proteins, was evaluated as a tool for accurately predicting the efficacy of SFN and confirmed in the validation cohort. We also established SFN‐resistant HepG2 cells (HepG2‐SR) and found that sCLU significantly increased in HepG2‐SR cells compared with normal HepG2 cells, and confirmed that HepG2‐SR cells treated with SFN were resistant to apoptosis. The mechanism underlying activation of sCLU expression in acquired SFN resistance involves aberrant signaling and expression of Akt, mammalian target of rapamycin (mTOR), and a nutrient‐related transcription factor, sterol regulatory element binding protein 1c (SREBP‐1c). Furthermore, the PI3K and mTOR inhibitor BEZ235 markedly decreased sCLU expression in HepG2‐SR cells. Conclusion: These results suggest that measurement of sCLU serum levels and the sCLU‐related NR‐index are promising clinical tools for the early prediction of SFN response in HCC. Additionally, sCLU‐overexpressing HCC might be susceptible to mTOR inhibition.

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The role and function of CLU in cancer biology and therapy

et al. 2022

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Oncogenic secretory clusterin in hepatocellular carcinoma: Expression at early staging and emerging molecular target

Cited by 19 publications

References 39 publications

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

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

Clusterin and Related Scoring Index as Potential Early Predictors of Response to Sorafenib in Hepatocellular Carcinoma

The role and function of CLU in cancer biology and therapy

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