Silencing clusterin gene transcription on effects of multidrug resistance reversing of human hepatoma HepG2/ADM cells

Zheng, Wenjie; Wang, Sai; Yao, Min; Gu, Heng; Yao, Yao; Qin, Qian; Yao, Dengfu

doi:10.1007/s13277-015-3043-9

Cited by 19 publications

(16 citation statements)

References 35 publications

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“…It has been proven that OGX‐011 improves the efficacy of chemotherapy by downregulating the expression of clusterin and promoting apoptosis in several preclinical and clinical studies . Several studies have demonstrated that clusterin confers resistance to anticancer agents in HCC, including sorafenib (unpublished data), doxorubicin, gemcitabine and oxaliplatin …”

Section: Biological Functions Of Hsps In Hccmentioning

confidence: 99%

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Heat shock proteins in hepatocellular carcinoma: Molecular mechanism and therapeutic potential

Wang

Zhang

Guo

et al. 2015

Intl Journal of Cancer

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Heat shock proteins (HSPs) are highly conserved proteins, which are expressed at low levels under normal conditions, but significantly induced in response to cellular stresses. As molecular chaperones, HSPs play crucial roles in protein homeostasis, apoptosis, invasion and cellular signaling transduction. The induction of HSPs is an important part of heat shock response, which could help cancer cells to adapt to stress conditions. Because of the constant stress condition in tumor microenvironment, HSPs overexpression is widely reported in many human cancers. In light of the significance of HSPs for cancer cells to survive and obtain invasive phenotype under stress condition, HSPs are often associated with poor prognosis and treatment resistance in many types of human cancers. It has been described that upregulation of HSPs may serve as diagnostic and prognostic markers in hepatocellular carcinoma (HCC). Targeting HSPs with specific inhibitor alone or in combination with chemotherapy regimens holds promise for the improvement of outcomes for HCC patients. In this review, we summarize the expression profiles, functions and molecular mechanisms of HSPs (HSP27, HSP70 and HSP90) as well as a HSP‐like protein (clusterin) in HCC. In addition, we address progression and challenges in targeting these HSPs as novel therapeutic strategies in HCC.

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Section: Biological Functions Of Hsps In Hccmentioning

confidence: 99%

“…Thus, siRNA or antisense oligodeoxynucleotide is used to knockdown the expression of clusterin. Silencing the expression of clusterin using siRNA obviously improves the efficacy of gemcitabine, oxaliplatin and doxorubicin in HCC treatment.…”

Section: Targeting Hsps In Hccmentioning

confidence: 99%

Heat shock proteins in hepatocellular carcinoma: Molecular mechanism and therapeutic potential

Wang

Zhang

Guo

et al. 2015

Intl Journal of Cancer

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“…It encodes two isoforms with paradoxical activities: nuclear clusterin (nCLU) and secretory clusterin (sCLU), and wide distribution in tissues and body fluids with various biological functions including lipid transport, senescence, complements cascade, membrane recycling, cell adhesion, and programmed cell death [5][6][7]. The nCLU is localized in nucleus and considered to participate in cell death; on the contrary, the sCLU is mainly distributed in cytoplasm and always plays a cellprotective role with anti-apoptosis activity [8], and its abnormality has been determined in a wide variety of tumors with development and progression by contributing to angiogenesis, chemo-resistance, cell survival, or metastasis [9,10].…”

Section: Introductionmentioning

confidence: 99%

Diagnostic and prognostic significance of secretory clusterin expression in patients with hepatocellular carcinoma

et al. 2015

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The upregulation of secretory clusterin (sCLU) is associated with tumor progression by contributing to angiogenesis, chemo-resistance, cell survival, and metastasis. However, its diagnostic or prognostic values for hepatocellular carcinoma (HCC) still remain to be clarified. The average serum sCLU level analyzed by an enzyme-linked immunosorbent assay was significantly higher (P < 0.001) in HCC patients than that in any of cases with cirrhosis, chronic hepatitis, or healthy control. The area under receiver operating characteristic curve and diagnostic sensitivity were 0.75 and 74.7 % in sCLU, and 0.74 and 58.7 % in α-fetoprotein (AFP), respectively. The combining detections of sCLU and AFP rose up to 90.7 % for HCC diagnosis. In liver, sCLU by immunohistochemistry was significantly higher (P < 0.001) in the HCC (77.3 %) group than that in their para-cancerous group (33.3 %). Abnormal serum or tissue sCLU expression was closely associated with tumor-node-metastasis (TNM) classification of malignant tumors and lymph node metastasis, as an independent prognosis factor (hazard ratio, 2.287; 95 % confidence interval, 1.044-5.007; P = 0.039), and higher sCLU expression significantly correlated (χ (2) = 4.252, P = 0.039) with poor survival of HCC patients analyzed by multivariate Cox regression or Kaplan-Meier method, suggesting that abnormal sCLU expression associated with tumor progression could be a potential diagnostic and prognostic biomarker for HCC.

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“…The well recognized mechanism of classical MDR is the significant overexpression of human MDR1 gene encoding MDR1/P-glycoprotein (P-gp) that acts as an efflux pump on cell surface [8,9] . Intracellular anti-cancer drugs increasingly flow from cells through the efflux pump, thus drug concentrations become lower and cancer cells become resistant to chemotherapeutic drugs such as doxorubicin [10,11] . Recently, some studies have found diverse anticancer effects of metformin in the cells of lung, gastric, endometrial, breast, and other types of cancer [12,13] .…”

Section: Introductionmentioning

confidence: 99%

Reversal of multidrug resistance of hepatocellular carcinoma cells by metformin through inhibitingNF-κBgene transcription

Yang

Wang

et al. 2016

WJH

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AIM:To interfere with the activation of nuclear factor-κB (NF-κB) with metformin and explore its effect in reversing multidrug resistance (MDR) of hepatocellular carcinoma (HCC) cells. METHODS:Expression of P-glycoprotein (P-gp) and NF-κB in human HepG2 or HepG2/adriamycin (ADM) cells RESULTS: P-gp overexpression in HepG2 and HepG2/ ADM cells was closely related to mdr1 mRNA (3.310 ± 0.154) and NF-κB mRNA (2.580 ± 0.040) expression. NF-κB gene transcription was inhibited by specific siRNA with significant down-regulation of P-gp and enhanced HCC cell chemosensitivity to doxorubicin. After pretreatment with metformin, HepG2/ADM cells were sensitized to doxorubicin and P-gp was decreased through the NF-κB signaling pathway. The synergistic effect of metformin and NF-κB siRNA were found in HepG2/ADM cells with regard to proliferation inhibition, cell cycle arrest and inducing cell apoptosis. Core tip: Metformin might target AMP-activated protein kinase mammalian target of rapamycin pathway, suppress hypoxia-inducible factor-1α and transcriptionally down-regulate P-glycoprotein (P-gp) and multidrug resistance (MDR)-associated protein 1, suggesting that metformin may reverse MDR by targeting the AMPactivated protein kinase/mammalian target of rapamycin/ hypoxia-inducible factor-1α/P-gp and MDR-associated protein 1 pathways. In the present study, HepG2/ADM cells pretreated with metformin were sensitized to doxorubicin and P-gp was decreased through the nuclear factor-κB (NF-κB) signaling pathway. The synergistic effects were found in the cells with regard to proliferation inhibition, cell cycle arrest and inducing apoptosis, and inhibiting P-gp expression via the NF-κB signaling pathway effectively reversed MDR by down-regulating MDR1/P-gp expression. CONCLUSION:

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Silencing clusterin gene transcription on effects of multidrug resistance reversing of human hepatoma HepG2/ADM cells

Cited by 19 publications

References 35 publications

Heat shock proteins in hepatocellular carcinoma: Molecular mechanism and therapeutic potential

Heat shock proteins in hepatocellular carcinoma: Molecular mechanism and therapeutic potential

Diagnostic and prognostic significance of secretory clusterin expression in patients with hepatocellular carcinoma

Reversal of multidrug resistance of hepatocellular carcinoma cells by metformin through inhibitingNF-κBgene transcription

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