RNAi silencing of c-Myc inhibits cell migration, invasion, and proliferation in HepG2 human hepatocellular carcinoma cell line: c-Myc silencing in hepatocellular carcinoma cell

Zhao, Yan; Wang, Jian; Gao, Wei; Zheng, Yaxin; Wang, Yongkun; Zhou, Zhuqing; Zhang, Hui; Wang, Congjun

doi:10.1186/1475-2867-13-23

Cited by 41 publications

(35 citation statements)

References 17 publications

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“…A recent report showed that knockdown of Myc suppressed proliferation of HepG2 cells (27), and we obtained results consistent with this by knockdown of Myc (data not shown), indicating that Myc expression is required for the proliferation of HepG2 cells. Thus, we studied the relevance of Skp2 to Myc in HepG2 hepatoma cells.…”

Section: Downregulation Of Skp2 With Hgf Reduces Myc Activitysupporting

confidence: 79%

ERK-Dependent Downregulation of Skp2 Reduces Myc Activity with HGF, Leading to Inhibition of Cell Proliferation through a Decrease in Id1 Expression

Bian²,

Takizawa³

et al. 2013

Molecular Cancer Research

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Hepatocyte growth factor (HGF) has an inhibitory effect on human HepG2 hepatoma cell proliferation. Previously, it was shown that HGF treatment downregulated Id1 and upregulated p16 INK4a in an ERK-dependent manner, leading to the inhibition of cellular proliferation. Here, new insight suggests that Skp2, an SCF complex component and potential prognosticator in cancer, is downregulated by injection of HGF into established HepG2 xenograft tumors. The downregulation was evident at both the mRNA and protein level and in an ERK-dependent manner. Critically, high expression of Skp2 restored HGF-inhibited cell proliferation, indicating that the inhibitory effect of HGF required the downregulation of Skp2. However, downregulation was not involved in the HGFinduced upregulation of a CDK inhibitor, p27 Kip1 , a known SCF-Skp2 target. Instead, data revealed that Skp2 regulated Myc activity, which has oncogenic potential in the generation of hepatocellular carcinoma. Elevated expression of Skp2 or a mutant that is unable to associate with the SCF complex was capable of activating Myc, suggesting that Skp2 does not act on Myc as a component of the SCF complex, and thus functions as an activator of Myc independent of its role in ubiquitination. Furthermore, Skp2 regulated Id1 expression by regulating Myc activity, and the regulation of Skp2 is involved in the activity of p16 promoter through regulation of Id1 expression. Overall, these mechanistic findings provide the first evidence that ERK-dependent downregulation of Skp2 reduced Myc activity, leading to HGF-induced inhibition of cell proliferation through decreased Id1 expression.

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Section: Downregulation Of Skp2 With Hgf Reduces Myc Activitysupporting

confidence: 79%

ERK-Dependent Downregulation of Skp2 Reduces Myc Activity with HGF, Leading to Inhibition of Cell Proliferation through a Decrease in Id1 Expression

Bian²,

Takizawa³

et al. 2013

Molecular Cancer Research

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“…5A). It has previously been demonstrated that c-myc is involved in cancer cell invasion ability (Zhao et al, 2013). Our findings suggests that Ran knockdown was not sufficient to inhibit cell invasion in melanoma cells since the signalling triggered by Ran silencing through the AurkA down-regulation resulted in a stable and/or increased c-myc protein level in A375 and 526 melanoma cell lines, respectively, suggesting a c-myc-dependent and Ran-independent invasion mechanism in melanoma.…”

Section: Resultsmentioning

confidence: 99%

“…This finding is in contrast with data previously reported (Yuen et al 2013; Deng et al 2014), and suggests a secondary role for Ran in the invasive properties of melanoma. It has been recently reported that c-myc plays a key role in enhancing the invasive capability of hepatocellular carcinoma cells (Zhao et al 2013), suggesting that the increase of the 526 cell invasive capability was Ran-independent and may be c-myc-dependent, although further experiments are needed to address this issue.…”

Section: Discussionmentioning

confidence: 99%

Ran signaling in melanoma: Implications for the development of alternative therapeutic strategies

et al. 2015

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We performed a comparative study between two human metastatic melanoma cell lines (A375 and 526), and melanocytes (FOM78) by gene expression profiling and pathway analysis, using Gene Set Enrichment Analysis (GSEA) and Ingenuity Pathway Analysis (IPA) software. Genes involved in Ran signaling were significantly over-represented (p≤ 0.001) and up-regulated in melanoma cells. A melanoma-associated molecular pathway was identified, where Ran, Aurora Kinase A (AurkA) and TERT were up-regulated, while c-myc and PTEN were down-regulated. A consistent high Ran and AurkA gene expression was detected in about 48% and 53%, respectively, of 113 tissue samples from metastatic melanoma patients. AurkA down-regulation was observed in melanoma cells, by Ran knockdown, suggesting AurkA protein is a Ran downstream target. Furthermore, AurkA inhibition, by exposure of melanoma cells to MLN8054, a specific AurKA inhibitor, induced apoptosis in both melanoma cell lines and molecular alterations in the IPA-identified molecular pathway. These alterations differed between cell lines, with an up-regulation of c-myc protein level observed in 526 cells and a slight reduction seen in A375 cells. Moreover, Ran silencing did not affect the A375 invasive capability, while it was enhanced in 526 cells, suggesting that Ran knockdown, by AurkA down-regulation, resulted in a Ran-independent enhanced melanoma cell invasion. Finally, AurK A inhibition induced a PTEN up-regulation and its action was independent of B-RAF mutational status. These findings provide insights relevant for the development of novel therapeutic strategies as well as for a better understanding of mechanisms underlying therapy resistance in melanoma.

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“…Recently, it has been reported the cooperation between c-MYC and HER2 and between c-MYC and β-CATENIN to drive mammary stem cell amplification and tumorigenesis [10, 12]. In fact, the down-regulation of c-MYC triggers the inhibition of cancer cell proliferation, invasion and migration [52]. Wnt/β-catenin signaling plays a critical role in CSCs, being β-CATENIN a key mediator of Wnt signaling [53].…”

Section: Discussionmentioning

confidence: 99%

HER2-signaling pathway, JNK and ERKs kinases, and cancer stem-like cells are targets of Bozepinib

et al. 2014

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Identification of novel anticancer drugs presenting more than one molecular target and efficacy against cancer stem-like cells (CSCs) subpopulations represents a therapeutic need to combat the resistance and the high risk of relapse in patients. In the present work we show how Bozepinib [(RS)-2,6-dichloro-9-[1-(p-nitrobenzenesulfonyl)-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]-9H-purine], a small anti-tumor compound, demonstrated selectivity on cancer cells and showed an inhibitory effect over kinases involved in carcinogenesis, proliferation and angiogenesis. The cytotoxic effects of Bozepinib were observed in both breast and colon cancer cells expressing different receptor patterns. Bozepinib inhibited HER-2 signaling pathway and JNK and ERKs kinases. In addition, Bozepinib has an inhibitory effect on AKT and VEGF together with anti-angiogenic and anti-migratory activities. Moreover, the modulation of pathways involved in tumorigenesis by Bozepinib was also evident in microarrays analysis. Interestingly, Bozepinib inhibited both mamo- and colono-spheres formation and eliminated ALDH+ CSCs subpopulations at a low micromolar range similar to Salinomycin. Bozepinib induced the down-regulation of c-MYC, β-CATENIN and SOX2 proteins and the up-regulation of the GLI-3 hedgehog-signaling repressor. Finally, Bozepinib shows in vivo anti-tumor and anti-metastatic efficacy in xenotransplanted nude mice without presenting sub-acute toxicity. These findings support further studies on the therapeutic potential of Bozepinib in cancer patients.

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RNAi silencing of c-Myc inhibits cell migration, invasion, and proliferation in HepG2 human hepatocellular carcinoma cell line: c-Myc silencing in hepatocellular carcinoma cell

Cited by 41 publications

References 17 publications

ERK-Dependent Downregulation of Skp2 Reduces Myc Activity with HGF, Leading to Inhibition of Cell Proliferation through a Decrease in Id1 Expression

ERK-Dependent Downregulation of Skp2 Reduces Myc Activity with HGF, Leading to Inhibition of Cell Proliferation through a Decrease in Id1 Expression

Ran signaling in melanoma: Implications for the development of alternative therapeutic strategies

HER2-signaling pathway, JNK and ERKs kinases, and cancer stem-like cells are targets of Bozepinib

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