Dataset Information

COMMD7 Regulates NF-?B Signaling Pathway in Hepatocellular Carcinoma Stem-like Cells.

ABSTRACT: Previous studies showed that the COpper Metabolism gene MURR1 Domain (COMMD) family of proteins was abnormally expressed in hepatocellular carcinoma (HCC). This study aimed to explore the roles of COMMD1 and COMMD7 in regulating nuclear factor ?B (NF-?B) signaling in HCC stem cells (HCSCs). In vivo, the expression of COMMD7 and COMMD1 was determined in 35 pairs of HCC cancer tissues and adjacent tissues, and the effect of COMMD7 silencing on xenograft tumor growth was evaluated. In vitro, the effects of COMMD7 silencing and COMMD1 overexpression on HCSC function were assessed. Results found that the expression levels of COMMD7 were higher, whereas COMMD1 levels were lower in HCC tissues and HCSCs. COMMD7 silencing or COMMD1 overexpression inhibited cell proliferation, migration, and invasion through suppression of NF-?B p65. Furthermore, COMMD7 positively regulated NF-?B by upregulating protein inhibitor for activated stat 4 (PIAS4). This study demonstrates that COMMD7 has a dual regulatory role in the NF-?B signaling pathway in Nanog+ HCSCs.

SUBMITTER: Zheng L

PROVIDER: S-EPMC6350112 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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COMMD7 Regulates NF-κB Signaling Pathway in Hepatocellular Carcinoma Stem-like Cells.

Zheng Lu L You Nan N Huang Xiaobing X Gu Huiying H Wu Ke K Mi Na N Li Jing J

Molecular therapy oncolytics 20181214

Previous studies showed that the COpper Metabolism gene MURR1 Domain (COMMD) family of proteins was abnormally expressed in hepatocellular carcinoma (HCC). This study aimed to explore the roles of COMMD1 and COMMD7 in regulating nuclear factor κB (NF-κB) signaling in HCC stem cells (HCSCs). <i>In vivo</i>, the expression of COMMD7 and COMMD1 was determined in 35 pairs of HCC cancer tissues and adjacent tissues, and the effect of COMMD7 silencing on xenograft tumor growth was evaluated. <i>In vit ...[more]

PMID: 30719501

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Project description:Hedgehog (Hh) signaling plays an important role in embryonic development and in the regulation of a variety of cellular functions. Aberrant activation of Hh signaling has been implicated in several human cancers including hepatocellular carcinoma (HCC). In this study we examined the pathobiological functions and molecular mechanisms of the Hh signaling pathway in HCC cells. Treatment of cultured human HCC cells (Huh7, Hep3B, and HepG2) with the Hh signaling ligand (recombinant Shh) or agonist, SAG and purmorphamine, prevented the induction of autophagy. In contrast, GANT61 (a small molecule inhibitor of Gli1 and Gli2) induced autophagy, as determined by immunoblotting for microtubule-associated protein light chain 3 (LC3) and p62, GFP-LC3 puncta, monodansylcadaverine (MDC) staining, and transmission electron microscopy. Hh inhibition-induced autophagy was associated with up-regulation of Bnip3, as determined by immunoblotting and real-time polymerase chain reaction (PCR) assay. Knockdown of Bnip3 by RNAi impaired GANT61-induced autophagy. Additionally, Hh inhibition-induced autophagy was associated with Bnip3-mediated displacement of Bcl-2 from Beclin-1, as determined by immunoblotting and immunoprecipitation assays. Furthermore, inhibition of Hh signaling increased HCC cell apoptosis and decreased cell viability, as determined by caspase and WST-1 assays. Pharmacological or genetic inhibition of autophagy by 3-methyladenine (3-MA) or Beclin-1 small interfering RNA (siRNA) partially suppressed GANT61-induced cell apoptosis and cytotoxicity. In a tumor xenograft model using SCID mice inoculated with Huh7 cells, administration of GANT61 inhibited tumor formation and decreased tumor volume; this effect was partially blocked by the autophagy inhibitor, 3-MA.These findings provide novel evidence that Hh inhibition induces autophagy through up-regulation of Bnip3 and that this mechanism contributes to apoptosis. Therefore, the status of autophagy is a key factor that determines the therapeutic response to Hh-targeted therapies.

Dataset Information

COMMD7 Regulates NF-?B Signaling Pathway in Hepatocellular Carcinoma Stem-like Cells.

Publications

COMMD7 Regulates NF-κB Signaling Pathway in Hepatocellular Carcinoma Stem-like Cells.

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