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Gene expression profiles of ATO-treated and negative control cells

ABSTRACT: Gene expression profile changes between ATO- treated and DMSO- treated Huh7 and Hep3B cells were analyzed To further explore the mechanism of ATO-induced differentiation, we performed a gene microarray assay to compare the differential gene expression profiles of low-dose ATO-treated (3 μM ATO treatment for 7 days) and negative control cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE128517 | GEO | 2019/07/01

REPOSITORIES: GEO

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Project description:BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) has a high mortality rate due to the lack of effective treatments and drugs. Arsenic trioxide (As2O3, ATO, arsenious acid), which has been proved to successfully treat acute promyelocytic leukemia (APL), was recently reported to show therapeutic potential in solid tumors including liver cancer. Although the mechanistic effects of ATO in APL are established, its anticancer mechanism of action in HCC is still unclear. METHODS: We established an HCC subcutaneous xenograft and intrahepatic metastasis mouse model. In CSC models, tumorspheres and the flow cytometry analysis of CSC markers together with limiting dilution and serial transplantation were used. We compared mRNA expression profiles of the ATO-treated and control cells with mRNA microarray. The expression of target molecule or a clinical correlation was analyzed by immunohistochemistry staining in tissues from ATO-treated mouse and 76 HCC patients. We generated five stable minichromosome maintenance protein 7 (MCM7)-knockdown and two stable MCM7-overexpression HCC cell lines. The chromatin immunoprecipitation (ChIP) assays, immunoprecipitation (IP) assays, the dual luciferase reporter assays, a green biarsenical labeling reagent (FlAsH-EDT2) and a “competing endogenous RNA” (ceRNA) analysis were used. RESULTS: ATO could inhibit the liver tumor-initiating capacity and distant metastasis and prolongs survival in mice. We then screened and found that ATO downregulates the overexpression of MCM7 which is correlated with the progression and prognosis in HCC patients. Knockdown of MCM7 expression recapitulates the inhibition function of ATO on self-renewal of cancer stem cells (CSCs), while overexpression of MCM7 abolishes the inhibition function of ATO on tumorsphere formation. Most importantly, we revealed that ATO directly binds to the MCM7 protein and disturbs the interaction between serum response factor (SRF) and MCM7, resulting in downregulation of MCM7 transcription. A ceRNA analysis also indicated the alterations of endogenous MCM7-associated gene networks involved in stemness-related signaling pathways and cell differentiation. CONCLUSIONS: Here, for the first time, we report that ATO inhibits liver CSCs through blocking the interaction between SRF/MCM7 and suppressing MCM7 autoregulation activity.

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Gene expression profiles of ATO-treated and negative control cells

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