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NF-kappaB Is Involved in the Regulation of EMT Genes in Breast Cancer Cells.

ABSTRACT: The metastatic process in breast cancer is related to the expression of the epithelial-to-mesenchymal transition transcription factors (EMT-TFs) SNAIL, SLUG, SIP1 and TWIST1. EMT-TFs and nuclear factor-?B (NF-?B) activation have been associated with aggressiveness and metastatic potential in carcinomas. Here, we sought to examine the role of NF-?B in the aggressive properties and regulation of EMT-TFs in human breast cancer cells. Blocking NF-?B/p65 activity by reducing its transcript and protein levels (through siRNA-strategy and dehydroxymethylepoxyquinomicin [DHMEQ] treatment) in the aggressive MDA-MB-231 and HCC-1954 cell lines resulted in decreased invasiveness and migration, a downregulation of SLUG, SIP1, TWIST1, MMP11 and N-cadherin transcripts and an upregulation of E-cadherin transcripts. No significant changes were observed in the less aggressive cell line MCF-7. Bioinformatics tools identified several NF-?B binding sites along the promoters of SNAIL, SLUG, SIP1 and TWIST1 genes. Through chromatin immunoprecipitation and luciferase reporter assays, the NF-?B/p65 binding on TWIST1, SLUG and SIP1 promoter regions was confirmed. Thus, we suggest that NF-?B directly regulates the transcription of EMT-TF genes in breast cancer. Our findings may contribute to a greater understanding of the metastatic process of this neoplasia and highlight NF-?B as a potential target for breast cancer treatment.

SUBMITTER: Pires BR

PROVIDER: S-EPMC5249109 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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NF-kappaB Is Involved in the Regulation of EMT Genes in Breast Cancer Cells.

Pires Bruno R B BR Mencalha Andre L AL Ferreira Gerson M GM de Souza Waldemir F WF Morgado-Díaz José A JA Maia Amanda M AM Corrêa Stephany S Abdelhay Eliana S F W ES

PloS one 20170120 1

The metastatic process in breast cancer is related to the expression of the epithelial-to-mesenchymal transition transcription factors (EMT-TFs) SNAIL, SLUG, SIP1 and TWIST1. EMT-TFs and nuclear factor-κB (NF-κB) activation have been associated with aggressiveness and metastatic potential in carcinomas. Here, we sought to examine the role of NF-κB in the aggressive properties and regulation of EMT-TFs in human breast cancer cells. Blocking NF-κB/p65 activity by reducing its transcript and protei ...[more]

PMID: 28107418

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Project description:BackgroundDuring the process of metastasis, cells are subjected to various apoptotic stimuli. Aberrant expression of apoptotic regulators often contribute to cell metastasis. Heat shock protein 27(HSP27) is confirmed as an apoptosis regulator, but its antiapoptotic mechanism in metastatic hepatocellular carcinoma (HCC) cells remains unclear.MethodsLevels of HSP27 protein and its phosphorylation in Hep3B, MHCC97L to MHCC97H cells with different metastatic potentials were determined by western blot analysis. MHCC97H cells were transfected with specific small interference RNA (siRNA) against HSP27. The in vitro migration and invasion potentials of cells were evaluated by Transwell assay. The apoptosis ratio of MHCC97H cells was analyzed by TUNEL staining and Flow Cytometry. Alteration of signal transduction pathway after HSP27 knockdown in MHCC97H cells was evaluated through a Human Q Series Signal Transduction in Cancer Gene Array analysis. Nuclear NF-kappaB contentration and endogenous IKK activity were demonstrated by ELISA assay. The association of IKKalpha, IKKbeta, IkappaBalpha with HSP27 and the association between IKKbeta and IKKalpha in MHCC97H cells were determined by co-immunoprecipitation assay followed by western blot analysis.ResultsHSP27 protein and its phosphorylation increased in parallel with enhanced metastatic potentials of HCC cells. siRNA-mediated HSP27 knockdown in MHCC97H significantly suppressed cells migration and invasion in vitro and induced cell apoptosis; the prominently altered signal transduction pathway was NF-kappaB pathway after HSP27 knockdown in MHCC97H cells. Furthermore, inhibition of HSP27 expression led to a significant decrease of nuclear NF-kappaB contentration and endogenous IKK activity. In addition, HSP27 was associated with IKKalpha, IKKbeta, IkappaBalpha in three HCC cells above. ELISA assay and western blot analysis also showed a decrease of the association between IKKbeta and IKKalpha, the association between phosphor-HSP27 and IKK complex, and an increase of total IkappaBalpha but reducing tendency of phosphor-IkappaBalpha when HSP27 expression was efficiently knocked down in MHCC97H cells.ConclusionAltogether, these findings revealed a possible effect of HSP27 on apoptosis in metastatic HCC cells, in which HSP27 may regulate NF-kB pathway activation.

Dataset Information

NF-kappaB Is Involved in the Regulation of EMT Genes in Breast Cancer Cells.

Publications

NF-kappaB Is Involved in the Regulation of EMT Genes in Breast Cancer Cells.

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