Abstract
ObjectivesTo determine whether the upregulation of basic leucine zipper ATF-like transcription factor 2 (BATF2) by calycosin suppresses the growth and epithelial-to-mesenchymal transition (EMT) in human colorectal cancer (CRC) cells.MethodCells were cultured and treated with different concentrations of calycosin for different periods of time. Protein and mRNA expression was determined by western blotting and quantitative PCR. Cell migration was assessed by Transwell experiments. Co-immunoprecipitation and luciferase assays were used to analyze the association between BATF2 and plasminogen activator inhibitor-1.(PAI-1). Cell apoptosis was determined by flow cytometry; β-catenin cellular localization was visualized by immunofluorescent staining.ResultsCalycosin up-regulated the expression of BATF2 via the signal transducer and activator of transcription 3 (STAT3) pathway, which was antagonized by transforming growth factor beta (TGF-β), calycosin promoted the cell apoptosis and growth inhibition via phosphoinositide 3-kinase (PI3K)/Akt pathway. TGF-β promoted cell growth, which was inhibited by calycosin regulating the expression of proliferating cell nuclear antigen (PCNA) via the phosphoinositide 3-kinase pathway. TGF-β suppressed expression of BAX via the phosphoinositide 3-kinase pathway but induced cell apoptosis .calycosin enhanced the effect of TGF-β on cell apoptosis,In addition, calycosin suppressed TGF-β-induced cell migration by increasing BATF2 to target PAI-1. TGF-β-induced EMT was inhibited by calycosin in human CRC LoVo and HCT116 cell lines via the Wnt signaling pathway.ConclusionsThe induction of BATF2 by calycosin may be a feasible therapeutic option for CRC.Graphical .
Highlights
The basic leucine zipper ATF-like transcription factor (BATF) family [1] is a subgroup of the larger family of bZIP transcription factors, and its members belong to the Active protein-1 (AP-1) family of transcription factors
It’s role in the epithelial-to-mesenchymal transition (EMT) of colorectal cancer (CRC) cells is unclear Transforming growth factor beta (TGF-β) signaling and activated Ras pathways have been implicated as key EMT inducers in CRC [8, 9], as localized CRC cells respond to TGF-β with growth inhibition and metastatic carcinoma cells proliferate after treatment with TGF-β [10,11,12]
LoVo cell growth in the treatment group was suppressed with 100 μM calycosin at 12, 24, and Calycosin up-regulates basic leucine zipper ATF-like transcription factor 2 (BATF2) expression, which is inhibited by TGF-β via the Signal transducer and activator of transcription 3 (STAT3) signaling pathway to promote growth inhibition involving Protein kinase B (Akt) phosphorylation To investigate the effects of calycosin- and TGF-β-induced BATF2 expression on cell growth and apoptosis, BATF2, STAT3, p-STAT3, BCL2-associated X (BAX), proliferating cell nuclear antigen (PCNA), and Phosphorylated protein kinase B (p-Akt) levels were evaluated by western blotting
Summary
The basic leucine zipper (bZIP) ATF-like transcription factor (BATF) family [1] is a subgroup of the larger family of bZIP transcription factors, and its members belong to the AP-1 family of transcription factors. The induction of BATF2 was found to inhibit the hepatocyte growth factor (HGF)/MET signaling pathway [4] and to suppress angiogenesis and tumor growth by directly targeting ceruloplasmin via inhibition of the activity of the hypoxia inducible factor 1 alpha (HIF-1α)/vascular endothelial growth factor (VEGF) axis in colorectal cancer (CRC) cells [5].BATF2 regulates numerous cellular processes including growth inhibition and promotion of apoptosis [6, 7]. Signal transducer and activator of transcription 3 (STAT3) is another important signaling pathway in the regulation of EMT in CRC. BATF is a direct target of STAT3 [18]; we were interested in determining the role of BATF2 in the STAT3-mediated inhibition of TGF-β-induced EMT in CRC
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