miR-23a inhibits E-cadherin expression and is regulated by AP-1 and NFAT4 complex during Fas-induced EMT in gastrointestinal cancer

• Published in: Carcinogenesis (New York) Vol. 35; no. 1; pp. 173 - 183
• Main Authors: Zheng, Haoxuan, Li, Wenjing, Wang, Yadong, Xie, Tingting, Cai, Yidong, Wang, Zhiqing, Jiang, Bo
• Format: Journal Article
• Language: English
• Published: England 01.01.2014
• Subjects: Animals; Cadherins - genetics; Cadherins - metabolism; Epithelial-Mesenchymal Transition; Extracellular Signal-Regulated MAP Kinases - metabolism; Fas Ligand Protein - genetics; Fas Ligand Protein - metabolism; fas Receptor - genetics; fas Receptor - metabolism; Gastrointestinal Neoplasms - genetics; Gastrointestinal Neoplasms - metabolism; Gastrointestinal Neoplasms - pathology; Gene Expression Regulation, Neoplastic; Glycogen Synthase Kinase 3 - metabolism; Glycogen Synthase Kinase 3 beta; Humans; Mice; Mice, Inbred BALB C; MicroRNAs - genetics; MicroRNAs - metabolism; NFATC Transcription Factors - genetics; NFATC Transcription Factors - metabolism; Precancerous Conditions - genetics; Precancerous Conditions - pathology; Signal Transduction; Transcription Factor AP-1 - genetics; Transcription Factor AP-1 - metabolism
• ISSN: 0143-3334; 1460-2180
• DOI: 10.1093/carcin/bgt274

Fas signaling has been shown to induce the epithelial-mesenchymal transition (EMT) to promote gastrointestinal (GI) cancer metastasis, but the involvement of microRNA in this mechanism remains unknown. We found that Fas ligand (FasL) treatment inhibited E-cadherin expression and promoted cell invasion by upregulation of miR-23a, but overexpression of the miR-23a inhibitor could partially block this activity. FasL-induced extracellular signal-regulated kinase/mitogen-activated protein kinase signaling activated the activator protein 1 (AP-1) complex and repressed glycogen synthase kinase-3β activity, which contributed to nuclear translocation of AP-1 and nuclear factor of activated T cells (NFAT4). Nuclear accumulation and interaction of AP-1 and NFAT4 and subsequent binding to the miR-23a promoter led to increased miR-23a expression. Inhibition of Fas signaling by downregulation of the Fas receptor led to a decrease in miR-23a expression and cell invasion ability in vivo and in vitro, as well as an increase in E-cadherin. Evaluation of human GI precancerous and cancer specimens showed that the expression of FasL and miR-23a increased, whereas the expression of E-cadherin decreased during GI cancer progression. A significant correlation was noted between any two of these three molecules. An EMT phenotype was shown to correlate with an advanced cancer stage and worse prognosis. Taken together, our results show that miR-23a participates in the mechanism of the FasL-induced EMT process and may serve as a potential therapeutic target for cancer metastasis.