Role of AP-2α and MAPK7 in the regulation of autocrine TGF-β/miR-200b signals to maintain epithelial-mesenchymal transition in cholangiocarcinoma

Abstract

BackgroundCholangiocarcinoma (CCA) is characterized by early lymphatic, metastasis, and low survival rate. Epithelial-mesenchymal transition (EMT) is able to induce tumor metastasis. Although the TGF-β/miR-200 signals promote EMT in various types of cancer, the regulatory mechanism in CCA is still unclear.MethodsExpression of miR-200b, TGF-β, and EMT markers were measured in tumor samples and cell lines by qRT-PCR and western blot. CCK8 assay was performed to measure the cell viability. Transwell assay was used to evaluate migration and invasion. The target genes of miR-200b and transcription factor of TGF-β were analyzed using dual-luciferase reporter system.ResultsWe have demonstrated that CCA exhibited remarkable EMT phenotype and miR-200b was reduced in CCA patients (n = 20) and negatively correlated to TGF-β. Moreover, two CCA cells, HCCC, and RBE, with epithelial appearances treated with TGF-β, showed fibroblastic-like cell morphology with downregulated miR-200b expression. Forced expression of miR-200b abrogated TGF-β-induced EMT initiation, with decreased cell proliferation, migration, and invasion in vitro. Also, TFAP2A (encode AP-2α) and MAPK7 were found to be targeted by miR-200b to downregulate EMT and AP-2α inhibited miR-200b by directly promoting transcription of TGFB1. Overexpression of MAPK7 significantly reversed miR-200b-induced inhibition of EMT, migration, and proliferation by increasing the expression of TGF-β, cyclin D1, and Cdk2. Further, the administration of miR-200b induced a remarkably tumor regression in vivo and reduced the effect of TGF-β-related EMT in AP-2α and MAPK7-dependent manner.ConclusionsOur study highlights that miR-200b-based gene therapy is effective in the treatment of CCA.

TFAP2A Induced KRT16 as an Oncogene in Lung Adenocarcinoma via EMT

“…TFAP2A modulates the expression of multiple downstream target genes involved in the development and progression of human cancers. TFAP2A was reported influencing epithelial-mesenchymal transition (EMT) in different types of cancers 12, 19, 20 and TFAP2A knockdown could undermine the migration and invasion ability in cancer cells. As it's reported in other types of cancers, TFAP2A influences tumor migration via EMT.…”

Impact of ERK5 on the Hallmarks of Cancer

“…A regulatory loop involving TGF-β and miR-200b was found to contribute to the maintenance of EMT in CCA via AP-2α and ERK5. The administration of miR-200b promotes tumor regression in vivo and abolishes the maintenance of TGF-β-related EMT in an AP-2α- and ERK5-dependent manner in CCA [95].…”

TFAP2A Induced ITPKA Serves as an Oncogene and Interacts with DBN1 in Lung Adenocarcinoma

“…As a result, the transcription factor TFAP2A could induce the hyper-expression of ITPKA in LUAD. As it's reported, TFAP2A influences tumor migration via EMT [8,16,17]. We designed the migration rescue assay.…”

“…In the current study, we further reported that TFAP2A could also induce the expression of ITPKA. The promotor region of ITPKA contains an AP2 motif which has the potential to bind with transcription factor TPAP2A, TFAP2A is hyper-expressed in LUAD and influencing EMT [8,16] and also positively correlated with ITPKA expression. By using three independent published ChIP-Seq data (GSM2817666, GSM1081381, and GSM588928), we found that in all three datasets TFAP2A could bind to the core promotor region of ITPKA, this indicates TFAP2A could be a transcription factor for ITPKA.…”