PRRX1 deficiency induces mesenchymal-epithelial transition through PITX2/miR-200-dependent SLUG/CTNNB1 regulation in hepatocellular carcinoma
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ABSTRACT: Metastasis is a major obstacle to better prognosis in patients with hepatocellular carcinoma (HCC). Mesenchymal-epithelial transition (MET) is the driving force for metastatic colonization in which E-cadherin reexpression is a critical procedure. It has been reported that the loss of paired-related homeobox transcription factor 1 (PRRX1) is required for cancer cell metastasis in vivo. However, the role of PRRX1 in MET and how its downregulation triggers E-cadherin reexpression are unknown. In this study, we performed a systematic, mechanistic study regarding the role of PRRX1 in MET of HCC. We observed PRRX1 downregulation in HCC tissues which correlated with early metastasis and short overall survival time. Overexpression of PRRX1 induced EMT, but did not promote metastasis formation, while knockdown of PRRX1 promoted metastasis and colonization of circulating HCC cells as shown in in situ liver tumor model and colonization model. PRRX1 protein levels reversely correlated with E-cadherin levels in HCC cell lines. PRRX1 knockdown promoted E-cadherin reexpression and cell proliferation, inhibited cell invasion and migration. The microarray results showed that PRRX1 deficiency regulated extracellular matrix (ECM) interaction, focal adhesion, TGF-β signaling and cancer pathways. PRRX1 knockdown upregulated PITX2 (paired like homeodomain 2) and inhibited CTNNB1 (catenin beta 1) and SLUG. Silencing of PITX2 reversed CTNNB1 and SLUG inhibition and E-cadherin reexpression. PITX2 upregulation increased miR-200a and miR-200b/429, which further inhibited the transcription of CTNNB1 and SLUG, respectively, thus abrogating the inhibitory effect on E-cadherin. In conclusion, our data showed that the downregulation of PRRX1 induced E-cadherin reexpression through PITX2/miR-200a/CTNNB1 and PITX2/miR-200b/429/SLUG pathway, making PRRX1 a novel prognostic factor for HCC.
ORGANISM(S): Homo sapiens
PROVIDER: GSE148851 | GEO | 2020/04/18
REPOSITORIES: GEO
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