Epigenetic deregulation of MLF1 drives intrahepatic cholangiocarcinoma progression through EGFR/AKT and Wnt/β-catenin signaling

Abstract

Background: Intrahepatic cholangiocarcinoma (iCCA) is an aggressive malignancy with multiple etiologies and is largely refractory to current treatment strategies. Myeloid leukemia factor 1 (MLF1) is associated with human cancer progression. Nevertheless, the function of MLF1 in iCCA remains unknown. Methods: We performed expression analyses of MLF1 in human iCCA. In vitro and in vivo experiments were conducted to investigate the role of MLF1 in iCCA progression. The upstream regulatory mechanism of MLF1 upregulation in iCCA was deciphered by luciferase and DNA methylation analyses. Results: MLF1 was significantly upregulated in clinical iCCA tissue specimens and human iCCA cell lines. MLF1 was positively correlated with KRT19 and MUC1 expression and epithelial-mesenchymal transition (EMT) gene set enrichment score in clinical iCCA. High MLF1 expression was independently associated with worse prognoses in iCCA patients after curative resection. In addition, experimental knockdown of MLF1 attenuated, while overexpression of MLF1 promoted the proliferation, invasiveness, and growth of iCCA cells in vitro and in vivo. Mechanically, MLF1 comodulated EGFR/AKT and Wnt/β-catenin signalings through regulating EGFR, AKT, WNT3, and p-GSK3β expression. Promoter CpG sites’ hypermethylation-induced downregulation of miR-29c-3p contributed to MLF1 upregulation in iCCA patients. The upregulation of DNA methyltransferase (DNMT)1, 3A, and 3B downregulated miR-29c-3p by dictating promoter DNA methylation pattern. MiR-29c-3p showed therapeutic potential by targeting MLF1 in iCCA. Conclusions: Our results demonstrated that hypermethylation-mediated miR-29c-3p downregulation contributes to MLF1 upregulation in iCCA, which resulted in tumor cells’ proliferation and metastasis through comodulating EGFR/AKT and Wnt/β-catenin signalings.

Exosomes in the Diagnosis of Neuropsychiatric Diseases: A Review

“…miR-335-5p targets glutamate metabotropic receptor 4 (GRM4) to regulate neuronal excitability [ 47 ], and reduced glutamate levels in specific brain regions have been implicated in the pathogenesis of depression [ 48 , 49 ]; miR-335-5p is significantly increased in the plasma exosomes of people with treatment-resistant depression [ 48 ]. miR-29c is activated by the Wnt signaling pathway [ 50 , 51 ], and in the prefrontal cortex exosomes of BD patients miR-29c is significantly increased [ 30 ].…”

Epithelial–mesenchymal plasticity in cancer: signaling pathways and therapeutic targets

“… 72 Moreover, recent research suggests that the upregulation of DNMTs leads to the downregulation of miR‐29c‐3p via dictating promoter CpG sites’ hypermethylation to mediate the EGFR/Akt as well as Wnt/β‐catenin signalings and finally induce the EMT process. 73 …”