Study On The Regulatory Molecular Mechanism Of Valproic Acid (VPA) Inducing Epithelial-mesenchymal Transition (EMT) Of Liver Cancer Cells

Valproic acid(VPA)was originally the most commonly used line of broad-spectrum antiepileptic drugs,but also widely used in the treatment of other neurological diseases.Recently,due to its low cost and favorable safety,valproic acid(VPA)has been considered a potential candidate for the treatment of various cancers.Hepatocellular carcinoma(HCC)is highly prevalent and deadly tumor formation,and its medical management has improved significantly over the past few years.But its better predictions of prognosis and the most appropriate treatment are not yet clear.Today’s major therapeutic therapies(resection,transplantation,ablation)can improve patients diagnosed at an early stage of the HCC to achieve longer survival and provide potential long-term treatment.Patients with moderate-term liver cancer benefit from chemoembolization,and those diagnosed with advanced patients benefit from sorafenib,a multi-kinase inhibitor with anti-angiogenic and antiproliferative effects Likewise,valproic acid(VPA)has been identified as a potential candidate for the treatment of various cancersEpithelial-mesenchymal transition(EMT)refers to the transformation of epithelium into stromal cells,which confer the ability to metastasize and invade cells,including stem cell characteristics,reduce apoptosis and senescence,and promote immunosuppression,not only during development Plays a key role,but also involved in tissue healing,organ fibrosis and cancer and other processes,the occurrence of cancer is of great significance.Epithelial-mesenchymal transition(EMT)is a series of events in which cell-cell and cell-extracellular matrix(ECM)interactions are altered to release epithelial cells from surrounding tissue,the cytoskeleton is recombined to confer mobility to the three-dimensional ECM,And induce new transcriptional procedures to maintain a mesenchymal phenotype.Snail is the induction gene of EMT,that is,E-cadherin inhibitory factor,for the study of epithelial transformation is of great significanceDue to the low cost and favorable safety profile,valproic acid(VPA)has been considered as a potential candidate drug for therapy of various cancers.Our present study revealed that VPA,at the concentration(1 mM)which has no effect on cell proliferation,can significantly increase the in vitro migration and invasion of hepatocarcinoma(HCC)HepG2 and Huh7 cells via induction of epithelial mesenchymal transition(EMT).VPA treatment can significantly increase the mRNA and protein expression of Snail,the key transcription factor of EMT.While knockdown of Snail can abolish VPA induced EMT of HCC cells.It suggested that Snail is essential for VPA induced EMT of HCC cells.VPA treatment also increased the phosphorylation of NF-κB p65.BAY 11-7082,the inhibitor of NF-κB,can significantly abolish VPA induced up regulation of Snail mRNA.Furthermore,VPA can increase the protein expression of Snail since 1 h treatment via up regulation of half-lives of Snail protein.The increased protein stabilization of Snail can be attributed to VPA induced phosphorylation of Akt and GSK-3β.Collectively,our present study revealed that VPA can promote the EMT of HCC cells via up regulation of Snail through activation of NF-κB and Akt/GSK-3 β signals.