Role of tight junction-associated MARVEL protein marvelD3 in migration and Epithelial–Mesenchymal Transition of hepatocellular carcinoma

Abstract

\n BackgroundTight junction (TJ) imbalance is associated with hepatocellular carcinoma (HCC). MarvelD3, which contains a conserved MARVEL (MAL and related proteins for vesicle trafficking and membrane link) domain similarly to occludin and tricellulin, is a recently identified integral membrane protein that forms TJs. However, little is known about the possible roles of marvelD3 in epithelial–mesenchymal transition (EMT) and metastasis of HCC. We aimed to demonstrate the role of marvelD3 in inhibiting HCC EMT and migration and further explore the underlying molecular mechanisms.MethodsMarvlD3 expression was assessed in HCC and normal liver tissues. Changes in marvelD3 expression were analyzed during transforming growth factor β1 (TGF-β1) and snail/slug-induced EMT. MarvelD3 knockdown HCC cell lines were established using marvelD3-siRNA to analyze correlations between marvelD3 and EMT-related proteins. Tumor cell behaviors were analyzed in marvelD3 knockdown HCC cells. Associations between marvelD3 and genes in the nuclear factor (NF)-κB pathway were also analyzed.ResultsLoss of marvelD3 expression was significantly correlated with the occurrence and TNM stage of HCC. MarvelD3 was downregulated in HCC cells with TGF-β and snail/slug-induced EMT. Expression of marvelD3 protein was significantly associated with E-cadherin and vimentin in HCC cell lines. Knockdown of marvelD3 promoted tumor cell migration concomitant with activation of the NF-κB signaling pathway and increased matrix metallopeptidase 9 expression.ConclusionsOur study demonstrated that MarvelD3 inhibited EMT and migration of HCC cells via NF-κB signaling pathway. This suggests that marvelD3 is a novel potential biomarker for the treatment and prognosis of HCC.