Depletion of VPS35 attenuates metastasis of hepatocellular carcinoma by restraining the Wnt/PCP signaling pathway

Vesicle Protein Sorting 35(VPS35)is a novel oncogene that promotes tumor growth through the PI3K/AKT signaling in hepatocellular carcinoma(HCC).However,the role of VPS35 in HCC metastasis and the underlying mechanisms remain largely unclear.In this study,we observed that overexpression of VPS35 enhanced hepatoma cell invasion and metastasis by inducing epithelialemesenchymal transition(EMT)-related gene expression.Conversely,knockout of VPS35 significantly inhibited hepatoma cell migration and invasion.Furthermore,depletion of VPS35 decreased the lung metastasis of HCC in nude mice.By transcriptome analysis,we determined that VPS35 promoted HCC metastasis by activating the Wnt/non-canonical planar cell polarity(PCP)pathway.Mechanistically,VPS35 activated the PCP pathway by regulating membrane sorting and trafficking of Frizzled-2(FZD2)and ROR1 in hepatoma cells.Collectively,our results indicate that VPS35 promotes HCC metastasis via enhancing the Wnt/PCP signaling,thus providing a potential prognostic marker and therapeutic target for HCC.

All-trans retinoic acid reverses malignant biological behavior of hepatocarcinoma cells by regulating miR-200 family members

As a potential chemo-therapeutic agent,all-trans retinoic acid(ATRA)can signif-icantly reverse epithelial-mesenchymal transition(EMT)of hepal-6 hepatocarcinoma cell line in vitro,but the mechanism is unclear.The expression profile of microRNA-200(miR-200)families is different in hepatocellular carcinoma.In this study,we found that ATRA trea tment could up-regulate the expression of miR-200a-3p,200c-3p,and 141-3p,which were involved in ATRA regulated proliferation and apoptosis of hepal-6 cell,but not colony formation.Meanwhile,miR-200a-3p,200c-3p,and 141-3p could recovery ATRA inhibited migration and invasion abilities of hepal-6 cells at various levels.miR-200a-3p and 200c-3p prevented ATRA from inducing the differentia tion and hepatic functions of hepal-6 cells.An-tagomir specific for miR-200a-3p and 200c-3p down-regulated the expression of CK18,but only miR-200a-3p anta gomir played prominent role in regula ting the expression of these mesenchymal markers,N-Cadherin,Snail and Twist.The transcriptional activities of 8 tran-scription factors were up-regulated and 35 transcription factors were down-regulated by ATRA.Compared with ATRA group,inhibition of miR-200a-3p,200c-3p,and 141-3p significantly strengthened the expression of Fra1/Jun(AP1),Ets1/PEA3,Brn3,and Zeb1/AREB6 at varying degrees.Therefore,this result suggested that ATRA may suppress EMT through down-regulating miR-200a-3p,200c-3p and 141-3p related transcription factors.miR-200 and their downstream genes might be the potentially specific targets for the treat-ment of hepatocarcinoma.