PCK1 attenuates tumor stemness via activating the Hippo signaling pathway in hepatocellular carcinoma

Liver cancer stem cells were found to rely on glycolysis as the preferred metabolic program.Phosphoenolpyruvate carboxylase 1(PCK1),a gluconeogenic metabolic enzyme,is down-regulated in hepatocellular carcinoma and is closely related to poor prognosis.The onco-genesis and progression of tumors are closely related to cancer stem cells.It is not completely clear whether the PCK1 deficiency increases the stemness of hepatoma cells and promotes the oncogenesis of hepatocellular carcinoma.Herein,the results showed that PCK1 inhibited the self-renewal property of hepatoma cells,reduced the mRNA level of cancer stem cell markers,and inhibited tumorigenesis.Moreover,PCK1 increased the sensitivity of hepatocellular carci-noma cells to sorafenib.Furthermore,we found that PCK1 activated the Hippo pathway by enhancing the phosphorylation of YAP and inhibiting its nuclear translocation.Verteporfin reduced the stemness of hepatoma cells and promoted the pro-apoptotic effect of sorafenib.Thus,combined treatment with verteporfin and sorafenib may be a potential anti-tumor strat-egy in hepatocellular carcinoma.

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.