14-3-3η is a novel growth-promoting and angiogenic factor in hepatocellular carcinoma.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. The continued search for novel therapeutic strategies for HCC is urgently required. In this study, we aimed to investigate the functions and clinical significance of 14-3-3η protein in HCC. METHODS: Expressions of genes and proteins were determined by quantitative reverse transcription polymerase chain reaction, Western blot, and immunohistochemistry. Their functions were assessed by endothelial cell recruitment, tube formation, wound healing, flow cytometry, immunostaining, immunoprecipitation, and xenograft assay. A tissue microarray followed by univariate and multivariate analyses was performed to indicate the clinical significance. RESULTS: In HCC specimens, overexpression of 14-3-3η was observed not only in tumors but also in intratumoral vessels. In HCC and vascular endothelial cells, 14-3-3η stimulated proliferation and angiogenesis, but attenuated the functions of sorafenib. Briefly, 14-3-3η facilitated the phosphorylation of extracellular signal-regulated kinase1/2 (ERK1/2). Then, by binding to the phosphorylated-ERK1/2 (p-ERK1/2), formed a functional positive feed-back loop. A xenograft model showed that, blockage of either 14-3-3η or ERK1/2 inhibited the tumor growth. Finally, tissue microarray analyses showed that overexpression of 14-3-3η, either in tumors or intratumoral vessels, contributed to the poor survival. CONCLUSIONS: The 14-3-3η-ERK1/2 feedback loop played a characteristic growth-promoting role in HCC, not only in tumors but also in intratumoral vessels. Further, 14-3-3η could be a potential therapeutic target for HCC and a biomarker for predicting sorafenib treatment response. LAY SUMMARY: Here we found that, 14-3-3η protein exhibited a characteristic growth-promoting effect in both tumor and intratumoral vessels of hepatocellular carcinoma by interacting with ERK1/2 signaling.

The Ser326Cys polymorphism of hOGG1 is associated with intrahepatic cholangiocarcinoma susceptibility in a Chinese population.

OBJECTIVE: Intrahepatic cholangiocarcinoma is a rare disease whose etiology is far from clear, the Ser326Cys polymorphism in human 8-hydroxyguanine glycosylase (hOGG1) has been shown associated with various cancers, however, the association of Ser326Cys (rsl052133) polymorphism and intrahepatic cholangiocarcinoma susceptibility has not been clarified. The purpose of this study is to investigate whether this polymorphism is related to the genetic susceptibility of intrahepatic cholangiocarcinoma. METHODS: A total 150 patients and 150 normal people were included in this study, the Ser326Cys polymorphisms in each group were genotyped using PCR-RFLP method. RESULTS: We found that individuals carrying Cys/Cys genotype were exposed to higher riskof intrahepatic cholangiocarcinoma (OR=2.924, 95% CI=1.475-5.780) compared with the individuals with wild type genotype Ser/Ser. Further analysis revealed that male individuals carrying Cys/Cys genotype also had increased risk (OR=2.762, 95% CI=1.233-6.173), whereas no significant difference was observed in female group. CONCLUSIONS: Therefore, our data indicates that the Ser326Cys (rs1052133) polymorphism is associated with intrahepatic cholangiocarcinoma susceptibility, and it shows preference in male population.

Remote ischemic preconditioning protects against liver ischemia-reperfusion injury via heme oxygenase-1-induced autophagy.

BACKGROUND: Growing evidence has linked autophagy to a protective role of preconditioning in liver ischemia/reperfusion (IR). Heme oxygenase-1 (HO-1) is essential in limiting inflammation and preventing the apoptotic response to IR. We previously demonstrated that HO-1 is up-regulated in liver graft after remote ischemic preconditioning (RIPC). The aim of this study was to confirm that RIPC protects against IR via HO-1-mediated autophagy. METHODS: RIPC was performed with regional ischemia of limbs before liver ischemia, and HO-1 activity was inhibited pre-operation. Autophagy was assessed by the expression of light chain 3-II (LC3-II). The HO-1/extracellular signal-related kinase (ERK)/p38/mitogen-activated protein kinase (MAPK) pathway was detected in an autophagy model and mineral oil-induced IR in vitro. RESULTS: In liver IR, the expression of LC3-II peaked 12-24 h after IR, and the ultrastructure revealed abundant autophagosomes in hepatocytes after IR. Autophagy was inhibited when HO-1 was inactivated, which we believe resulted in the aggravation of liver IR injury (IRI) in vivo. Hemin-induced autophagy also protected rat hepatocytes from IRI in vitro, which was abrogated by HO-1 siRNA. Phosphorylation of p38-MAPK and ERK1/2 was up-regulated in hemin-pretreated liver cells and down-regulated after treatment with HO-1 siRNA. CONCLUSIONS: RIPC may protect the liver from IRI by induction of HO-1/p38-MAPK-dependent autophagy.