PDCD4 is a novel tumor suppressor to show multi-functions inhibiting cell growth, tumor invasion, metastasis, and inducing apoptosis. PDCD4 protein binds to the translation initiation factor eIF4A, some transcription factors, and many other factors and modulates the function of the binding partners. PDCD4 downregulation stimulates and PDCD4 upregulation inhibits the TPA-induced transformation of cells. However, PDCD4 gene mutations have not been found in tumor cells but gene expression was post transcriptionally downregulated by micro environmental factors such as growth factors and interleukins. In this review, we focus on the suppression mechanisms of PDCD4 protein that is induced by the tumor promotors EGF and TPA, and in the inflammatory conditions. PDCD4-protein is phosphorylated at 2 serines in the SCF^βTRCP ubiquitin ligase binding sequences via EGF and/or TPA induced signaling pathway, ubiquitinated, by the ubiquitin ligase and degraded in the proteasome system. The PDCD4 protein synthesis is inhibited by microRNAs including miR21.

Glucagon-like peptide-1 (GLP-1) receptor agonists are used to treat diabetes, but their effects on nonalcoholic steatohepatitis (NASH) and the development of hepatocellular carcinoma (HCC) remain unclear. In this study, mice with streptozotocin- and high-fat diet-induced diabetes and NASH were subcutaneously treated with liraglutide or saline (control) for 14 weeks. Glycemic control, hepatocarcinogenesis, and liver histology were compared between the groups. Fasting blood glucose levels were significantly lower in the liraglutide group than in the control group (210.0 ± 17.3 mg/dL vs. 601.8 ± 123.6 mg/dL), and fasting insulin levels were significantly increased by liraglutide (0.18 ± 0.06 ng/mL vs. 0.09 ± 0.03 ng/mL). Liraglutide completely suppressed hepatocarcinogenesis, whereas HCC was observed in all control mice (average tumor count, 5.5 ± 3.87; average tumor size, 8.1 ± 5.0 mm). Liraglutide significantly ameliorated steatosis, inflammation, and hepatocyte ballooning of non-tumorous lesions in the liver compared with the control findings, and insulin-positive β-cells were observed in the pancreas in liraglutide-treated mice but not in control mice. In conclusion, liraglutide ameliorated NASH and suppressed hepatocarcinogenesis in diabetic mice. GLP-1 receptor agonists can be used to improve the hepatic outcome of diabetes.

Purpose: Menatetrenone, a vitamin K2 analogue, plays an important role in the production of blood coagulation factors. Menatetrenone has also bee shown to have antineoplastic effects against several cancer cell lines including hepatocellular carcinoma (HCC) cells. However, the mechanisms by which vitamin K2 inhibits HCC cell growth have not bee fully clarified, and we therefore investigated the molecular basis of vitamin K2–induced growth inhibition of HCC cells.