No abstract

Fatty liver (FL) is associated with development of hepatocellular carcinoma (HCC). However, whether FL itself promotes the progression of HCC is unclear. We recently found that hepatic stellate cells (HSCs) were prominently activated in the steatotic liver. Here, we investigated whether steatotic livers promote HCC progression and whether HSCs of steatotic liver are associated with HCC progression. We implanted rat HCC cells into diet-induced steatotic livers in rats via portal vein injection. Thereafter, HSCs and HCC cells were co-implanted subcutaneously into nude rats. Migration and proliferation of HCC cells were measured, and activation of ERK and Akt in these cells was determined by western blotting. Chemokines secreted from HSCs and HCC cells were also evaluated by ELISA. Steatotic livers significantly promoted HCC metastasis compared with nonsteatotic livers. Additionally, co-implantation of HCC cells with HSCs from steatotic livers produced significantly larger tumors in recipient rats as compared to those induced by HCC cells co-implanted with HSCs from normal livers (NLs). HSCs isolated from steatotic livers, compared with HSCs isolated from NLs, secreted greater amounts of interleukin-1a, vascular endothelial growth factor, and transforming growth factor-b. These cytokines may enhance the proliferation and migration of HCC cells by increasing the phosphorylation of ERK and Akt in HCC cells. Moreover, we noted that the Rho-kinase inhibitor deactivated activated HSCs and attenuated HCC progression. In conclusion, the rat steatotic liver microenvironment favors HCC metastasis, and this effect appears to be promoted by activated HSCs in the steatotic liver.Non-alcoholic fatty liver disease (NAFLD) is one of the most common hepatic disorders in developed countries. The epidemic of obesity in developed countries has increased along with its attendant complications, including metabolic syndrome and NAFLD. Recently, there is increasing evidence that NAFLD, including the more aggressive non-alcoholic steatohepatitis (NASH), is associated with hepatocellular carcinoma (HCC).1-3 Diabetes and obesity are established independent Key words: HCC, hepatic stellate cell, fatty liver, Rho-kinase Abbreviations: CDD: choline-deficient diet; CM: conditioned media; DMEM: Dulbecco's modified Eagle's medium; ELISA: enzymelinked immunosorbent assay; FL: fatty liver; FBS: fetal bovine serum; HCC: hepatocellular carcinoma; HGF: hepatocyte growth factor; HSCs: hepatic stellate cells; HSCFL: hepatic stellate cells isolated from fatty liver; HSCNL: hepatic stellate cells isolated from normal liver; HFD: high-fat diet; HIF: hypoxia inducible factor; IL-1a: interleukin-1a; IQGAP1: IQ motif containing GTPase activating protein 1; MMPs: matrix metalloproteinases; MTT: methyl thiazolyl tetrazolium; MAPK: mitogen-activated protein kinase; NAFLD: non-alcoholic fatty liver disease; NASH: non-alcoholic steatotic hepatitis; NL: normal liver; ROCK: Rho-associated kinase; SASP: senescence-associated secretory phenotype; SDF-1: stromal derive...

The maximum sensitivity of Gd-EOB-MRI for HCC was only 69.0% even when diagnostic criteria that included all previously reported HCC patterns were adopted.

The prognosis of patients with HCC was found to be associated with preoperative antithrombin III levels. ATIII may be useful for predicting outcomes of patients with HCC after curative hepatectomy.

Anaplastic thyroid cancer is one of the most aggressive human malignancies and is resistant to multimodal treatments. The expression of h-prune, the human homologue of Drosophila prune, has been reported to be correlated with progression and aggressiveness in various cancers including breast, colorectal and pancreatic cancers. We examined the role of h-prune in anaplastic thyroid cancer cell migration, invasion and metastasis. Immunohistochemical analysis of h-prune was performed with 15 surgically resected specimens of anaplastic thyroid cancers. To investigate cell motility, Boyden chamber, wound healing and matrigel invasion assays were performed using cells from anaplastic thyroid cancer cell lines. A murine orthotopic thyroid cancer model was used to investigate metastatic ability. In the immunohistochemical analysis, only weak focal or no staining of h-prune was observed in non-tumor tissue. In contrast, diffuse staining of h-prune was observed in anaplastic thyroid cancer and lymph node metastasis samples. Both inhibition of h-prune phosphodiesterase activity with dipyridamole and small interfering RNA for h-prune suppressed 8505C and KTC-3 cell motility. In addition, treatment with dipyridamole and decreased expression of h-prune suppressed tumor invasion and pulmonary metastasis in a NOD/Shi-scid, IL-2Rγnull (NOG) mouse orthotopic thyroid cancer model. In conclusion, h-prune is frequently expressed in anaplastic thyroid cancer cells and lymph nodes metastasis, and promotes migration and invasion of anaplastic thyroid cancer cells and metastasis in an anaplastic thyroid cancer model. Thus, h-prune shows promise as a targeting candidate against anaplastic thyroid cancer.