MicroRNA-543 promotes cell invasion and impedes apoptosis in pituitary adenoma via activating the Wnt/ß-catenin pathway by negative regulation of Smad7.

Pituitary adenomas (PA) are commonly occurring benign neoplasms. Identification of molecular pathway resulting in pituitary tumorigenesis remains challenges in endocrine oncology. The present study was conducted with aim of investigating the role of microRNA-543 (miR-543) in PA development. Up-regulated miR-543 and downregulated Smad7 were observed in PA tissues. Afterwards, the specific mechanism of miR-543 and Smad7 in PA were determined with the use of ectopic expression, depletion and reporter assay experiments. Smad7 was confirmed as a target gene of miR-543. HP75 cells treated with overexpressed miR-543 exhibited increased cell proliferation, migration and invasion, while decreased cell apoptosis as well as expression of Cleaved caspase-3 and Cleaved caspase-8 were observed. Suppression of miR-543 contributed to an opposite trend to the above findings. Based on the findings, the inhibition of miR-543 was found to play a tumor suppressive role in PA through the down-regulation of Wnt/ß-catenin pathway by negatively regulating Smad7.

The structural organization of the liver in the Chinese fire-bellied newt (Cynops orientalis) / Organización estructural del hígado en el tritón de vientre de fuego chino (Cynops orientalis)

The morphology of Chinese fire-bellied newt liver consists of 5 lobes, with exception of a few individual differences present, which are composed by a number of hepatic lobules. Passing through the center of the lobules, a central vein radiates and is arranged in orderly row from one to several layers. The interval of the hepatic cords or masses are irregular and variable sinusoid. The hepatic sinusoidal wall consists of one layer endothelial cells or Macrophagocytus stellatus (Kupffer cells), which have protrusions and elongations. The intervals of the hepatic cells have perisinusoidal space (space of Disse). The hepatic cell is polygonal in shape with uniform, round or oval nucleus, 17.8­12.4um in diameter, mean 14.2 um 2-6 nucleoli, nuclear-cytoplasmic volume ratio was 0.24:1. There is a lot of pigmentation in the hepatic parenchyma.

La morfología del hígado del tritón de vientre de fuego chino está constituida por 5 lóbulos, excepto unos pocos que presentan diferencias individuales, los cuales se componen de una gran cantidad de lóbulos hepáticos. Pasando por el centro de los lóbulos, se encuentra una vena central radial y los organiza en cordones o placas hepáticas. La vena central es delgada de 61,6-30,2 um de diámetro, con una media 42 de um. Los hepatocitos alrededor de la vena central están organizados en filas ordenadas por una a varias capas. El intervalo de los cordones hepáticos o masas es irregular y sinusoidal variable. La pared del sinusoide hepático está formada por una capa de células endoteliales o macrófagos hepáticos (células de Kupffer) que tienen protuberancias y elongaciones. El intervalo de las células hepáticas tienen el espacio perisinusoidal (de Disse). La célula hepática es de forma poligonal con un núcleo redondo u oval uniforme de 17,8-12,4 um de diámetro, con una media 14,2um. 2 a 6 nucléolos, con un radio de volumen nuclear-citoplasmático de 0,24:1. Hay una gran cantidad de pigmentación en el parénquima hepático.

Nuclear factor high-mobility group box1 mediating the activation of Toll-like receptor 4 signaling in hepatocytes in the early stage of nonalcoholic fatty liver disease in mice.

UNLABELLED: One of the challenges surrounding nonalcoholic fatty liver disease (NAFLD) is to discover the mechanisms that underlie the initiation of it. The aim of the present study was to elucidate the effects of Toll-like receptor 4 (TLR4) signaling in liver parenchymal cells during the early stage of NAFLD. Male TLR4-wildtype, TLR4-knockout, TLR2-knockout, MyD88-knockout, and TRIF-knockout mice were fed a normal diet or high-fat diet (HFD). Liver steatosis, alanine aminotransferase levels, nuclear translocation of nuclear factor kappa B (NF-κB) (p65), macrophage accumulation, and neutrophil infiltration were assessed. Using Kupffer cell depletion or bone marrow transplantation, we examined the potential role of Kupffer cells and myeloid infiltrating cells during the initiation of NAFLD. Immunohistochemistry and western blotting were implemented to determine the release of high-mobility group box1 (HMGB1). The neutral-antibody against HMGB1 was used to block the activity of free HMGB1. Here we report that the activation of TLR4 signaling in hepatocytes, accompanied with the relocation of P65 in nucleus, was proven to play an important role during the initiation of NAFLD. Importantly, HMGB1 releasing from hepatocytes in response to free fatty acid (FFA) infusion was first reported as the key molecule for the TLR4/MyD88 activation and cytokines expression in vitro and in vivo. Treatment with neutralizing antibody to HMGB1 protects against FFA-induced tumor necrosis factor alpha and interleukin-6 production. CONCLUSION: Our study supports the notion that TLR4/MyD88 signaling in liver parenchymal cells plays a pivotal role during the early progression of HFD-induced NAFLD, in which free HMGB1 served as a positive component mediating TLR4 activation.

Inhibition of active autophagy induces apoptosis and increases chemosensitivity in cholangiocarcinoma.

Intrahepatic cholangiocellular carcinomas (ICCs) are usually fatal neoplasms originating from bile duct epithelia. However, many cholangiocarcinoma cells are shown to be resistant to chemotherapeutic drugs, which induce cell apoptosis. The role of autophagy and the therapeutic value of autophagy-associated genes are largely unknown in ICC. Here, we showed that autophagy was activated in nutrient starvation and xenograft cholangiocarcinoma cells. Furthermore, expression of autophagic genes and their autophagic activity were higher in clinical ICC specimens than that in normal cholangiocytes separated by laser capture microdissection. Inhibition of autophagy by autophagy inhibitors or siRNA, cholangiocarcinoma cells showed detention of proliferation and increase of apoptosis during nutrient starvation. In addition, autophagy inhibitor treatment or knockdown of beclin 1 suppressed tumor growth and sensitized ICC cells to chemotherapeutic agent-induced cell death. In conclusion, our data showed that autophagy is activated in ICC, and inactivation of autophagy may lead to cell apoptosis and enhance chemotherapy sensitivity.

Prognostic significance of Beclin 1 in intrahepatic cholangiocellular carcinoma.

Autophagy enables cells to recycle long-lived proteins or damaged organelles. Beclin 1 plays important roles in autophagy, differentiation, apoptosis and the development and progression of cancer, but the expression of Beclin 1 and its possible role in primary intrahepatic cholangiocarcinoma (ICC) has not been reported yet. This study aimed to investigate Beclin 1 expression and its prognostic significance in ICC. First, we assessed the expression levels of Becn1 by real-time PCR in 50 ICC samples and found Becn1 mRNA expression was markedly increased in 78% (39 of 50) samples compared with normal bile duct epithelium. Beclin 1 protein expression in 108 tumor specimens from patients diagnosed with ICC was examined by immunohistochemistry and the correlation between Beclin 1 expression and clinicopathological factors were investigated. Immunopositivity for Beclin 1 was found in 72.2% (78 of 108) samples and low Beclin 1 expression was significantly associated with lymph node metastasis. The correlation between Beclin 1 expression and metastasis was validated in 46 ICC samples with lymph node metastasis. In survival analysis, low Beclin 1 expression was associated with worse overall survival (OS; p = 0.025) and disease-free survival (DFS; p = 0.027). In multivariate analysis, Beclin 1 expression, intrahepatic metastasis, lymph node metastasis and tumor size were found to be independent prognostic factors of OS. Thus, our results suggested the expression of Beclin 1 was correlated with progression and metastasis of ICC and it might serve as a novel prognostic marker for patients with ICC.