RESUMO
Chronic liver injury could lead the formation of liver fibrosis, eventually some would develop to hepatocellular carcinoma (HCC), one of the leading malignancies worldwide. The aim of the study is to dissect the role of extracellular signal-regulated kinase 2 (ERK2) signaling in liver fibrosis and inflammation. The choline-deficient, ethionine-supplemented (CDE) diet could lead to fatty livers and generate oval cells, activate hepatocyte stellate cell (HSC) and recruit immune cells as the liver fibrosis model mice. WT and ERK2 deficient (ERK2-/-) mice were compared in terms of liver weight/body weight, liver function, liver fibrosis markers and the differential gene expression in hepatotoxicity. ERK2-/- mice display the less degree of liver fibrosis when compared to WT mice. The protein level of alpha smooth muscle (α-SMA) was reduced and several hepatocellular carcinoma-related genes such as MMP9, FoxM1 were down-regulated. In addition, the cell proliferation and the percentages of activated T cells were reduced in ERK2-/- mice upon liver injury. Therefore, ERK2 plays an important role in regulating liver cirrhosis and inflammation.
Assuntos
Cirrose Hepática/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/genética , Actinas/metabolismo , Animais , Proliferação de Células , Proteína Forkhead Box M1/metabolismo , Cirrose Hepática/genética , Cirrose Hepática/patologia , Ativação Linfocitária , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Mutação , Linfócitos T/imunologiaRESUMO
Overexpression of Sonic Hedgehog signaling (Shh) pathway molecules is associated with invasiveness and recurrence in breast carcinoma. Therefore, inhibition of the Shh pathway downstream molecule Glioma-associated Oncogene Homolog (Gli) was investigated for its ability to reduce progression and invasiveness of patient-derived breast cancer cells and cell lines. Human primary breast cancer T2 cells with high expression of Shh signaling pathway molecules were compared with breast cancer line MDA-MB-231 cells. The therapeutic effects of Gli inhibitors were examined in terms of the cell proliferation, apoptosis, cancer stem cells, cell migration and gene expression. Blockade of the Shh signaling pathway could reduce cell proliferation and migration only in MDA-MB-231 cells. Hh pathway inhibitor-1 (HPI-1) increased the percentages of late apoptotic cells in MDA-MB-231 cells and early apoptotic cells in T2 cells. It reduced Bcl2 expression for cell proliferation and increased Bim expression for apoptosis. In addition, Gli inhibitor HPI-1 decreased significantly the percentages of cancer stem cells in T2 cells. HPI-1 worked more effectively than GANT-58 against breast carcinoma cells. In conclusion, HPI-1 could inhibit cell proliferation, reduce cell invasion and decrease cancer stem cell population in breast cancer cells. To target Gli-1 could be a potential strategy to suppress breast cancer stem cells.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Proteínas Hedgehog/genética , Células-Tronco Neoplásicas/efeitos dos fármacos , Proteína GLI1 em Dedos de Zinco/genética , Apoptose/efeitos dos fármacos , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proteínas Hedgehog/antagonistas & inibidores , Humanos , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Piridinas/administração & dosagem , Transdução de Sinais/efeitos dos fármacos , Tiofenos/administração & dosagem , Proteína GLI1 em Dedos de Zinco/antagonistas & inibidoresRESUMO
BACKGROUND: Rat liver epithelial (RLE) cells could inhibit the proliferation and invasiveness of hepatoma cells in vitro. This study is to understand the tropism and the effect of RLE cells on mouse hepatoma cells both in vitro and in vivo. METHODS: RLE cells were isolated from new-born rats and characterized their stem cell markers. Co-culture and HCC mouse model was established to detect therapeutic effect of RLE cells. RESULTS: RLE cells (including Thy-1+ RLE cells, Thy-1- RLE cells, RLE cells) displayed a selective tropism toward ML-1 hepatoma cells both in vitro and in vivo. They altered the gene expression of some cancer stem cell markers in the liver tumor. CONCLUSION: Liver epithelial cells have a selective tropism toward HCC in vitro and in vivo. They could alter the gene expression of cancer stem cells.
