RESUMO
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer deaths, worldwide. MicroRNAs, inhibiting gene expression by targeting various transcripts, are involved in genomic dysregulation during hepatocellular tumorigenesis. In previous studies, microRNA-198 (miR-198) was shown to be significantly downregulated in HCV-positive hepatocellular carcinoma (HCC). Herein, the function of miR-198 in hepatocellular carcinoma cell growth and gene expression was studied. In hepatoma cell-types with low levels of liver-specific transcription factor HNF1α indicating a low differentiation grade, miR-198 expression was most downregulated. However, miR-198 treatment did not restore the expression of the liver-specific transcription factors HNF1α or HNF4α. Importantly, overexpression of miR-198 in Pop10 hepatoma cells markedly reduced cell growth. In agreement, comprehensive gene expression profiling by microarray hybridisation and real-time quantification revealed that central signal transducers of proliferation pathways were downregulated by miR-198. In contrast, genes mediating cellular adherence were highly upregulated by miR-198. Thus, the low expression of E-cadherin and claudin-1, involved in cell adhesion and cell-cell contacts, was abolished in hepatoma cells after miR-198 overexpression. This definite induction of both proteins by miR-198 was shown to be accompanied by a significantly impaired migration activity of hepatoma Pop10 cells. In conclusion, miR-198 acts as a tumor suppressor by repression of mitogenic and motogenic pathways diminishing cell growth and migration.
Assuntos
Carcinoma Hepatocelular , Transformação Celular Neoplásica , Regulação Neoplásica da Expressão Gênica , MicroRNAs , Caderinas/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Claudina-1/metabolismo , Fator 1-alfa Nuclear de Hepatócito/metabolismo , Fator 4 Nuclear de Hepatócito/metabolismo , Humanos , MicroRNAs/genética , MicroRNAs/metabolismoRESUMO
BACKGROUND: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease leading to cirrhosis and cholangiocellular carcinoma. Inhibitors of the renin-angiotensin system or the sympathetic nervous system delay liver fibrogenesis in animal models. AIMS: We investigated the antifibrotic potential of telmisartan, an angiotensin II type 1 receptor antagonist, and the ß-adrenoceptor blocker propranolol in the PSC-like Abcb4 knockout mouse model. METHODS: Sixty-five Abcb4 (-/-) mice were treated with telmisartan for 3 or 5 months (T) and with telmisartan plus propranolol for 3, 5, or 8 months (TP), or for 2 or 5 months starting with a delay of 3 months (TP delayed). Liver hydroxyproline content, inflammation, fibrosis, and bile duct proliferation were assessed; fibrosis-related molecules were analyzed by real-time polymerase chain reaction and Western blotting. RESULTS: Compared to controls, telmisartan monotherapy had no significant influence on hydroxyproline; however, telmisartan plus propranolol reduced hydroxyproline (TP 3 months, p = 0.008), fibrosis score (TP 3 months and TP 8 months, p = 0.043 and p = 0.008, respectively; TP delayed 8 months, p < 0.0005), bile duct proliferation (TP 8 months and TP delayed 8 months, p = 0.006 and p < 0.0005, respectively), and procollagen α1(I), endothelin-1, TIMP-1 and MMP3 mRNA as well as α-SMA, CK-19, and TIMP-1 protein. CONCLUSIONS: Telmisartan plus propranolol reduces liver fibrosis and bile duct proliferation in the PSC-like Abcb4 (-/-) mouse model, even when started at late stages of fibrosis, and may thus represent a novel therapeutic option for cholestatic liver diseases such as PSC.
Assuntos
Antagonistas Adrenérgicos beta/uso terapêutico , Benzimidazóis/uso terapêutico , Benzoatos/uso terapêutico , Colangite Esclerosante/tratamento farmacológico , Propranolol/uso terapêutico , Receptor Tipo 1 de Angiotensina/uso terapêutico , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Antagonistas Adrenérgicos beta/farmacologia , Animais , Benzimidazóis/farmacologia , Benzoatos/farmacologia , Ductos Biliares/efeitos dos fármacos , Ductos Biliares/patologia , Colangite Esclerosante/metabolismo , Colágeno Tipo I/metabolismo , Cadeia alfa 1 do Colágeno Tipo I , Citocinas/metabolismo , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Quimioterapia Combinada , Fígado/efeitos dos fármacos , Fígado/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Miofibroblastos/metabolismo , Propranolol/farmacologia , RNA Mensageiro/metabolismo , Telmisartan , Membro 4 da Subfamília B de Transportadores de Cassetes de Ligação de ATPRESUMO
Surgeons frequently utilize frozen sections as a tool to gain information intraoperatively. The use of frozen sections has certain benefits as well as limitations which vary according to the situation. After reviewing the available literature we provide the reader with an idea of when and how to use frozen sections in common situations involving the gastrointestinal tract and liver as well as address the benefits and limitations in each setting.