RESUMO
Glioma-associated oncogene homolog-1 (Gli-1) is considered a marker of Hedgehog pathway activation and is associated with the progression of several cancers. We have previously reported that Gli-1 was correlated with invasion and metastasis in hepatocellular carcinoma (HCC). However, the exact roles and mechanisms of Gli-1 in HCC invasion are unclear. In this study, we found that small interfering RNA mediated down-regulation of Gli-1 expression significantly suppressed adhesion, motility, migration, and invasion of both SMMC-7721 and SK-Hep1 cells. Furthermore, down-regulation of Gli-1 significantly reduced expressions and activities of both matrix metalloproteinase (MMP)-2 and MMP-9. In addition, we found that down-regulation of Gli-1 resulted in up-regulation of E-cadherin and concomitant down-regulation of Snail and Vimentin, consistent with inhibition of epithelial-mesenchymal transition (EMT). Taken together, our results suggest that down-regulation of Gli-1 suppresses HCC cell migration and invasion likely through inhibiting expressions and activations of MMP-2, 9 and blocking EMT.
Assuntos
Carcinoma Hepatocelular/genética , Movimento Celular/genética , Neoplasias Hepáticas/genética , Fatores de Transcrição/genética , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/patologia , Metaloproteinase 2 da Matriz/biossíntese , Metaloproteinase 9 da Matriz/biossíntese , Invasividade Neoplásica/genética , RNA Interferente Pequeno , Transdução de Sinais/genética , Fatores de Transcrição/antagonistas & inibidores , Proteína GLI1 em Dedos de ZincoRESUMO
Somatostatin can suppress the growth of various tumor cells including colonic cancer. Activated Wnt/ beta-catenin signaling pathway plays a critical role in tumorgenesis and development of colorectal cancer. However, the effect of somatostatin on Wnt/beta-catenin signaling pathway remains unknown. Thus, we investigated the effect of octreotide on Wnt/beta-catenin signaling pathway in human colonic cancer cell SW480. The results of 3-(4,5-imethyl thiazol-2-yl)-2, 5-diphenyl tetrazolium bromide (MTT) and flow cytometric assays showed that octreotide inhibited growth, induced apoptosis and arrested the G1 cell cycle of SW480 cells in a dose-dependent manner. We demonstrated that octreotide significally up-regulated and down-regulated 13 genes and 17 genes in Wnt/beta-catenin signaling using microarray, respectively. Furthermore, as evidenced by western blot, beta-catenin protein level decreased, whereas phosphorylated beta-catenin protein level increased under octreotide. The present study reveals that octreotide can inhibit human colonic cancer cell growth through inhibition of Wnt/beta-catenin signaling pathway.
Assuntos
Antineoplásicos Hormonais/farmacologia , Neoplasias do Colo/tratamento farmacológico , Octreotida/farmacologia , Proteínas Wnt/efeitos dos fármacos , beta Catenina/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Western Blotting , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Neoplasias do Colo/patologia , Citometria de Fluxo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Indicadores e Reagentes , Análise de Sequência com Séries de Oligonucleotídeos , Transdução de Sinais/efeitos dos fármacos , Sais de Tetrazólio , Tiazóis , Proteínas Wnt/genética , Proteínas Wnt/fisiologia , beta Catenina/genética , beta Catenina/fisiologiaRESUMO
Some microRNAs (miRNAs) have been implicated in hepatocellular carcinoma (HCC) development and progression. However, the roles and mechanisms of several miRNAs in HCC remain poorly understood. Here, we report that miR-379-5p, which is down-regulated in HCC tissues and cell lines, is associated with advanced TNM stage and metastasis in HCC. The ectopic overexpression of miR-379-5p inhibited HCC cell migration, invasion, epithelial-to-mesenchymal transition (EMT) and metastasis both in vitro and in vivo. Conversely, miR-379 knockdown increased migration, invasion and EMT in HCC cells. Moreover, miR-379-5p exerted this function by directly targeting focal adhesion kinase (FAK) 3'-UTR and repressing FAK expression, thus leading to suppression of AKT signaling. Furthermore, the tumor suppressive effects of miR-379-5p in HCC cells were reversed by activating AKT signaling or restoring FAK expression. In clinical samples of HCC, miR-379-5p negatively correlated with FAK, which was up-regulated in HCC. Taken together, our findings highlight the important role of miR-379-5p in regulating the EMT and metastasis of HCC by targeting FAK/AKT signaling, suggesting that miR-379-5p may represent a novel potential therapeutic target and prognostic marker for HCC.