RESUMO
C5a and its receptor, C5a receptor (C5aR), play critical roles in tumor progression. However, mechanisms of C5a-C5aR axis in hepatocellular carcinoma (HCC) cell invasiveness are not fully elucidated. In this study, we found that C5aR expression was highly expressed in HCC cell lines and tumor tissues, and associated with capsular invasion, tumor stage and some epithelial-mesenchymal transition (EMT)-related markers. Activation of C5aR by C5a promoted HCC cell invasion and migration, whereas depletion of C5aR expression significantly impaired C5a-stimulated invasion and migration. Furthermore, we found that C5aR induced EMT in HCC cells, through downregulation of E-cadherin and Claudin-1 expression, and upregulation of Snail expression. Finally, we demonstrated that C5aR stimulated activation of ERK1/2, and ERK1/2 pathway was involved in C5aR-mediated EMT, cell invasion and migration of HCC cells. Thus, our data suggest that C5aR stimulates cell invasion and migration via ERK1/2-mediated EMT in HCC cells, and implicate that blocking C5aR expression has therapeutic promise to inhibit HCC invasiveness.
Assuntos
Carcinoma Hepatocelular/genética , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica/genética , Neoplasias Hepáticas/genética , Receptor da Anafilatoxina C5a/genética , Adulto , Idoso , Caderinas/metabolismo , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Movimento Celular/genética , Feminino , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Sistema de Sinalização das MAP Quinases/genética , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Receptor da Anafilatoxina C5a/metabolismoRESUMO
BACKGROUND: As a pro-inflammatory cytokine, IL-33 has been demonstrated to play an important role in tumor progression. It is reported that IL-33 is highly expressed in the serum and tumor tissues of patients with gastric cancer. However, the function of IL-33 in gastric cancer remains elusive. We here tried to elucidate the effects of IL-33 on gastric cancer cell invasion and migration. METHODS: Invasion assay and migration assay were performed to assess the effects of IL-33 on gastric cancer cell invasion and migration. ST2 receptor was silenced by siRNA, and ERK1/2 pathway was inhibited by U0126. Protein levels of MMP-3 and IL-6 in cell supernatant were measured by ELISA. RESULTS: IL-33 promoted the invasion and migration of gastric cancer cells, in a dose-dependent manner. Knockdown of the IL-33 receptor ST2 attenuated the IL-33-mediated invasion and migration. Furthermore, via ST2 receptor, IL-33 induced the activation of ERK1/2 and increased the secretion of MMP-3 and IL-6. In addition, blockage of ERK1/2 pathway resulted in inhibition of invasion and migration induced by IL-33, and downregulation of MMP-3 and IL-6 production. CONCLUSIONS: IL-33 promotes gastric cancer cell invasion and migration by stimulating the secretion of MMP-3 and IL-6 via ST2-ERK1/2 pathway. Thus, IL-33 may be a useful marker for the diagnosis and treatment of gastric cancer.
Assuntos
Movimento Celular/efeitos dos fármacos , Interleucinas/farmacologia , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Receptores de Superfície Celular/metabolismo , Neoplasias Gástricas/enzimologia , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Ativação Enzimática , Humanos , Proteína 1 Semelhante a Receptor de Interleucina-1 , Interleucina-33 , Interleucina-6/metabolismo , Metaloproteinase 3 da Matriz/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 3 Ativada por Mitógeno/antagonistas & inibidores , Invasividade Neoplásica , Inibidores de Proteínas Quinases/farmacologia , Interferência de RNA , Receptores de Superfície Celular/antagonistas & inibidores , Receptores de Superfície Celular/genética , Transdução de Sinais/efeitos dos fármacos , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Fatores de Tempo , TransfecçãoRESUMO
OBJECTIVE: To assess the risk factors for spontaneous rupture of hepatocellular carcinoma (SRHC). METHODS: A retrospective analysis of 34 consecutive patients with SRHC treated by emergency interventional embolization in our hospital from July 2003 to July 2011 was conducted. General condition, laboratory examination and imaging data were analyzed, and compared with the data of 34 patients with primary hepatocellular carcinoma but without rupture, randomly selected from 215 concurrent patients. The patients with SRHC were selected for risk factor analysis, and the non-SRHC patients were taken as control group. RESULTS: No significant difference between the SRHC group and control group was found in age, sex, Child-Turcotte-Pugh (CTP) grade, Barcelona clinic liver cancer (BCLC) stage, HBsAg, HBsAb, HBeAg, HBeAb, HBcAb, prothrombin time (PT), thrombin time (TT), international normalized ratio (INR), glucose (GLU), cirrhosis, portal tumor thrombus, the maximum diameter of tumor, location, and cholecystitis or cholelithiasis. The univariate analysis showed that activated partial thromboplastin time (APTT), lower or normal plasma fibrinogen (FIB) level, alpha fetoprotein (AFP), tumor protrusion > 1 cm above the liver surface were all associated with increased risk of SRHC (P < 0.05). Multivariate analysis only showed that lower or normal level of FIB (P = 0.033) and tumor protrusion > 1 cm above the liver surface (P = 0.041) were significant independent risk factors for SRHC. CONCLUSION: Lower or normal level of FIB and tumor protrusion > 1 cm above the liver surface are significant independent risk factors for spontaneous rupture of hepatocellular carcinoma.