RESUMO
Hypoxia is a microenvironmental factor which plays a critical role in tumor development and chemoresistance. Epithelial-to-mesenchymal transition (EMT) induced by hypoxia is one of the critical causes of treatment failure and chemoresistance in different types of human cancers. Stabilization of the hypoxia-inducible factor-1α (HIF-1α) transcription complex, caused by intratumoral hypoxia, promotes tumor progression and chemoresistance. Previous evidence suggests that hypoxia can also activate nuclear factor-κB (NF-κB), a known mediator of EMT, which is accompanied by reduced expression of epithelial marker E-cadherin and enhanced expression of the mesenchymal markers Vimentin and N-cadherin as well as overexpression of various transcription factors of EMT, such as Snail and Twist. Based on this evidence, the present study aimed to investigate whether downregulation of the p65 subunit of NF-κB or HIF-1α by small interfering RNA (siRNA) may reverse the EMT phenotype and inhibit the proliferation and induce the apoptosis of pancreatic cancer cell lines (PANC-1, BxPC3) under hypoxic conditions in vitro and enhance the efficacy of gemcitabine in the treatment of pancreatic cancer. These results provide molecular evidence showing that the activation of the HIF-1α and NF-κB loop is mechanistically linked with the chemoresistance phenotype (EMT phenotype) of pancreatic cancer cells under hypoxic conditions, suggesting that the inactivation of HIF-1α and NF-κB signaling by novel strategies may be a potential targeted therapeutic approach for overcoming EMT and chemoresistance induced by hypoxia.
Assuntos
Hipóxia Celular/fisiologia , Resistencia a Medicamentos Antineoplásicos/fisiologia , Transição Epitelial-Mesenquimal/fisiologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , NF-kappa B/metabolismo , Neoplasias Pancreáticas/metabolismo , Acetilcisteína , Apoptose , Western Blotting , Ensaio de Desvio de Mobilidade Eletroforética , Humanos , Neoplasias Pancreáticas/patologia , Fenótipo , Transdução de Sinais/fisiologia , TransfecçãoRESUMO
AIM: To explore the dynamic changes of prion protein (PrPc) in the process of gastric cancer drug resistance and the role of PrPc expression in the prognosis of gastric cancer patients receiving chemotherapy. METHODS: A series of gastric cancer cell lines resistant to different concentrations of adriamycin was established, and the expression of PrPc, Bcl-2 and Bax was detected in these cells. Apoptosis was determined using Annexin V staining. Western blotting and immunohistochemistry were performed to detect the expression of PrPc in patients receiving chemotherapy and to explore the role of PrPc expression in predicting the chemosensitivity and the outcome of gastric cancer patients receiving chemotherapy. Follow-up was performed for 2 years. RESULTS: PrPc expression was increased with the increase in drug resistance. Bcl-2, together with PrPc, increased the level of anti-apoptosis of cancer cells. Increased PrPc expression predicted the enhanced level of anti-apoptosis and resistance to anticancer drugs. PrPc expression could be used as a marker for predicting the efficacy of chemotherapy and the prognosis of gastric cancer. Increased PrPc expression predicted both poor chemosensitivity and a low 2-year survival rate. Contrarily, low PrPc expression predicted favorable chemosensitivity and a relatively high 2-year survival rate. CONCLUSION: PrPc expression is associated with histological types and differentiation of gastric cancer cells; The PrPc expression level might be a valuable marker in predicting the efficacy of chemotherapy and the prognosis of gastric cancer patients receiving chemotherapy.