RESUMO
Nasopharyngeal carcinoma (NPC) is endemic in Southern China and Southeast Asia. Hyperthermia is widely used in combination with chemotherapy and radiotherapy to enhance therapeutic efficacy in NPC treatment, but the underlying anti-tumor mechanisms of hyperthermia remain unclear. Complement C3 has been reported to participate in the activation of immune system in the tumor microenvironment, leading to tumor growth inhibition. In this study, we aimed to explore the effect and mechanisms of hyperthermia and investigate the functional role of complement C3 in NPC hyperthermia therapy (HT). The serum levels of complement C3 before and after hyperthermia therapy in patients with NPC were analyzed. NPC cell lines SUNE1 and HONE1 were used for in vitro experiment to evaluate the function of complement C3 and HT on cell proliferation and apoptosis. SUNE1 xenograft mouse model was established and tumor-bearing mice were treated in water bath at a constant temperature of 43°C. Tumor samples were collected at different time points to verify the expression of complement C3 by immunohistochemical staining and western blot. The differential expressed genes after hyperthermia were analyzed by using RNA sequencing. We found that complement could enhance hyperthermia effect on suppressing proliferation and promoting apoptosis of tumor cells in NPC. Hyperthermia decreased the mRNA expression of complement C3 in tumor cells, but promoted the aggregation and activation circulating C3 in NPC tumor tissue. By using in vitro hyperthermia-treated NPC cell lines and SUNE1 xenograft tumor-bearing mice, we found that the expression of heat shock protein 5 (HSPA5) was significantly upregulated. Knockdown of HSPA5 abrogated the anti-tumor effect of hyperthermia. Moreover, we demonstrated that hyperthermia downregulated CD55 expression via HSPA5/NFκB (P65) signaling and activated complement cascade. Our findings suggest that therapeutic hyperthermia regulates complement C3 activation and suppresses tumor development via HSPA5/NFκB/CD55 pathway in NPC.
Assuntos
Hipertermia Induzida , Neoplasias Nasofaríngeas , Humanos , Animais , Camundongos , Carcinoma Nasofaríngeo/terapia , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/patologia , Chaperona BiP do Retículo Endoplasmático , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/terapia , Neoplasias Nasofaríngeas/metabolismo , Complemento C3/genética , Complemento C3/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/genética , Antígenos CD55 , Regulação Neoplásica da Expressão Gênica , Microambiente TumoralRESUMO
To monitor the biological effects of marine pollution, choosing a native fish species and establishing suitable biomarkers are required. In this study, the full-length cDNA of cyp1a1 was cloned from Sebastiscus marmoratus (SM-CYP1A1). Then the dose-response and time-course induction of hepatic CYP1A1 mRNA by the crude oil water-soluble fraction (WSF) were determined. Subsequently, SM-CYP1A1 mRNA was applied to investigate the biological effect of petroleum hydrocarbon pollution in Quanzhou Bay, China. The transcription levels of hepatic CYP1A1 were significantly elevated in fish caged in the polluted sites for 2weeks compared with those of the reference site, which were correlated with the concentrations of petroleum hydrocarbon and polycyclic aromatic hydrocarbon (PAH) in the surface seawaters. The results suggest that S. marmoratus is a potential sentinel organism to monitor marine pollutants and the hepatic CYP1A1 mRNA can serve as a sensitive biomarker to organic xenobiotics in aquatic environments.
Assuntos
Exposição Ambiental , Peixes/genética , Peixes/metabolismo , Petróleo/efeitos adversos , Hidrocarbonetos Policíclicos Aromáticos/efeitos adversos , Poluentes Químicos da Água/efeitos adversos , Sequência de Aminoácidos , Animais , Sequência de Bases , Baías , China , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1A1/metabolismo , Relação Dose-Resposta a Droga , Monitoramento Ambiental , Proteínas de Peixes/genética , Proteínas de Peixes/metabolismo , Perfilação da Expressão Gênica/veterinária , Poluição por Petróleo , Filogenia , Espécies Sentinelas/genética , Espécies Sentinelas/metabolismo , Alinhamento de Sequência/veterináriaRESUMO
The aim of this study was to characterize dose- and time-dependent responses of gill 7-ethoxyresorufin O-deethylase (EROD) activity from Juvenile marbled rockfish (Sebastiscus marmoratus) exposed to the water-accommodated fraction (WAF) of crude oil and heavy metal Cd(â ¡) or Pb(â ¡) alone or in mixture. Compared to the control group, gill filament EROD activity in S. marmoratus was significantly induced after exposure to the WAF from 80 to 320µg/L for 5 days in dose response experiment and after exposure to 40µg/L WAF for 6-10 days in time course experiment, respectively. In the other hand, gill filament EROD activity were not significantly affected compared to the control group or related WAF groups no matter in the dose response experiment or in the time course experiment of Cd(â ¡), Pb(â ¡) or its mixture with WAF. The results suggest the use of gill filament EROD activity as a biomarker of exposure to waterborne AhR agonists in marine ecosystems while simultaneously being exposed to environmental concentrations of Cd(â ¡) or Pb(â ¡).