RESUMO
Tumor-associated macrophages (TAM), which are found in the tumor microenvironment of solid tumors, not only mediate cancer immune evasion but also promote tumor growth. The transcription factor NF-κB, which is a crucial link between inflammation and tumors, can accelerate tumor occurrence and development. NEMO, the regulatory subunit of the IKK complex, plays a pivotal role in activating the NF-κB signaling pathway. However, the function of myeloid NEMO in the tumor microenvironment remains unclear. Here, we found that conditional knockout of NEMO in myeloid cells promoted tumor growth in a transplanted cancer mouse model. In Nemofl/fl lyz-cre+/- mice, the deletion of Nemo in myeloid cells increased the recruitment of M2 macrophages and myeloid-derived suppressor cells (MDSCs) into the tumor, reduced the expression of apoptosis-related proteins, and upregulated the expression of the chemokine receptor CCR2, thereby promoting tumor growth in vivo. Then, we showed that blocking the MCP1-CCR2 pathway could inhibit tumor growth, especially in mice with myeloid NEMO deletion. In this study, we examined the mechanism of NEMO in myeloid cells and explored the role of NEMO in the prevention and treatment of cancer.
Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/genética , Células Mieloides/metabolismo , Evasão Tumoral/genética , Animais , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Deleção de Genes , Tolerância Imunológica/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células Mieloides/patologia , Células Supressoras Mieloides/metabolismo , Células Supressoras Mieloides/fisiologia , Neoplasias/genética , Neoplasias/imunologia , Neoplasias/metabolismo , Neoplasias/patologia , Receptores CCR2/genética , Receptores CCR2/metabolismo , Transdução de Sinais/genética , Células Tumorais Cultivadas , Evasão Tumoral/imunologia , Microambiente Tumoral/genética , Microambiente Tumoral/imunologiaRESUMO
Objective To study the vulnerability of astrocytes bearing mutant SOD1 under the oxidative stress.Methods The cytotoxicity of the serum deprived astrocytes was measured by MTT.The level of ROS was shown by fluorescence of DCF through confocal microscopy.The expression of Nrf2,HO1 and NQO1 in the different cells was detected by Western blot.Results The level of cellular toxicity was higher in the astrocytes bearing mutant SOD1 exposed to the oxidative stress than the astrocytes hearing wild type SOD1.In the astrocytes bearing mutant SOD1,the expression of Nrf2,HO1 and NQO1 decreased.In the presence of mutant SOD1,an unexpected 44 per-cent decrease of Nrf2 was detected.This was associated with a decreases in multiple downstream phase Ⅱ detoxif-ying enzymes and antioxidant enzymes,known as NQO1 and HO1.Furthermore,our results showed that the ex-pression of NQO1 increased 1.5 and 2.5-fold by EGCG at 5 and 10 μmol/L.EGCG also elevated the expression of total Nrf2.Confocal microscopy showed that EGCG caused Nrf2 translocation from the cytoplasm to the nucleus.Conclusion Decrease in Nrf2 expression is the mechanism to explain the vulnerability of astrocytes bearing mutant SOD1 and EGCG strengthened antioxidation function by upregulating the activity of Nrf2.