肿瘤相关巨噬细胞自噬经NRF2-IL-10途径调节膀胱癌细胞上皮间质样转化的分子机制

Bladder cancer is one of the most common malignancies of the urinary tract, and it is very difficult to decrease effectively the high recurrence percentage in clinical work. Our previous study has shown that the expressions of autophagy are increased in TAMs in bladder cancer tissues, which is consistent with the changes of EMT-associated factors in bladder cancer. And autophagy was increased in rapamycin-treated TAMs which induced the development of EMT in bladder cancer cells in vitro. Further studies demonstrated that rapamycin-induced autophagy could up-regulate obviously the expressions of IL-10 and promoted transcription factor NRF2 transfer into the nucleus and expression levels in TAMs. According to these meaningful results, we hypothesize that “TAMs autophagy regulates the EMT in bladder cancer cells through NRF2-IL-10 pathway”. To confirm the hypothesis, we induced and established TAMs, performed TAMs and bladder cancer cells co-culture model in vitro and in vivo, and a series of approaches, including gene transfection, flow cytometry, confocal laser scanning microscope and so on, were employed in the present study to study the role of TAMs autophagy in development of EMT in bladder cancer cells and reveal the mechanism of TAMs autophagy-NRF2-IL-10 pathway participating in EMT in bladder cancer.

膀胱癌是最常见的泌尿系恶性肿瘤之一，有效地抑制其复发和转移是临床上亟待解决的难题。前期研究表明自噬在膀胱癌肿瘤相关巨噬细胞（Tumor associated macrophages，TAMs）中表达增高，并与上皮间质样转化（Epithelial–mesenchymal transition， EMT）相关调节因子表达一致；体外证实雷帕霉素干预的TAMs自噬增强，且与膀胱癌细胞共培养可促进后者EMT改变；TAMs自噬可显著上调IL-10表达，促进转录因子NRF2的核内转移和表达。基于此，我们推测“TAMs自噬经NRF2-IL-10途径调节膀胱癌细胞EMT”，拟在成功诱导TAMs前提下，通过TAMs与膀胱癌细胞体外共培养及裸鼠膀胱癌模型，应用基因转染、流式细胞学、激光共聚焦等方法探讨TAMs自噬对膀胱癌细胞EMT的调节，揭示TAMs自噬-NRF2-IL-10途径参与膀胱癌细胞EMT的分子机制。

膀胱癌是最常见的泌尿系恶性肿瘤之一，有效地抑制其复发和转移是临床上亟待解决的难题。前期研究表明自噬在膀胱癌肿瘤相关巨噬细胞(Tumor associated macrophages，TAMs) 中表达增高，并与上皮间质样转化(Epithelial–mesenchymal transition， EMT)相关调节因子表达一致;体外证实雷帕霉素干预的TAMs自噬增强，且与膀胱癌细胞共培养可促进后者EMT改变;TAMs自噬可显著上调IL-10表达，促进转录因子NRF2的核内转移和表达。基于此，我们推测“TAMs自噬经NRF2-IL-10途径调节膀胱癌细胞EMT”，并在成功诱导TAMs前提下，通过TAMs与膀胱癌细胞体外共培养及裸鼠膀胱癌模型，应用基因转染、流式细胞学、激光共聚焦等方法探讨TAMs自噬对膀胱癌细胞EMT的调节，揭示TAMs自噬-NRF2-IL-10途径参与膀胱癌细胞EMT 的分子机制。