REGγ调控肿瘤相关巨噬细胞浸润和极化促进肾癌侵袭转移的机制研究

Renal cell carcinoma (RCC), originating from the renal tubule epithelial cells, is the most common kidney tumor in adults. A large number of studies demonstrated that the proteasome activator REGγ is involved in the initiation and development of multiple tumors. However, little is known about the functions of REGγ in RCC. Tumor-associated macrophage (TAM), the macrophage infiltrated in tumor microenvironment, can promote the proliferation, invasion, metastasis and angiogenesis of various tumors including renal cell carcinoma. In our preliminary study, we found that REGγ is overexpressed in RCC, knockdown of REGγ significantly inhibited cell proliferation and TAM infiltration in RCC. In this study, we will firstly detect the infiltration of TAM in RCC tissue samples, followed by analyze the relationship between TAM infiltration and the clinicopathological features/prognosis of patients with RCC. Then, we will determine the effects of activated TAMs co-culture on RCC cells biological behaviors. Finally, we will perform a series of experiments in vitro and in vivo to explore the potential mechanisms that REGγ regulates the infiltration and M2 polarization of TAM via CK1ε/MST1/FOXO1 signaling to promote the invasion and metastasis of RCC. Our study may provide some novel approach for early diagnosis and better treatment in RCC.

肾细胞癌(RCC)是起源于肾实质小管上皮细胞的成人最常见的肾脏肿瘤。大量研究表明蛋白酶体激活因子REGγ与多种癌症的发生发展相关。然而，REGγ在肾癌中的作用研究尚少。肿瘤相关巨噬细胞（TAM）是浸润在肿瘤微环境中的巨噬细胞，可促进包括肾癌在内的多种肿瘤的生长、侵袭、转移及血管生成。本课题组前期研究发现REGγ在肾癌中高表达，敲除REGγ可抑制肾癌细胞的增殖和TAM浸润。本课题将（1）检测肾癌临床样本中TAM的浸润情况，分析TAM 浸润与肾癌患者的临床病理特征及预后的相关性。（2）研究活化的TAMs共培养对肾癌细胞生物学行为的影响。（3）通过体外和体内实验研究REGγ通过CK1ε/MST1/FOXO1信号通路调控TAM的浸润和M2型极化促进肾癌侵袭转移的机制。为肾癌的早期诊断和治疗提供新的可能。

背景：肿瘤相关巨噬细胞（TAMs）可促进多种肿瘤的增殖和转移等。本研究的目的旨在研究肾癌中TAMs的浸润情况及作用。.主要研究内容：本课题组通过利用免疫组化（IHC）检测肾癌组织中CD163和CD206的表达检测TAMs在肾癌中的浸润情况。Elisa实验和qRT-PCR用来验证M2型巨噬细胞的诱导成功。一系列的功能实验用来研究TAMs对肾癌细胞迁移和侵袭等的影响。Western blot用来检测肾癌细胞中STAT3、p-STAT3、E-cadherin和vimentin的表达情况。免疫荧光用来检测肾癌细胞中的上皮-间质转化情况及p-STAT3的表达情况。.研究结果：TAMs在肾癌中的浸润明显增加并与肾癌患者的进展和不良预后密切相关。TAMs的条件培养基（TAMs-CM）明显促进了肾癌细胞的迁移、侵袭和上皮-间质转化（EMT）。另外，我们发现IL-6参与了TAMs对肾癌的作用，TAMs可通过激活IL-6/STAT3信号通路促进肾癌的迁移、侵袭和上皮-间质转化。.结论和意义：TAMs在肾癌中浸润增加并可通过激活IL-6/STAT3信号通路促进肾癌的迁移、侵袭和上皮-间质转化。该研究结果提示靶向TAMs或IL-6可能成为肾癌患者新的治疗策略。