AEP阳性微泡在肿瘤微环境中的调控机制研究

Asparagine endopeptidase (AEP) is a newly discovered cysteine protease with high expression in breast cancer and other solid tumors. It has been found to be closely related with clinical pathological changes of tumor. Studies have shown that AEP plays an important role in tumorigenesis, tumor growth and metastasis. However, the molecular mechanism of AEP still remains elusive. We found in previous experiments that AEP in extracellular mainly exists in tumor-derived microvesicles (TMVs), while the latter is considered to be a powerful tool to educate the tumor microenvironment, promote tumor cell proliferation, angiogenesis, and to be engaged in multiple processes such as tumor metastasis and immune escape. This project proposes to use AEP-/- C57BL/6 and MMTV-PyVT spontaneous breast cancer hybrid mouse model to investigate the function of AEP in breast cancer and to further analyze AEP positive tumor-derived microvesicles(TMV-AEP+) regulatory mechanism of the tumor microenvironment. Our research would not only deepen the understanding of the function of AEP and TMVs, but also offers an alternative and more effective tool and target in cancer progression monitoring, metastasis prediction and clinical treatment.

天冬酰胺内肽酶（AEP）是新近发现的在乳腺癌等实体瘤中高表达的半胱氨酸蛋白酶，与肿瘤的临床病理变化密切相关。研究表明AEP在肿瘤发生、侵袭和转移等过程中发挥着重要作用，但其中的分子机理尚不为人知。我们在前期实验中发现AEP在胞外主要存在于肿瘤微泡（TMV）中，而后者被认为对肿瘤微环境有极其重要的影响，能够促进肿瘤细胞增殖、血管新生，参与肿瘤转移和免疫逃逸等多个过程。本项目拟利用AEP-/- C57BL/6和MMTV-PyVT的自发乳腺癌杂交小鼠，在体内系统地研究AEP在乳腺癌发展过程中的作用，并进一步分析AEP阳性微泡（TMV-AEP+）对肿瘤微环境的调控机制。我们的研究将加深人们对AEP和TMVs功能的认识，为相关研究提供更好的切入点，并能为乳腺癌病人建立一种更加有效的检查手段和治疗靶点。

天冬酰胺内肽酶(AEP)在乳腺癌、胃癌、结肠癌等实体瘤的肿瘤细胞和基质细胞中高表达，与肿瘤的临床病理变化密切相关。目前研究主要集中在肿瘤细胞中AEP的生物学功能，肿瘤基质细胞中表达的AEP对肿瘤进展、转移的影响却鲜有报道。我们的研究显示在肿瘤细胞和基质细胞AEP同时缺失情况下，小鼠乳腺癌发生、转移与野生型相比并没有显著差异；AEP在肿瘤细胞中调控细胞增殖和肿瘤微环境构建，促进肿瘤进展，而在基质细胞中抑制炎性反应和肿瘤进展；巨噬细胞中AEP能够剪切STAT3，并能够调控STAT3的活化、影响下游基因转录。这些研究对于深入认识AEP在炎症反应过程中的作用及STAT3活性调控机制有重要科学意义。