CST6在乳腺癌骨转移中的作用机制研究

Secretory proteins play important roles in modifying tumor microenvironment during cancer metastasis. Because they can be easily detected and targeted, the studies on the roles of secretory proteins in cancer metastasis hold great promise for therapeutic application. Previously we performed differential secretome analysis of bone-tropic breast cancer cells and identified a list of secreted proteins that were associated with breast cancer bone metastasis. Among these proteins, the cysteine protease inhibitor CST6 was significantly down-regulated in metastatic cancer cells and poor-prognostic clinical samples. Functional analyses demonstrated that CST6 indeed suppressed breast cancer cell invasion and metastasis to bone. However, the molecular mechanism of CST6 in breast cancer metastasis remains elusive. Recent preliminary data of our group suggested that CST6 may be involved in the regulation of the complement system during anti-tumor immune response and the remodeling of bone microenvironment. This study aims at understanding the mechanism of CST6 to regulate breast cancer bone metastasis. We will take advantage of current cell and mouse models in our group, as well as clinical analyses, to elucidate whether and how CST6 protects the C3 activity in the complement system, or regulates the osteoclast differentiation and maturation in the bone milieu. Further, we will study whether the regulation of anti-tumor immune response and osteoclast activity by CST6 mediates its suppressive roles in breast cancer bone relapse. Finally, we will find out the downstream molecular effectors of CST6. Overall, the completion of this study will help understand how tumor cells interact and remodel the microenvironment during metastasis and may open new avenues for the prognosis and treatment of malignant breast cancer.

癌细胞分泌蛋白对微环境的改造对肿瘤转移起到重要调控作用。由于分泌蛋白的易检测性和易靶向性，对其功能的研究有重要的临床应用前景。在前期工作中，我们通过对乳腺癌细胞分泌蛋白组学分析，发现半胱氨酸蛋白酶抑制分子CST6在高骨转移癌细胞中的分泌显著下调，进一步发现CST6与病人预后相关，功能上抑制乳腺癌细胞的转移能力。但是，CST6抑制转移的分子机制尚不清楚。我们最新的研究数据提示CST6可能遏制肿瘤细胞对机体补体系统的逃逸，并参与骨组织转移微环境的改造。本课题旨在研究CST6在乳腺癌转移过程中的作用机理，将利用细胞、动物模型以及临床样本分析，确认CST6是否保护C3补体分子避免被剪切，以及影响破骨细胞的分化成熟，并分析其作用机制，发现CST6分子途径下游的蛋白酶及细胞因子，为CST6通路在肿瘤转移临床预后诊断和治疗中的应用提供分子靶点和理论基础。

癌细胞分泌蛋白对微环境的改造对肿瘤转移起到重要调控作用。由于分泌蛋白的易检测性和易靶向性，对其功能的研究有重要的临床应用前景。在前期工作中，我们通过对乳腺癌细胞分泌蛋白组学分析，发现半胱氨酸蛋白酶抑制分子CST6 在高骨转移癌细胞中的分泌显著下调，进一步发现CST6 与病人预后相关。在本项目中，我们研究了CST6在乳腺癌骨转移中的作用及机制，并对CST6相关多肽在骨转移治疗中的作用进行了初步研究。结果发现CST6能显著抑制乳腺癌的骨转移，机制研究表明CST6通过抑制下游LGMN、CTSL等蛋白酶的活性，从而下调乳腺癌细胞诱导破骨细胞成熟的能力；同时发现CST6重组蛋白及一个截断体的多肽能够有效的抑制乳腺癌骨转移，初步证实了其成药性。本项目基本完成全部计划研究内容，发表SCI论文6篇。