Periostin蛋白调控乳腺组织基质硬度在乳腺癌发生发展中的功能

The alternation of tissue extracellular matrix (ECM) stiffness is closely related to the development of various diseases such as tumors; however, it is still unknown whether the functions of periostin in the development of breast cancer are involved in tissue ECM stiffness. Our preliminary data showed that knockdown of periostin significantly inhibits collagen cross-linking degree and tissue stiffness related with aging of the breast tissue, and suppresses cross-linking of collagen in breast tumor tissues. Moreover, mouse mammary fibroblasts express more periostin in the stiffness-increased matrix gel. In addition, we also found that the expression of periostin is positively correlated with the level of activated LOX in human and mouse breast cancer tissues. These data demonstrated that periostin may contribute to the development of breast cancer via the regulation of tissue ECM stiffness; however, the underlying mechanisms are still unclear. On the basis of our previous studies about the roles of periostin in tumorigenesis and metastasis of breast cancer, this project will use the periostin-knockout mouse and MMTV-PyMT mouse models to investigate the functions and mechanisms of periostin in regulating tissue ECM stiffness in the development of breast cancer. This study will help us learn more about the functions of periostin in breast tumor progressioin from the point of view of tissue ECM stiffness and provide clues and a new target to the prevention and therapeutic intervention against breast cancer.

组织基质硬度的改变与肿瘤等疾病的发生密切相关，但目前对Periostin是否可以通过调控组织硬度来参与乳腺癌等肿瘤的发生发展并不清楚。我们的初步研究结果显示，Periostin敲除可显著抑制乳腺组织中由机体衰老引起的胶原交联程度的增强和组织硬度的增加，并抑制乳腺肿瘤组织中的胶原交联；基质胶硬度的增加可促进小鼠乳腺成纤维细胞高表达Periostin；且在人和小鼠乳腺癌肿瘤组织中Periostin与活化的LOX的表达呈正相关，初步表明Periostin蛋白参与调控乳腺癌发生发展过程中的组织基质硬度，但对其作用机制并不清楚。本项目将应用Periostin基因敲除小鼠和MMTV-PyMT小鼠等模型，研究Periostin蛋白调控组织基质硬度在乳腺癌发生发展中的功能及其作用机制，以进一步从组织硬度角度阐明Periostin在乳腺癌发生发展中的功能，并为乳腺癌早期预防及治疗提供理论依据和新的作用靶点。

我们已发现Periostin蛋白是乳腺癌肺转移的关键限制性的肿瘤微环境因子，但对其是否参与调控乳腺癌发生发展过程中的组织硬度增加及其作用机制并不清楚。我们的研究显示：（1）小鼠和人乳腺癌肿瘤组织中Periostin与LOX的表达呈正相关，Periostin敲除可显著抑制小鼠乳腺组织中由机体衰老引起的胶原交联程度的增强和组织硬度的增加，并抑制乳腺肿瘤组织中的胶原交联，进而抑制乳腺癌原位癌的生长和转移；（2）小鼠体内实验以及临床样本分析也发现Periostin的表达与表征乳腺癌组织硬度的胶原表达水平呈正相关；（3）基质胶硬度的增加可通过促进小鼠乳腺肿瘤成纤维细胞Src的激活，进而促进YAP入核并直接上调Periostin的表达与分泌；（4）小鼠体内实验以及临床样本分析也发现Periostin的表达与YAP的活性呈正相关；（5）乳腺肿瘤成纤维细胞来源的Periostin蛋白可通过与乳腺癌细胞膜上的整合素αvβ3和αvβ5结合，激活FAK、ERK以及Rac1、Cdc42，通过调控F-actin的组装来促进乳腺癌细胞的集体性侵袭，从而最终促进乳腺癌细胞肺转移。以上结果表明，肿瘤成纤维细胞高表达Periostin可增加乳腺组织硬度，乳腺组织硬度增加则进一步通过Src的激活来促进YAP的入核和Periostin的高表达；高水平的Periostin则通过Integrin-FAK通路将胞外机械应力传导到肿瘤细胞内，进而通过促进F-actin的组装来促进肿瘤细胞集体性侵袭。该研究是国际上首次发现组织硬度增加可促进肿瘤细胞集体性侵袭，首次发现Periostin是YAP的新靶基因，首次发现Periostin是乳腺肿瘤组织硬度的重要调控因子，是将组织硬度信号传导到肿瘤细胞内的重要组织微环境因子。该研究对进一步阐明Periostin促进乳腺癌转移的机制具有重要意义，也为乳腺癌治疗提供了新的作用靶点。