CAFs依赖的HA交联缺失在乳腺癌恶性进展中的作用及机制研究

透明质酸（Hyaluronan,HA）是细胞外基质主要成分，在生理条件下呈交联状态，具有细胞保护作用。乳腺癌发生时，肿瘤相关成纤维细胞（CAF）合成大量HA分子，并发生动态重构。既往研究多聚焦不同分子量HA在肿瘤恶性进展中的作用，而HA构象改变（交联失衡）鲜有报道。已证实，细胞外基质中胶原分子交联缺失与获得在肿瘤恶性进展中发挥重要作用，但是HA交联失衡是否发挥类似作用，尚待澄清。本课题前期研究发现：①相对正常组织，乳腺癌组织中HA交联状态消失；②乳腺肿瘤微环境中HA主要来源于CAF。据此本研究推测，肿瘤微环境中CAF依赖的HA交联缺失可影响乳腺癌恶性进展。本课题拟首次探讨：①乳腺成纤维细胞HA交联状态改变对乳腺癌恶性进展的调控作用；②聚焦介导HA交联的关键分子TSG6，阐明肿瘤微环境中HA交联缺失的上游分子机制，力求从新视角揭示乳腺癌发生发展机制。

Hyaluronan (HA) is the main component of extracellular matrix. When breast cancer occurs, cancer-associated fibroblasts (CAFs) synthesize a large amount of HA and undergo dynamic remodeling. Previous studies have focused on the role of HA with different molecular weights in tumor malignancy. However, HA conformational changes (cross-linking imbalance) have been rarely reported. It has been proved that the deficiency and acquisition of collagen cross-linking in extracellular matrix plays an important role in tumor malignancy. However, whether the HA cross-linking imbalance has a similar role remains to be clarified. Our previous study found that: ①Compared to normal tissues, HA cross-linking in breast cancer tissues was deficient; ②HA was mainly derived from CAFs in the breast cancer microenvironment. Therefore, this study speculated that the absence of CAFs-dependent HA cross-linking in the tumor microenvironment could affect the malignant progression of breast cancer. For the first time, this study is intended to explore: ① How the HA cross-linking imbalance in breast fibroblasts regulates the malignant progression of breast cancer; ②Focusing on the key molecule TSG6 that mediate HA cross-linking, the upstream molecular mechanism of HA cross-linking deficiency in tumor microenvironment is to be clarified. This study aims to reveal the pathogenesis of breast cancer from a new perspective.