癌旁组织BAG3在乳腺浸润性导管癌侵袭转移中的作用及机制研究

BAG3 is increased in many cancers and plays important roles in survival and proliferation of tumor cells, indicating that BAG3 functions as an oncogene. In previous work, for the first time we found that the high BAG3 level in paracancerous tissue of breast invasive ductal carcinoma was positively correlated with the status of lymph node metastasis. We also found that overexpression of BAG3 induced senescent phenotype of mammary epithelial MCF-10A cell, as well as increased IL-6 and IL-8 expression, two key cytokines of senescence-associated secretory phenotype (SASP). Cellular senescence serves as a tumor-suppressor mechanism by preventing the malignant transformation induced by the activation of oncogene. SASP secreted by the senescent cells can maintain cellular senescence and activate immune surveillance, on the other hand, as well as can promote tumor invasion and metastasis. Therefore, we hypothesize that BAG3 may induce mammary epithelial cells to secrete SASP, which change the breast cancer microenvironment actively and promote the invasion and metastasis of breast cancer. The current project aims to investigate the potential role of BAG3 in the induction of mammary epithelial cell senescence and SASP, as well as its underlying mechanism and potential involvement in progression of breast invasive ductal carcinoma. The current study might provide potential preventive/therapeutic targets for invasion and metastasis of breast invasive ductal carcinoma.

BAG3在许多肿瘤中表达增加，维持肿瘤细胞存活与增殖，提示其发挥癌基因的功能。前期工作我们首次发现癌旁乳腺上皮细胞BAG3表达水平与乳腺浸润性导管癌淋巴结转移正相关；另外，过表达BAG3诱导乳腺上皮细胞MCF-10A呈现衰老，并且衰老相关分泌表型（SASP）关键因子IL-6、IL-8表达增加。单纯癌基因活化诱导细胞衰老是机体防止细胞恶性转化的一种机制。虽然衰老细胞所产生的SASP维持细胞衰老并激活免疫监视，但是另一方面SASP又可促进肿瘤生长及侵袭转移。因此我们推测BAG3可能通过诱导癌旁乳腺上皮细胞呈现SASP，主动改变乳腺肿瘤细胞微环境，进而促进乳腺癌的侵袭转移。本项目旨在阐明该科学假说，明确BAG3诱导乳腺上皮细胞衰老及SASP的作用及机制，解析乳腺上皮细胞BAG3过表达对乳腺浸润性导管癌侵袭转移的影响及机制，为乳腺浸润性导管癌侵袭转移的防治提供潜在的新靶标。

乳腺癌是常见的恶性肿瘤之一，严重威胁女性的健康与生命。多数乳腺癌患者早期没有临床症状，发现时癌细胞已经通过淋巴系统或者循环系统发生远处转移。肿瘤的侵袭转移及治疗后复发是导致乳腺癌患者死亡的主要原因，寻找能对其进行干预的靶蛋白，阻止肿瘤复发及侵袭转移，对乳腺癌的临床治疗具有重要意义。.BAG3是一种在进化上保守的共分子伴侣，在多种肿瘤中高表达，促进肿瘤生存。本项目研究发现，悬浮培养条件能够诱导BAG3表达，这种悬浮培养也富集了乳腺癌干细胞。实验证明了异位BAG3过表达增加了CD44+/CD24-干细胞亚群、第一代和第二代微球形成，提示BAG3能够促进乳腺癌干细胞的自我更新和维持。我们在研究中还发现了BAG3在转录后上调了CXCR4的表达。具体的调节机制是BAG3通过与CXCR4 mRNA编码区和3＇端非翻译区相互作用而稳定CXCR4 mRNA。乳腺癌患者BAG3表达水平与CXCR4表达水平及其预后不良呈正相关。因此，我们的实验数据充分表明，BAG3通过与CXCR4转录本的相互作用促进了乳腺癌干细胞样表型。本项目的研究结果提示BAG3可能作为乳腺癌不良预后因子和潜在的治疗靶点。.