FSTL1在乳腺癌脑转移细胞中高表达的作用及其机制研究

The incidence of brain metastases from primary breast cancer has steadily increased. However, no effective treatment has been reported, which significantly limits survival of patients with breast cancer brain metastases (BCBM). To identify factors critical to BCBM has important implications for its prevention and treatment. In the preliminary study, we found for the first time that Follistatin-like protein 1 (FSTL1) is up-regulated in 231-BR, the brain metastatic breast cancer cell line, and it also showed inhibitory effects on cell growth, migration and invasion of 231-BR and its parental breast cancer cells. After the detection of protein expression, FSTL1 is found to activate the TGF-β1/Smad2/3 pathway and down-regulate the expression of N-cadherin, which may partly contribute to its effects on cell behaviors. These results suggest a role of FSTL1 in BCBM. To verify this hypothesis, we will perform in vitro and in vivo study to clarify the significance of the high expression of FSTL1 in 231-BR, to understand the involvement of FSTL1 in BCBM, and to explore its underlying mechanisms. The study will further enrich the understanding of BCBM, and may shed new light on the prevention and therapeutics of it.

乳腺癌脑转移(breast cancer brain metastases, BCBM)发生率逐年提高，是乳腺癌致死的主要原因之一。探寻脑转移过程中的调控因子是预防及治疗BCBM的关键。本课题预实验结果显示卵泡抑素样蛋白1（Follistatin-like protein 1，FSTL1）在乳腺癌特异性脑转移细胞231-BR中高表达，并且FSTL1表达水平的变化可影响231-BR及其亲代细胞MDA-MB-231的生长、迁移和侵袭。进一步检测发现FSTL1可增强TGF-β1/Smad2/3信号通路，并抑制N-cadherin的表达。上述结果提示FSTL1可能参与BCBM的发生和进展，但具体机制尚需进一步明确。本课题拟从细胞和动物水平系统研究231-BR中FSTL1高表达的意义和对BCBM的调控，并探寻其分子机制。研究结果将有助于为BCBM的预防和治疗提供理论基础。

乳腺癌脑转移(breast cancer brain metastases, BCBM)是乳腺癌致死的主要原因之一，探寻脑转移过程中的关键因子是预防及治疗BCBM的关键。本课题组在前期研究中发现卵泡抑素样蛋白1（Follistatin-like protein 1，FSTL1）在乳腺癌特异性脑转移细胞231-BR中高表达，且FSTL1对231-BR的生长、迁移和侵袭均有抑制作用，提示FSTL1可能影响BCBM的发生和进展。本项目中，课题组以特异性脑转移乳腺癌细胞231-BR及其亲代MDA-MB-231为载体，分别从细胞水平和整体动物水平探讨了FSTL1在乳腺癌脑转移细胞中高表达的意义，其对BCBM的影响及具体的分子机制。项目组发现，特异性脑转移细胞株231-BR的增殖能力较其亲代细胞MDA-MB-231降低，而在MDA-MB-231细胞中过表达FSTL1后，细胞增殖及荷瘤鼠的肿瘤生长均受到抑制，同样的，在231-BR细胞中敲低FSTL1可促进其增殖及荷瘤鼠的肿瘤生长。通过进一步研究，项目组发现TGF-β1-Smad2/3信号通路在231-BR及过表达FSTL1的MDA-MB-231中被活化，这可能是FSTL1抑制细胞增殖的机制之一，此外，敲低Smad3可恢复由FSTL1过表达引起的细胞抑制，这证明FSTL1可通过Smad3调控TGF-β信号通路抑制乳腺癌脑转移细胞的增殖。此外，课题组收集了部分乳腺癌患者的癌组织、癌旁组织以及血清样本，对其病理分型进行了初步的统计，结果显示乳腺癌患者血清中FSTL1含量降低，癌组织中FSTL1的水平也低于癌旁组织，这也提示FSTL1在乳腺癌的发生发展中起着重要的作用。本项目探讨了FSTL1对乳腺癌脑转移细胞增殖的作用及其分子机制，丰富了BCBM的相关理论，为BCBM靶向药物的开发提供了新的理论依据。