FSIP1自分泌调控乳腺癌干细胞特性的作用和机制

Cancer stem cells (CSC) have the capacity of self-renewal and differentiation into multiple cancer cells. CSC have the characters of mensenchymal cells and express high levels of drug efflux transporter proteins, such as P-gp and BCRP, naturally resistant to many drugs. Accordingly, CSC are thought to be key of recurrence，relapse and drug resistance of cancer. However, little is known about the factors regulating the stemness of CSC. Our preliminary studies found that fibrous sheath interacting protein 1 (FSIP1), one of the cancer testis antigens, was selectively expressed in breast cancer cells and associated with metastasis and poor prognosis. FSIP1 was also expressed and secreted by breast cancer cell lines as well as freshly isolated breast CSC. Furthermore, FSIP1 silencing inhibited the proliferation, migration and invasion of breast cancer cells, reduced the stemness of breast CSC, and anti-FSIP1 sensitized breast cancer cells to several chemotherapeutic drugs. Accordingly, we hypothesize that autocrine FSIP1 regulates the proliferation, EMT, invasion and stemness of breast CSC and contributes to the recurrence, metastasis and drug resistance of breast CSC. We will examine the frequency of FSIP1+ CSC in breast cancer specimens and its association with clinical pathogenic characteristics of breast cancer; investigate its role and molecular mechanisms as well as the potential signaling that result in FSIP1 regulating proliferation, EMT, invasion, stemness and drug resistance of breast CSC; and identify the FSIP1 receptors on breast cancer cells. Our data will reveal novel molecular mechanisms underlying the action of FSIP1 in regulating the growth, metastasis and drug resistance and provide new targets for therapy design of intervention of breast cancer.

肿瘤干细胞是导致乳腺癌复发、转移和耐药的关键因素。前期工作发现纤维鞘蛋白FSIP1与乳腺癌转移及不良预后显著相关(Oncotarget,2015)，预实验表明乳腺癌和乳腺癌干细胞表达和分泌FSIP1，沉默FSIP1明显抑制乳腺癌细胞的增殖和迁移，且中和自分泌的FSIP1显著增强乳腺癌细胞系对化疗药物的敏感性，但FSIP1促进乳腺癌干细胞特性的机制尚不清楚。本研究拟在细胞水平上通过沉默或过表达FSIP1确认其对乳腺癌干细胞增殖、EMT和耐药性的调控；进而从分子水平确定介导FSIP1促进乳腺癌干细胞特性的信号通路，筛选并鉴定乳腺癌细胞表面FSIP1受体及下游信号传导蛋白；然后在动物水平上验证FSIP1表达变化对乳腺癌干细胞成瘤和转移能力的影响；最终在乳腺癌样本中检测FSIP1阳性乳腺癌干细胞比率与生物学行为关系。本研究将揭示FSIP1调控乳腺癌干细胞特性的分子机制，为乳腺癌新靶点筛选提供依据。