细胞极性蛋白CRB3调控原纤毛生成影响乳腺癌细胞恶性进程的机制研究

细胞原纤毛生成异常与多种肿瘤的发生发展密切相关，对原纤毛生成的研究是目前肿瘤学研究的前沿与热点领域之一。原纤毛是一种极化的细胞结构，细胞极性的建立是原纤毛生成的必要条件。近年来研究表明，顶部极性蛋白参与原纤毛生成过程并与肿瘤进程高度相关，然而很多关键机制尚不清楚。我们课题组前期结果表明，敲低顶部极性蛋白CRB3可导致乳腺上皮细胞原纤毛丢失，在乳腺癌细胞中外源性表达CRB3可诱导原纤毛生成并导致癌细胞凋亡。基于文献报道及我们的前期工作，我们设想：CRB3缺失可导致乳腺上皮细胞原纤毛生成异常并与乳腺癌细胞干样特征及其恶性行为相关；CRB3可诱导纤毛生成并在肿瘤治疗中具有重要作用。我们拟以乳腺癌细胞及临床组织标本为研究对象，通过体内外实验对CRB3调控原纤毛生成的机制进行深入探究。该项目的完成，将可阐明CRB3调控原纤毛生成参与乳腺癌恶性进程中的全新机制，并为筛选抗癌新靶点提供理论依据。

Abnormality of cell primary cilium formation is closely related to tumorigenesis and tumor development, studies on the mechanism underlying loss of cell primary cilium formation in tumorigenesis and development has become one of the hottest fields in tumor research. Primary cilium is a kind of polarized structure of cell, the establishment of cell polarity is required for primary cilium formation. Recent studies have shown that apical polarity proteins are required for primary cilium formation and play crucial roles in tumorigenesis and tumor development. However, the mechanism is still unclear. Our preliminary data have shown that knockdown of CRB3 lead to loss of primary cilium in mammary epithelial cells, and overexpression of CRB3 induce primary cilium formation and lead to apoptosis in breast cancer cells. Based on previous literature reports and our preliminary data, we hypothesize that loss of CRB3 may lead to disorder of primary cilium formation, and be closely related to malignant progression of breast cancer, and consequently, give rise to breast cancer stem cell-like traits. We also hypothesize that the restore of CRB3 may induce primary cilium formation and give rise to apoptosis in breast cancer cells and that CRB3 may be a novel target for cancer therapy. By using multiple cellular and molecular biological techniques in vitro and in vivo, We plan to conduct research on the effects of loss of CRB3 on malignant progression of human breast cancer by regulating cell primary cilium formation, and clarify and to clarify a novel mechanism by which CRB3 affects the malignant progression of breast cancer by regulating primary cilium formation. This project is expected to provide a theoretical basis for breast cancer malignant progression and for screening a novel anti-cancer target.