原癌基因XB130促进乳腺癌干细胞自我更新的分子机制

It has been reported that cancer stem cells, a small subset of cancer cells with high self-renewal properties, play key roles in tumorigenesis, metastasis, drug resistance and tumor recurrence. The mechanisms of cancer stem cells self-renewal, however, still remain largely unclear. Importantly, our recent preliminary data showed that XB130 was upregulated in human breast cancer tissues than the paired adjacent non-tumor tissues, and significantly upregulated in all of the tested breast cancer cell lines compared to normal cells. Furthermore, overexpression of XB130 significantly upregulated the expression levels of multiple reprogram factors, including ABCG2, Sox2, OCT-4, KLF4 and NANOG. Moreover, we found that ectopically expressing XB130 dramatically induced tumor cell sphere-formation. Meanwhile, less XB130-transduced cells could form more aggressive tumor in the nude mice breast as compared with control cells. Thus, these results indicate that XB130 plays an important role in the self-renewal of breast cancer stem cells. Moreover, we also found that XB130 could interact with β-catenin, and overexpresson of XB130 induced nuclear translocation of β-catenin and activated wnt/β-catenin signaling pathway. Therefore, in the current study, using in vivo and in vitro systems, and combined with clinical samples, we aim to further investigate the molecular mechanisms and biological effect of XB130 on self-renewal of breast cancer stem cells, which would provide a novel and useful prognostic marker and a potential target for human breast cancer treatment.

目前已知肿瘤干细胞是肿瘤发生、转移、耐药与复发的主要原因；然而肿瘤干细胞自我更新的调控机制仍不清楚。我们预实验结果显示XB130在乳腺癌组织及细胞系中的表达都明显高于癌旁组织及正常乳腺上皮细胞，并且高表达XB130可显著上调乳腺癌细胞中重编程因子的表达、促进球囊形成能力。少量高表达XB130的乳腺癌细胞在裸鼠乳房原位即可形成高度恶性肿瘤。以上结果表明XB130在促进乳腺癌干细胞自我更新中具有重要的功能。同时，我们发现XB130 可与β-catenin 相互结合，且高表达XB130促进β-catenin 进核而激活Wnt/β-catenin 信号通路。本项目将在前期研究基础上，采用体内、体外实验系统，并结合临床样品，深入探讨XB130 通过激活Wnt/β-catenin 信号通路而促进肿瘤干细胞自我更新的分子机制及生物学功能，为乳腺癌的诊治提供新靶点及新的理论依据。

我们前期研究表明接头蛋白XB130在乳腺癌中表达增高，但其与乳腺癌的发生发展、生物学功能及分子机制尚不明确。为了进一步阐明XB130在乳腺癌发生发展中的生物学功能及分子机制，本课题从四个方面进行探讨。① 本课题研究中发现XB130在乳腺癌组织及细胞中明显高表达，并与乳腺癌临床病理分期及患者的生存预后明显相关。② 通过生物学功能实验发现高表达XB130显著增强乳腺癌干细胞自我更新的能力。③ 本课题证明XB130促进β-catenin的转录活性及入核情况，从而激活β-catenin下游基因（E-cadherin、CD133、CD44等）的表达。④ 乳腺癌组织中XB130的表达与β-catenin的表达明显相关，多因素分析发现XB130与β-catenin是乳腺癌患者的独立风险预后因素。（文章待发表中）