剪接因子TDP43对三阴性乳腺癌干细胞的调控作用及其机制研究

Among different breast cancer subtypes, triple-negative breast cancer (TNBC) is associated with higher mitotic activity, high incidence of metastasis and drug resistance, and lack of effective targeted therapies. Breast cancer stem cells are well-known to be important factors for tumorgenesis, metastasis and recurrence of breast cancer. We first revealed the unique alternative splicing pattern in TNBC, and identified TDP43 as an important factor for TNBC splicing pattern. However, it remains unknown whether alternative splicing is involved in the regulation of triple-negative breast cancer stem cells to induce tumor progression. Our preliminary data showed that TDP43 was highly expressed in triple-negative breast cancer stem cells, and knockdown of TDP43 inhibited breast cancer stem cell self-renewal ability. Thus, we hypothesized TDP43 might have a role on triple-negative breast cancer stem cell by the regulation of alternative splicing. To test this hypothesis, we will explore how the splicing factors TDP43 co-regulates with lncRNA to promote the self-renewal capacity of triple-negative breast cancer stem cells through in vivo and in vitro experiments, and we will also use mouse xenograft models to determine the probability of combination chemotherapy drugs and interference TDP43 for TNBC treatment. This project would uncover the important role of alternative splicing on TNBC tumor progression and thus provide potential therapies for TNBC.

三阴性乳腺癌具有高增殖、高转移、容易耐药和缺乏靶向药物等特点，是乳腺癌治疗的一大难题。目前认为，肿瘤干细胞是肿瘤发生发展、转移和复发的重要因素。我们首次揭示三阴性乳腺癌存在独特可变剪接特征，并鉴定TDP43作为重要调控因子。然而，尚不清楚可变剪接是否参与三阴性乳腺癌干细胞调控过程。我们前期数据显示，TDP43在三阴性乳腺癌干细胞中高表达，而且下调TDP43抑制乳腺癌干细胞自我更新能力。由此，我们推测剪接因子TDP43可能通过调节可变剪接调控三阴性乳腺癌干细胞影响肿瘤进程。基于早期数据，我们将通过体内和体外实验进一步探讨TDP43如何通过与lncRNA共同调控CD44的剪接，进而贡献于乳腺癌干细胞的自我更新；我们也将利用小鼠异种移植模型确定联合化疗药物与干扰TDP43是否能进一步抑制三阴性乳腺癌进展。本课题的开展将有利于揭示可变剪接在三阴性乳腺癌发生发展中的重要作用，为其临床治疗提供新思路。

乳腺癌是全球女性发病率最高的恶性肿瘤。课题组前期揭示三阴性乳腺癌存在特异性的可变剪接特征，并进一步鉴定TDP43作为重要的调控因子。乳腺肿瘤干细胞是乳腺癌复发与转移的关键因素。本项目围绕剪接因子TDP43对三阴性乳腺肿瘤干细胞的调控作用与机制这一问题，我们发现下调TDP43抑制三阴性乳腺癌干细胞自我更新能力；并确定CD44作为重要的TDP43下游可变剪接事件，介导SRSF3/TDP43对乳腺癌干细胞的促进作用。lncRNA lnc7144能结合TDP43，参与CD44可变剪接调控。本课题揭示了剪接因子TDP43在乳腺肿瘤干细胞中的重要作用，同时阐明了可变剪接CD44对乳腺癌发生发展中的重要功能，为乳腺癌在临床治疗提供了新的理论基础与潜在靶点。