可变剪接体FGFR1-238在三阴性乳腺癌发生和转移中的作用及机制研究

Breast cancer ranks the first in the incidence of female malignancies. Triple-negative breast cancer is highly aggressive and lacks effective therapeutic targets, and is currently the subtype of breast cancer with the worst prognosis. Studies have shown that alternative splicing events are significantly enriched in malignancies, suggesting that cancer-associated alternative splicing plays an important role in the development and progression of tumors. In the previous study, we performed the transcriptome sequencing of the clinical samples of triple negative breast cancer. Through the analysis with a novel bioinformatics tool AIDE, we found that the alternative splicing isoform FGFR1-238 was distinctly expressed between the primary tumor of triple-negative breast cancer and paired normal breast tissue, and between the involved lymph node and paired primary tumor. Besides, inhibition of FGFR1-238 significantly reduced the proliferation and migration of triple-negative breast cancer cells. On this basis, we plan to explore the regulatory function of FGFR1-238 on triple-negative breast cancer cells and its clinical significance, and to analyze the binding protein and regulatory signaling molecules of FGFR1-238 through cellular, animal experiments and analysis of clinical samples. This study aims to systematically elucidate the biological function and molecular mechanism of FGFR1-238 in promoting the development and metastasis of triple-negative breast cancer, and to clarify its potential application value as a potential drug target, thus to provide new insights for the treatment of triple-negative breast cancer.

乳腺癌居女性恶性肿瘤发病率首位。三阴性乳腺癌侵袭性高，且缺乏有效的治疗靶点，是目前预后最差的乳腺癌亚型。已有研究表明，可变剪接事件在恶性肿瘤中明显富集，提示肿瘤相关可变剪接在肿瘤发生发展过程中具有重要作用。前期研究中，我们通过三阴乳腺癌临床样本转录组测序，采用生物信息学工具AIDE分析，发现可变剪接体FGFR1-238在配对的三阴乳腺癌原发灶与正常乳腺组织、淋巴结转移灶与原发灶之间均呈显著差异表达。功能实验发现，抑制FGFR1-238可明显降低三阴乳腺癌细胞增殖及迁移能力。在此基础上，拟结合细胞、动物实验及临床样本检测，明确FGFR1-238对三阴乳腺癌细胞的调控功能及临床意义，并对FGFR1-238结合蛋白和调控的信号分子进行分析。本课题旨在系统地阐明FGFR1-238促进三阴乳腺癌发生和转移的生物学功能及分子机制，明确其作为药物靶标的潜在应用价值，为三阴乳腺癌的治疗提供新思路。

乳腺癌是全球范围内发病率最高的恶性肿瘤。三阴性乳腺癌具有侵袭性强、复发转移风险高等特征，且缺乏有效的治疗靶点，是目前预后最差的乳腺癌亚型。当前，对于三阴性乳腺癌新治疗靶点的筛选验证依然是乳腺癌领域的研究热点。在恶性肿瘤中，可变剪接通过调控肿瘤细胞的迁移、侵袭和血管生成，以及肿瘤治疗过程中的耐药发生等，在肿瘤发生和演进过程中发挥了重要作用。本研究通过三阴性乳腺癌临床样本转录组测序及生物信息学工具AIDE分析，预测并鉴定三阴性乳腺癌发生和转移中的关键可变剪接体。本研究验证了可变剪接体FGFR1-238在三阴性乳腺癌中的作用及功能。此外，进一步的生物信息学挖掘及实验研究发现可变剪接体EIF4E-201、EIF4E-208和BAK1-203的特异性上调可促进三阴性乳腺癌细胞增殖，加快细胞周期；可变剪接体ARHGAP25-209可以促进三阴性乳腺癌细胞迁移、侵袭和增殖，其促进细胞转移可能是通过激活STAT3和PI3K/AKT通路实现的。本研究通过可变剪接体功能研究和机制探索，为三阴性乳腺癌预警体系的构建和靶向治疗方案的建立提供了新的思路。