巨噬细胞外泌体LINC01410通过PCBP1/PHD2抑制HIF1A羟基化降解介导乳腺癌内分泌耐药的机制研究

肿瘤相关巨噬细胞（TAMs）主导的肿瘤微环境与乳腺癌耐药密切相关，但具体机制尚未阐明。我们前期研究证明：肿瘤可调控TAMs选择性极化；TAMs外泌体调控HIF1A诱导乳腺癌内分泌耐药；TAMs传递LINC01410至癌细胞抑制HIF1A降解；生信预测LINC01410可能结合PCBP1。HIF1A可补偿受损的ERα通路，诱导乳腺癌内分泌耐药；而PCBP1可结合激活PHD2促进HIF1A羟基化并降解。因此，我们推测：TAMs外泌体LINC01410通过干扰PCBP1/PHD2结合，抑制HIF1A羟基化降解，进而介导乳腺癌内分泌耐药。本项目拟在细胞水平、动物模型及临床样本中，研究TAMs外泌体LINC01410干扰PCBP1/PHD2结合，抑制HIF1A降解的分子机制；探索其调控乳腺癌PCBP1/PHD2/HIF1A通路的对乳腺癌内分泌耐药的作用机理，为内分泌耐药的乳腺癌提供防治新思路。

Patients with estrogen-positive breast cancer have endocrine resistance and poor prognosis. The tumor microenvironment dominated by TAMs is closely related to the endocrine resistance of breast cancer, but the specific mechanism has not been elucidated. Our previous studies have shown that tumor cells can mediate the selective polarization of TAMs. Further in vitro experiments found that TAMs deliver exosomes to regulate breast cancer HIF1A to induce endocrine resistance. Preliminary experiments show that TAMs can deliver LINC01410 to breast cancer cells to inhibit the degradation of HIF1A, and LINC01410 may bind to PCBP1 directly. The increased stability and activity of HIF1A can compensate for the damaged ERα signal during endocrine therapy, and induce endocrine resistance in breast cancer. PCBP1 can activate PHD2 to promote HIF1A degradation. Therefore, we propose the hypothesis that LINC01410 in TAMs exosomes inhibits the hydroxylation and degradation of HIF1A by interfering with PCBP1/PHD2 binding, thereby mediating breast cancer endocrine resistance. This project intends to rely on animal models and clinical samples, with mechanism research as the core, and innovatively explore the mechanism of TAMs exosomal LINC01410 to regulate PCBP1/PHD2/HIF1A-mediated endocrine resistance of breast cancer, which provide new ideas for prevention and treatment.