细胞外囊泡转运的lncRNA LINC01235通过调控MCM复合体促进HER2阳性乳腺癌耐药的临床和机制研究

近年来HER2阳性乳腺癌随着靶向药物上市预后明显改善，但仍有较多患者因耐药无法获益。细胞外囊泡（EVs）可参与细胞间信号传递，调控肿瘤微环境，lncRNA作为信使发挥重要作用。本研究选取HER2+乳腺癌新辅助化疗前空芯针标本，结合血浆EVs测序数据分析发现LINC01235在non-pCR组显著高表达。TCGA数据库发现其可预测不良预后。LINC01235可经EVs分泌，在细胞间传递。细胞内LINC01235可促进增殖，提高对拉帕替尼的IC50。LINC01235可能通过MCM复合物促进细胞G1/S期改变，增加复制叉数量，活化HER2信号通路。体外制备的高表达EVs可重复细胞内表型。课题组拟通过独立样本验证血浆EVs中LINC01235对治疗的预测价值；利用细胞、动物及类器官模型阐明其通过EVs进入肿瘤细胞后影响HER2耐药的机制，为后续HER2阳性乳腺癌治疗提供新的液体标志物和治疗靶点。

The prognosis of HER2 positive breast cancer has been improved significantly，however，some patients still suffer from prolapse or metastasis. Extracellular vesicles (EVs) are involved in intercellular signal crosstalk in tumor microenvironment, among which, long non-coding RNAs play a vital role as messengers. We carried out RNA-seq analysis with core needle biopsy specimens and serum EVs extracted from HER2 positive breast cancer patients prepared to receive neoadjuvant chemotherapy. LINC01235 was found to be highly expressed in non-pCR patients compared with pCR group. TCGA data showed LINC01235 correlated with poor prognosis. We further demonstrated that LINC01235 could be secreted through EVs and received by other breast cancer cells. Overexpression of LINC01235 could promote cell proliferation and increase cell IC50 on lapatinib. RNA-seq analysis of LINC01235 stable cells showed LINC01235 might possibly promote the G1/S phase transition, increase the number of replication forks and activate the HER2 pathway through the MCM complex. Addition In vitro prepared high LINC01235 expression EVs to HER2 breast cancer cells showed the same phenotype as LINC01235 transduced cells. Our further research is to r confirm the prognostic value of LINC01235 in liquid biopsy with an independent cohort. Through cell, animal, and organoid models, we will demonstrate the biological mechanism of LINC01235 on HER2 treatment resistance by EVs transmission, and provide new biomarkers and therapeutic targets for clinical translation.