功能未知的LncRNA:RP11-727M10.1逆转乳腺癌HER2靶向治疗耐药的功能与机制研究

Previous study had demonstrated via microarray technique that the LncRNA-RP11-727M10.1 is significantly down-regulated in the herceptin resistant breast cancer. The research reveals that the down regulation of LncRNA-RP11-727M10.1 may be involved in the development of herceptin resistance in the Her 2 positive breast cancer. We could significantly increase the sensitivity to herceptin by over expressing RP11-727M10.1 in the breast cancer cell. Amphiregulin was supposed to be a potential target of RP11-727M10.1 via bioinformatics analysis and experimental results. Amphiregulin could induce the resisitance to herceptin. Above all,we hypothezed that RP11-727M10.1 might regulated herceptin resistant ability via Amphiregulin. This study will confirm the role of RP11-727M10.1, using overexpression and knock down strategies in the breast cancer cells which is resisitant to herceptin by analyzing the cell behavior and molecular characteristics; subsequently clarify the underlying mechanism between RP11-727M10.1 and Amphiregulin. The innovative proposal by this study could possibly find a new target gene to avoid herceptin resistance of breast cancer.

RP11-727M10.1是我们通过高通量lncRNA芯片技术筛选获得的、显著低表达于赫赛汀耐药乳腺癌组织的、功能未知的一条lncRNA。前期研究发现：RP11-727M10.1过表达显著增加HER2阳性细胞株对赫赛汀的敏感性；生物信息学分析及实验结果初步表明Amphiregulin可能是RP11-727M10.1的下游靶基因；Amphiregulin诱导乳腺癌赫赛汀耐药的发生。据此，我们推测RP11-727M10.1可能通过Amphiregulin调控乳腺癌赫赛汀耐药性。本研究拟采用过表达/沉默及挽救策略，以RP11-727M10.1为切入点、Amphiregulin为机制主线，系统评判RP11-727M10.1通过Amphiregulin调控乳腺癌耐药性的作用与机制。本研究将有助于阐明乳腺癌赫赛汀耐药的分子机制，并有可能为HER2+乳腺癌的诊疗提供新的思路。

人类表皮生长因子受体 2（human epidermal growth factor 2, HER2）是乳腺癌中常见的过表达蛋白，在浸润性乳腺癌中高达 20%，整体而言 HER2 阳性的乳腺癌病人预后较差。曲妥珠单抗等针对 HER2 受体开发的靶向药物，目前已广泛用于 HER2 阳性乳腺癌患者的治疗，并获得较好的临床疗效。但是，越来越多的临床数据表明，HER2 阳性乳腺癌患者在接受靶向治疗1年内容易产生耐药，导致治疗失败、预后较差，5年生存率不到 40%。近年来，关于 HER2 靶向治疗耐药机制的研究，已逐渐成为乳腺癌研究领域的热点。因此，积极寻找 HER2 靶向治疗耐药相关线索，将有可能指导临床改善 HER2 阳性乳腺癌靶向治疗耐药患者的诊疗方案。. RP11-727M10.1 是我们前期筛选赫赛汀耐药和赫赛汀敏感的乳腺癌组织的差异表达 lncRNA。我们前期研究发现与赫赛汀敏感组织/细胞相比，RP11-727M10.1 在赫赛汀耐药组织/细胞中显著低表达；RP11-727M10.1 过表达显著增加 HER2+细胞株对赫赛汀的敏感性；生物信息学分析及实验结果初步表明Amphiregulin 可能是 RP11-727M10.1 的下游靶基因；文献和实验结果均证实Amphiregulin 过表达可显著增强 HER2+细胞的赫赛汀耐药能力。以上结果表明RP11-727M10.1 可能通过Amphiregulin 调控 HER2+乳腺癌细胞的赫赛汀耐药能力。. 本研究以 Amphiregulin 为机制主线，通过挽救策略、RIP、RNA pull down 等多种技术探讨其可能的作用机制，有助于阐明RP11-727M10.1的生物学特征，有助于理解RP11-727M10.1在 Herceptin 耐药中的作用及分子机制，并可能为 HER2 靶向治疗耐药提供新线索和潜在的干预靶标。