多个非编码RNA共同调控POU3F2介导的乳腺癌耐受紫杉醇的作用机制研究及其临床意义

Breast cancer is the most common malignancy in women, and chemoresistance is responsible for the failure of most chemotherapeutic treatment. The mechanism of chemoresistance is so complicated that it remains elusive. Recent studies have reported that POU3F2 is a transcription factor which possesses oncogenic characteristics. We found that overexpression of POU3F2 was significantly correlated with drug resistance and poor prognosis of breast cancer patients by analyzing clinical data. Celluar experiments also demonstrated that down-regulation of POU3F2 effectively reduced paclitaxel resistance of breast cancer cells. Subsequent studies on mechanism identified that miR-204 and miR-27b directly down-regulated POU3F2 in breast cancer cells. Evidences indicate a pivotal role of lncRNA in POU3F2/miRNA networks. However, the specific mechanism remains unknown. Based on previous identification of the regulatory role of miR-204/miR-27b-POU3F2 in breast cancer resistant to PTX, we will next study lncRNA involved in modulation of miRNA, and finally confirm the regulatory role of lncRNA-miR-204/miR-27b-POU3F2 axis in paclitaxel resistance of breast cancer. This project will provide novel clues for elucidation of the mechanism about breast cancer drug resistance and development of effective therapeutic targets.

乳腺癌是女性最常见的恶性肿瘤，其化疗耐药是患者化疗失败的主要原因之一。由于耐药机制复杂，目前尚未研究透彻。新近报道POU3F2是具有促癌特性的转录因子。通过分析临床数据，我们发现POU3F2的过表达与乳腺癌患者的化疗耐药及不良预后显著相关。细胞实验也证实下调其表达可有效降低细胞对紫杉醇的耐药性。进一步的机制研究发现miR-204、miR-27b是直接调控POU3F2表达的关键miRNA。已有研究表明，lncRNA在POU3F2/miRNA调控网络中也起着重要作用，但具体机制尚不清楚。因此在明确miR-204/miR-27b-POU3F2对乳腺癌耐受紫杉醇的调控作用的基础上，进一步研究miRNA上游参与调控的lncRNA，以确定lncRNA-miR-204/miR-27b-POU3F2轴在乳腺癌耐受紫杉醇中的调控作用，为乳腺癌耐药机制的阐明以及有效治疗靶点的开发提供新思路。

乳腺癌是一种常见的恶性肿瘤，患者预后差。miRNA和lncRNA是一类内源性非编码RNA，其异常表达与肿瘤发生和进展相关。本研究通过系统生物信息学方法筛选，并开展一系列体内外实验，主要取得两方面成果。第一，证实了miRNA-27b及其靶蛋白CBLB/GRB2、lncRNA RP11-480I12.5-004及其靶点miR-29c-3p可以调控乳腺癌的耐药，并通过一系列研究阐述了两个调控轴“miRNA-27b-CBLB/GRB2-PI3K/AKT轴”和“RP11-480I12.5-004/miR-29c-3p/AKT3/CDK6轴”在乳腺癌耐药机制中的作用和表达受调机制，这些结果不仅可以为今后乳腺癌治疗、诊断和预后提供了潜在的靶点和有效的生物标志物，而且可以为未来研究非编码RNA的功能和作用机制提供思路和借鉴。第二，成功构建两大与乳腺癌耐药和进展相关的lcnRNA-miRNA-mRNA调控网络，为今后开发非编码RNA成为耐药逆转剂，解决乳腺癌耐药问题提供更多的选择和理论基础。