MicroRNAs调控解偶联蛋白2的表达及对乳腺癌发生发展和内分泌治疗药物抵抗的作用

Breast cancer is the most common invasive cancer in women with a high morbidity and mortality. Tamoxifen is the standard endocrine therapy as a selective estrogen receptor modulator (SERM) in breast cancer. However, a proportion of patients become resistant to tamoxifen therapy. Therefore, better understanding the mechanisms underlying tamoxifen resistance is of great clinical significance. Uncoupling protein-2 (UCP2) is a mitochondrial protein that inhibits cell apoptosis by reducing the production of reactive oxygen species (ROS) in response to oxidative stress. Recently UCP2 has been found to be overexpressed in breast cancer. However, whether UCP2 plays a role in the development of breast cancer and tamoxifen resistance is not clear. In this study, UCP2 expression and regulation by miRNAs were investigated in paired breast cancer tissues and breast cells. The role of UCP2 in oxidative stress induced cell apoptosis is explored by overexpression or knockdown of UCP2. Furthermore, the apoptotic pathway mediated by mitochondria or endoplasmic reticulum is determined. Tamoxifen resistance is possibly associated with genes or miRNAs that regulates cell apoptosis and proliferation. Finally, the regulatory role of UCP2 by miRNAs in tamoxifen resistance is elucidated. This may suggest novel strategies to overcome tamoxifen resistance and provide therapeutic options for breast cancer patients.

乳腺癌是严重危害女性健康的常见肿瘤，其发病率和死亡率逐年升高，然而随着乳腺癌内分泌治疗药物雌激素受体调节剂它莫昔芬（TAM）的应用，药物抵抗现象越来越普遍，成为限制TAM临床治疗的瓶颈。解偶联蛋白2（UCP2）是线粒体膜蛋白，通过抑制氧化应激诱导活性氧（ROS）产生而抑制细胞凋亡。最近发现UCP2在乳腺癌中高表达，但UCP2在乳腺癌发生发展中的作用以及对TAM治疗抵抗的影响，目前尚未报道。因此，本研究从乳腺癌组织和细胞出发，探讨UCP2在乳腺癌中表达和乳腺癌进展的关系，并从细胞水平证实UCP2受miRNAs转录后调控。进一步通过基因过表达或敲减干扰UCP2表达，阐明UCP2在氧化应激和TAM治疗引起细胞凋亡中的作用及凋亡途径，揭示miRNAs可能通过调控UCP2表达影响TAM治疗敏感性，这不但为降低TAM抵抗增强药物敏感性开辟了新的思路，而且为临床治疗乳腺癌提供新的靶点和潜在应用价值。

乳腺癌是世界上严重危害女性健康的常见妇科恶性肿瘤，其发病率和死亡率逐年升高，然而随着乳腺癌内分泌治疗药物雌激素受体调节剂他莫昔芬（TAM）和氟维司群（FUL）的应用，内分泌药物抵抗已经成为限制乳腺癌病人成功治疗的瓶颈。本研究主要探讨了内分泌药物抵抗的分子机制，寻求降低TAM和FUL药物抵抗的治疗策略。因此，本项目从雌激素受体阳性和TAM敏感的MCF-7细胞和抗雌激素抵抗的MCF-7/LCC9细胞以及配对的乳腺癌组织出发，探讨miRNAs对UCP2的调控及其在内分泌药物抵抗中的作用。结果表明4-OHT和FUL诱导乳腺癌细胞凋亡和自噬，细胞自噬可能是发生内分泌药物4-OHT和FUL抵抗的主要原因。MiR-214通过抑制细胞自噬提高了4-OHT和FUL诱导的乳腺癌细胞凋亡。进一步在配对的乳腺癌组织标本中研究发现miR-214和UCP2表达存在负相关，并在细胞水平证实UCP2是miR-214的靶基因。更为重要的是，在MCF-7/LCC9细胞中，过表达UCP2促进了细胞自噬并通过激活PI3K-Akt-mTOR信号途径调控内分泌药物敏感性。总之，miR-214通过调控靶基因UCP2抑制细胞自噬增加了乳腺癌细胞对于TAM和FUL的药物敏感性，这不但为降低内分泌治疗药物抵抗开辟了新的思路，而且MiR-214可能作为克服ER+乳腺癌内分泌抵抗的潜在治疗靶点，为临床增强药物敏感性奠定了理论基础和潜在应用价值。