LncRNA329作为新型乳腺抑癌基因的分子机制的研究

Approximately 1.7 million of new women breast cancers are diagnosed worldwide, accounting for 520,000 death annually. Targeted therapies have improved the clinical outcomes, but drug resistance and disease relapse occur frequently. Therefore, new targeted therapies are in urgent need. Long non-coding RNA (lncRNA) plays a critical role in breast cancer. LncRNA329 is a novel RNA transcript located in Chromosome 16q22.1, a region frequently deleted in breast cancer. Preliminary data from our laboratory have shown that the lncRNA329 was down-regulated in breast cancer. Targeted expression of lncRNA329 in breast cancer cells led to inhibition of cell proliferation and orthotopic tumor growth in nude mice. In these cells, p53 was activated with increased half-life. Our hypothesis is that lncRNA329 may suppress tumor growth by activating p53. In this study, we will examine the expression of lncRNA329 in breast cancer and determine the correlation of lncRNA329 expression with tumor growth and lymph node metastasis. Furthermore, we will use breast cancer cell models with targeted lncRNA329 expression or silencing to delineate the signaling pathway through which the lncRNA329 induces apoptosis and suppresses tumor growth. We will elucidate the molecular mechanism that lncRNA329 activates p53 and characterize the functional domain. This study will define lncRNA329 as a new tumor suppressor in breast cancer and a p53 activator, developing a novel target for targeted therapy of this disease.

全球每年新发女性乳腺癌达170万，死亡52万。目前广泛使用的靶向治疗取得一定疗效，但肿瘤抗药性和复发普遍存在，因此急需开发新的靶向治疗。长链非编码RNA（lncRNA）在乳腺癌发病中起重要作用。LncRNA329位于乳腺癌中频繁缺失的染色体16q22.1区，是一个新的RNA转录本。前期研究发现，lncRNA329在乳腺癌中表达下调，靶向表达lncRNA329抑制乳腺癌细胞增值及在裸鼠中成瘤性生长，其机制可能与lncRNA329激活p53，延长其半衰期有关。本研究拟确定lncRNA329在乳腺癌中的表达及与肿瘤生长转移的关系。进一步地，将用lncRNA329高表达与沉默的乳腺癌细胞模型，探讨lncRNA329诱导细胞凋亡、抑制肿瘤生长的信号途径，阐明lncRNA329激活p53的机制，并鉴定其功能域。本研究将率先鉴定一个新型lncRNA抑癌基因与p53激活因子，为乳腺癌的防治提供新靶点。

乳腺癌已成为重大的公共卫生健康问题，严重威胁女性的身心健康。目前广泛使用的靶向治疗取得一定疗效，但肿瘤抗药性和复发普遍存在，因此急需开发新的靶向治疗。长链非编码RNA（lncRNA）在乳腺癌发病中起重要作用。LncRNA329位于乳腺癌中频繁缺失的染色体16q22.1区，是一个新的RNA转录本。通过本项目研究发现，lncRNA329在乳腺癌中表达下调，用lncRNA329高表达与沉默的乳腺癌细胞模型，探讨lncRNA329诱导细胞凋亡、抑制肿瘤生长的信号途径，阐明lncRNA329激活p53的机制，并鉴定其功能域。本研究将率先鉴定一个新型lncRNA抑癌基因与p53激活因子，为乳腺癌的防治提供新靶点。