SNORA51-DKC1通过RPL23-MDM2-p53轴介导乳腺癌干细胞生物学特性分子机制的研究

乳腺癌干细胞（BCSCs）与乳腺癌的发生发展及转移复发密切相关，介导BCSCs生物学特性的相关分子机制尚不明确。SnoRNAs是肿瘤领域研究热点之一。课题组前期通过snoRNAs芯片检测到BCSCs中SNORA51高表达，与DKC1蛋白结合形成snoRNP，与BCSCs的干性密切相关。前期研究中乳腺癌细胞过表达SNORA51后p53表达下调、SOX2表达上调。本研究旨在探索SNORA51影响BCSCs干性的分子机制。我们前期发现干预SNORA51后BCSCs干性发生改变，且在此过程中p53与SOX2启动子关键位点结合从而调控转录，影响SOX2的表达，本研究拟进一步明确“SNORA51与DKC1形成的snoRNP通过影响核糖体蛋白RPL23的表达调节MDM2和p53泛素化介导BCSCs的干性”的研究假说，为深入研究BCSCs干性维持机制提供新的思路，为乳腺癌的治疗寻找新靶点和提供有效线索。

Breast cancer stem cells (BCSCs) seem to be the key for understanding carcinogenesis and advancement of breast cancer. The underlying mechanism is not clear. Recent published studies showed that small-nucleolar RNAs (snoRNAs) play an important role in the acquisition of stemness of BCSCs. Our previous work demonstrated that SNORA51 (one of the snoRNA) was expressed at higher levels in BCSCs than that in breast cancer cells when quantified by using snoRNA microarray method. The snoRNP, which consists of snoRNAs and DKC1, is known to associate with acquisition of stemness of BCSCs. The SNORA51 is capable of promoting the stemness of BCSCs, while interference of SNORA51 attenuate stemness of BCSCs, most likely via the p53-p21 pathway as demonstrated by decreased SOX2 expression. We hypothesize that snoRNP (consisting of SNORA51 and DKC1) promotes BCSC stemness by regulating expression of ribosomal protein L23 (RPL23) through altered expression of MDM2 and p53 ubiquitination. The aim of this project, therefore, is to elucidate mechanism of BCSC stemness and identify potentially new therapeutic target for breast cancer treatment.