三阴性乳腺癌是乳腺癌领域的治疗难点。铂类是三阴性乳腺癌治疗的一线药物，但多数患者治疗后仍出现耐药。小核仁RNA（snoRNA）参与肿瘤发生发展并可通过血浆检测。课题组前期研究发现，顺铂耐药的三阴性乳腺癌细胞SNORD33低表达，血浆SNORD33低水平的患者铂类治疗疗效不佳；下调SNORD33的细胞表现为顺铂耐药，凋亡减少；未见其宿主基因及miRNA样作用参与调控铂类敏感性，而发现SNORD33可与甲基CpG结合蛋白2（MeCP2）结合。提示SNORD33可能通过与MeCP2结合，调控下游凋亡相关靶基因转录，影响铂类敏感性。本项目拟结合使用分子生物学技术、小鼠原位肿瘤及PDX模型等手段，深入研究SNORD33通过与MeCP2相互作用、干扰铂类药物作用等机制影响铂类耐药，并探索其作为预测疗效及提高铂类敏感性靶点的可行性。以期丰富对snoRNA这种非编码RNA的认知，拓展其临床应用价值。

Triple-negative breast cancer (TNBC) represents a continuing challenge due to limited approaches of treatments. Platinum has a favorable efficacy in the treatment of TNBC. However, many patients relapse despite having received platinum therapy, and resistance inevitably develops. ..Small nucleolar RNAs (snoRNAs), a subclass of small non-coding RNAs with the function of rRNA modification and RNA slicing, play a crucial role in controlling cell behavior and carcinogenesis. snoRNAs can also be detected in plasma and is considered as potential non-invasive biomarkers for early cancer diagnosis and prognosis prediction. ..In our preliminary experiments, we found that small nucleolar RNA 33 (SNORD33) was significantly decreased in cisplatin-resistant TNBC cells. Patients with low plasma SNORD33 level showed worse efficacy of cisplatin. Downregulation of SNORD33 promoted the resistance of cisplatin in TNBC cells, and inhibited cell apoptosis. Despite no changes have been found in resistance of cisplatin due to interfering host gene or slicing to miRNA-like fragments, we found that SNORD33 could bind to methyl-CpG binding protein 2 (MeCP2).These data suggested that SNORD33 might interact with MeCP2 and regulate the transcription of target genes involving apoptosis pathway. ..In this proposal, we plan to investigate the interaction between SNORD33 and MeCP2 and interference of platinum. We will employ multidiscipline approaches encompassing biochemistry and molecular biology, breast tumor in situ model and patient-derived xenograft model to pursue our aims above. The proposed studies in this application will not only allow us to advance the knowledge of molecular mechanisms in snoRNA research, but may also produce new leads to predict efficacy and treat TNBC.