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众所周知，三阴性乳腺癌是一类具有高度差异性的恶性肿瘤，根据不同特征可被进一步分为各种亚型。不过，控制三阴性乳腺癌基因转录后核糖核酸化学修饰的可变多腺苷酸化特征尚不明确。 2020年12月，常春藤旗下《治疗诊断学》第10卷第23期将正式发表复旦大学附属肿瘤医院王磊、郎冠天、杨柳、陈力、姚玲、李小光、胡欣、邵志敏、中国科学院上海高等研究院干细胞与纳米医学研究中心薛梦竹、中国科学院上海营养与健康研究所王鹏等学者的研究报告，剖析了三阴性乳腺癌基因转录后核糖核酸化学修饰水平的可变多腺苷酸化特征。 该研究首先利用转录组微阵列数据，对复旦大学附属肿瘤医院165例三阴性乳腺癌标本和33例配对正常组织的可变多腺苷酸化特征进行分析。随后，对23个核心切割和多腺苷酸化基因短发夹核糖核酸进行汇总筛选，以确定关键核心切割和多腺苷酸化因子。 结果，确定了由四种稳定亚型组成的非常规可变多腺苷酸化亚型：
抑制亚型患者与其他亚型患者相比，无病生存显著较差（对数秩P=0.021）。 对四种可变多腺苷酸化亚型的临床可靶向通路和可变多腺苷酸化事件进行分析，进一步发现核心切割和多腺苷酸化特异因子CPSF1和多腺苷酸化结合核蛋白PABPN1为控制其他多腺苷酸化事件和三阴性乳腺癌转移的主要核心切割和多腺苷酸化因子。 利用CPSF1或PABPN1靶向抑制剂可减少细胞增殖、增加细胞凋亡，引起细胞周期重新分布，并逆转乳腺癌肿瘤形成、增殖、转移、化疗敏感性相关基因的其他多腺苷酸化事件。 因此，该研究结果揭示了可变多腺苷酸化对三阴性乳腺癌肿瘤差异性的控制，并为发现三阴性乳腺癌靶向治疗的新靶点奠定了基础。 相关链接 Theranostics. 2020 Aug 21;10(23):10531-10547. Dissecting the heterogeneity of the alternative polyadenylation profiles in triple-negative breast cancers. Wang L, Lang GT, Xue MZ, Yang L, Chen L, Yao L, Li XG, Wang P, Hu X, Shao ZM. Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China; Shanghai Medical College, Fudan University, Shanghai, China; Institutes of Biomedical Sciences, Fudan University, Shanghai, China; Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai, China; Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China; School of Life Science and Technology, ShanghaiTech University, Shanghai, China. BACKGROUND: Triple-negative breast cancer (TNBC) is an aggressive malignancy with high heterogeneity. However, the alternative polyadenylation (APA) profiles of TNBC remain unknown. Here, we aimed to define the characteristics of the APA events at post-transcription level among TNBCs. METHODS: Using transcriptome microarray data, we analyzed APA profiles of 165 TNBC samples and 33 paired normal tissues. A pooled short hairpin RNA screen targeting 23 core cleavage and polyadenylation (C/P) genes was used to identify key C/P factors. RESULTS: We established an unconventional APA subtyping system composed of four stable subtypes: 1) luminal androgen receptor (LAR), 2) mesenchymal-like immune-activated (MLIA), 3) basal-like (BL), 4) suppressed (S) subtypes. Patients in the S subtype had the worst disease-free survival comparing to other patients (log-rank p = 0.021). Enriched clinically actionable pathways and putative therapeutic APA events were analyzed among each APA subtype. Furthermore, CPSF1 and PABPN1 were identified as the master C/P factors in regulating APA events and TNBC proliferation. The depletion of CPSF1 or PABPN1 weakened cell proliferation, enhanced apoptosis, resulted in cell cycle redistribution and a reversion of APA events of genes associated with tumorigenesis, proliferation, metastasis and chemosensitivity in breast cancer. CONCLUSIONS: Our findings advance the understanding of tumor heterogeneity regulation in APA and yield new insights into therapeutic target identification in TNBC. KEYWORDS: CPSF1; PABPN1; alternative polyadenylation; subtype; triple-negative breast cancer PMID: 32929364 PMCID: PMC7482814 DOI: 10.7150/thno.40944
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