U2AF2-SNORA68 promotes triple-negative breast cancer stemness through the translocation of RPL23 from nucleoplasm to nucleolus and c-Myc expression

IF 6.1 1区 医学 Q1 ONCOLOGY Breast Cancer Research Pub Date : 2024-04-09 DOI:10.1186/s13058-024-01817-6
Wenrong Zhang, Xinyue Song, Zining Jin, Yiqi Zhang, Shan Li, Feng Jin, Ang Zheng
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Abstract

Small nucleolar RNAs (snoRNAs) play key roles in ribosome biosynthesis. However, the mechanism by which snoRNAs regulate cancer stemness remains to be fully elucidated. SNORA68 expression was evaluated in breast cancer tissues by in situ hybridization and qRT‒PCR. Proliferation, migration, apoptosis and stemness analyses were used to determine the role of SNORA68 in carcinogenesis and stemness maintenance. Mechanistically, RNA pull-down, RNA immunoprecipitation (RIP), cell fractionation and coimmunoprecipitation assays were conducted. SNORA68 exhibited high expression in triple-negative breast cancer (TNBC) and was significantly correlated with tumor size (P = 0.048), ki-67 level (P = 0.037), and TNM stage (P = 0.015). The plasma SNORA68 concentration was significantly lower in patients who achieved clinical benefit. The SNORA68-high patients had significantly shorter disease-free survival (DFS) (P = 0.036). Functionally, SNORA68 was found to promote the cell stemness and carcinogenesis of TNBC in vitro and in vivo. Furthermore, elevated SNORA68 expression led to increased nucleolar RPL23 expression and retained RPL23 in the nucleolus by binding U2AF2. RPL23 in the nucleolus subsequently upregulated c-Myc expression. This pathway was validated using a xenograft model. U2AF2-SNORA68 promotes TNBC stemness by retaining RPL23 in the nucleolus and increasing c-Myc expression, which provides new insight into the regulatory mechanism of stemness.
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U2AF2-SNORA68通过RPL23从核质到核仁的易位和c-Myc的表达促进三阴性乳腺癌干性的形成
小核RNA(snoRNA)在核糖体生物合成中发挥着关键作用。然而,snoRNA调控癌症干性的机制仍有待全面阐明。通过原位杂交和 qRT-PCR 技术评估了 SNORA68 在乳腺癌组织中的表达。增殖、迁移、凋亡和干性分析用于确定 SNORA68 在癌变和干性维持中的作用。从机制上讲,进行了 RNA 拉取、RNA 免疫沉淀(RIP)、细胞分馏和共免疫沉淀试验。SNORA68在三阴性乳腺癌(TNBC)中高表达,并与肿瘤大小(P = 0.048)、ki-67水平(P = 0.037)和TNM分期(P = 0.015)显著相关。临床获益患者的血浆 SNORA68 浓度明显较低。SNORA68高的患者无病生存期(DFS)明显较短(P = 0.036)。研究发现,SNORA68在体外和体内可促进TNBC的细胞干性和癌变。此外,SNORA68表达升高导致核仁RPL23表达增加,并通过结合U2AF2将RPL23保留在核仁中。核仁中的 RPL23 随后会上调 c-Myc 的表达。这一途径通过异种移植模型得到了验证。U2AF2-SNORA68通过将RPL23保留在核仁中并增加c-Myc的表达来促进TNBC干性,这为干性的调控机制提供了新的见解。
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来源期刊
Breast Cancer Research
Breast Cancer Research 医学-肿瘤学
自引率
0.00%
发文量
76
期刊介绍: Breast Cancer Research is an international, peer-reviewed online journal, publishing original research, reviews, editorials and reports. Open access research articles of exceptional interest are published in all areas of biology and medicine relevant to breast cancer, including normal mammary gland biology, with special emphasis on the genetic, biochemical, and cellular basis of breast cancer. In addition to basic research, the journal publishes preclinical, translational and clinical studies with a biological basis, including Phase I and Phase II trials.
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