Chao Yvonne L, Zhou Katherine I, Forbes Kwame K, Porrello Alessandro, Gentile Gabrielle M, Zhu Yinzhou, Chack Aaron C, John Mary Dixcy J S, Liu Haizhou, Cockman Eric, Edatt Lincy, Goda Grant A, Zhao Justin J, Abou Assi Hala, Wiedner Hannah J, Tsai Yihsuan, Wilkinson Lily, Van Swearingen Amanda E D, Carey Lisa A, Giudice Jimena, Dominguez Daniel, Holley Christopher L, Pecot Chad V
University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA.
Division of Hematology & Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Nat Commun. 2025 May 2;16(1):4118. doi: 10.1038/s41467-025-59406-w.
Previously considered "housekeeping" genes, small nucleolar RNAs (snoRNAs) are increasingly understood to have wide-ranging functions in cancer, yet their role in metastasis has been less well studied. Here, we identify the snoRNA Snord67 as a regulator of lymph node (LN) metastasis in breast cancer. Snord67 expression is enriched in LN metastases in an immune-competent mouse model of female breast cancer. In an orthotopic breast cancer model, loss of Snord67 decreases LN metastasis. In a model of lymphatic metastasis, Snord67 loss decreases LN tumor growth and distant metastases. In breast cancer cell lines, Snord67 knockout results in loss of targeted 2'-O-methylation on U6 small nuclear RNA, as well as widespread changes in splicing. Together, these results demonstrate that Snord67 regulates splicing and promotes the growth of LN metastases and subsequent spread to distant metastases. SnoRNA-guided modifications of the spliceosome and regulation of splicing may represent a potentially targetable pathway in cancer.
小核仁RNA（snoRNAs）以前被认为是“管家”基因，现在人们越来越认识到它们在癌症中具有广泛的功能，但其在转移中的作用尚未得到充分研究。在这里，我们确定snoRNA Snord67是乳腺癌淋巴结（LN）转移的调节因子。在具有免疫活性的雌性乳腺癌小鼠模型中，Snord67的表达在LN转移灶中富集。在原位乳腺癌模型中，Snord67的缺失会减少LN转移。在淋巴转移模型中，Snord67的缺失会减少LN肿瘤生长和远处转移。在乳腺癌细胞系中，Snord67基因敲除导致U6小核RNA上靶向2'-O-甲基化的缺失，以及剪接的广泛变化。总之，这些结果表明Snord67调节剪接并促进LN转移灶的生长以及随后向远处转移的扩散。SnoRNA引导的剪接体修饰和剪接调节可能代表了癌症中一个潜在的可靶向途径。
