拉曼光谱揭示细胞周期蛋白Y通过调控脂质代谢促进乳腺癌进展的新机制

文献信息

中文摘要

拉曼光谱是一种通过在单细胞水平直接测量细胞代谢物的分子特征来进行疾病诊断和治疗评估的技术。然而，拉曼光谱在研究乳腺癌机制方面的应用仍然有限。细胞周期蛋白是细胞增殖活性的关键调节因子，在癌症中常常失调。尽管细胞周期蛋白Y（CCNY）作为一种关键细胞周期蛋白，在包括肺癌、肾癌、肝细胞癌、卵巢癌和喉癌在内的多种癌症中越来越被认为是癌基因，但CCNY对乳腺癌进展至关重要这一点仍不清楚。在此，我们研究CCNY在乳腺癌进展中的功能，重点关注对核酸水平和脂质代谢活性的调节。我们发现，在体外，CCNY缺失显著抑制DNA合成和纺锤体形成，并伴随乳腺癌细胞增殖减少和细胞周期停滞。CCNY缺失显著抑制小鼠模型和患者来源异种移植模型中的乳腺癌进展和转移。在机制上，单细胞拉曼光谱和RNA-seq揭示，CCNY通过调节关键细胞周期调节因子、核酸产生和代谢重编程来介导乳腺癌的进展。此外，高CCNY表达与乳腺癌不良预后相关。我们的发现揭示了CCNY通过调节核酸水平和脂质代谢活性在调控乳腺癌肿瘤进展中的关键作用，这表明探索靶向CCNY的治疗可能是未来乳腺癌治疗的一个潜在方向。

英文摘要

Raman spectroscopy is a technique for disease diagnosis and treatment evaluation through directly measuring the molecular features of cellular metabolites at the single-cell level. Nevertheless, the application of Raman spectroscopy in studying the mechanisms of breast cancer remains limited. Cyclins are critical regulators of cell proliferative activity that are often dysregulated in cancer. Although cyclin Y (CCNY), as a key cyclin, is increasingly recognized as an oncogene in various cancers, including lung, renal, hepatocellular, ovarian and laryngeal cancers, CCNY, which is essential for the progression of breast cancer, remains elusive. Here, we investigate the function of CCNY in breast cancer progression, focusing on the regulation of nucleic acid levels and lipid metabolism activity. We find that deletion of CCNY dramatically inhibits DNA synthesis and spindle formation coupled with reduced proliferation and arrested cell cycle of breast cancer cells in vitro. Loss of CCNY significantly suppresses breast cancer progression and metastasis in murine and patient-derived xenograft models. Mechanistically, single-cell Raman spectroscopy and RNA-seq reveal that CCNY mediates the progression of breast cancer by regulating key cell cycle regulators, nucleic acid production and metabolic reprogramming. Moreover, high CCNY expression is associated with poor prognosis in breast cancer. Our findings uncover a critical role of CCNY in regulating tumor progression of breast cancer through regulating nucleic acid levels and lipid metabolism activity, which suggests that exploring CCNY-targeted therapies could be a potential future direction for breast cancer treatment.