Department of Breast Surgery, General Surgery, Qilu Hospital of Shandong University, Wenhua Xi Road No. 107, Jinan, Shandong, 250012, P.R. China.
Department of Breast Surgery, Mianyang Central Hospital, Mianyang, Sichuan, 621000, P.R. China.
Mol Cancer. 2024 Jun 8;23(1):125. doi: 10.1186/s12943-024-02037-4.
Breast cancer is the most common malignant tumor, and metastasis remains the major cause of poor prognosis. Glucose metabolic reprogramming is one of the prominent hallmarks in cancer, providing nutrients and energy to support dramatically elevated tumor growth and metastasis. Nevertheless, the potential mechanistic links between glycolysis and breast cancer progression have not been thoroughly elucidated.
RNA-seq analysis was used to identify glucose metabolism-related circRNAs. The expression of circSIPA1L3 in breast cancer tissues and serum was examined by qRT-PCR, and further assessed its diagnostic value. We also evaluated the prognostic potential of circSIPA1L3 by analyzing a cohort of 238 breast cancer patients. Gain- and loss-of-function experiments, transcriptomic analysis, and molecular biology experiments were conducted to explore the biological function and regulatory mechanism of circSIPA1L3.
Using RNA-seq analysis, circSIPA1L3 was identified as the critical mediator responsible for metabolic adaption upon energy stress. Gain- and loss-of-function experiments revealed that circSIPA1L3 exerted a stimulative effect on breast cancer progression and glycolysis, which could also be transported by exosomes and facilitated malignant behaviors among breast cancer cells. Significantly, the elevated lactate secretion caused by circSIPA1L3-mediated glycolysis enhancement promoted the recruitment of tumor associated macrophage and their tumor-promoting roles. Mechanistically, EIF4A3 induced the cyclization and cytoplasmic export of circSIPA1L3, which inhibited ubiquitin-mediated IGF2BP3 degradation through enhancing the UPS7-IGF2BP3 interaction. Furthermore, circSIPA1L3 increased mRNA stability of the lactate export carrier SLC16A1 and the glucose intake enhancer RAB11A through either strengthening their interaction with IGF2BP3 or sponging miR-665, leading to enhanced glycolytic metabolism. Clinically, elevated circSIPA1L3 expression indicated unfavorable prognosis base on the cohort of 238 breast cancer patients. Moreover, circSIPA1L3 was highly expressed in the serum of breast cancer patients and exhibited high diagnostic value for breast cancer patients.
Our study highlights the oncogenic role of circSIPA1L3 through mediating glucose metabolism, which might serve as a promising diagnostic and prognostic biomarker and potential therapeutic target for breast cancer.
乳腺癌是最常见的恶性肿瘤，转移仍然是预后不良的主要原因。葡萄糖代谢重编程是癌症的突出特征之一，为支持肿瘤生长和转移的急剧增加提供营养和能量。然而，糖酵解与乳腺癌进展之间的潜在机制联系尚未得到彻底阐明。
采用 RNA-seq 分析鉴定与葡萄糖代谢相关的 circRNAs。通过 qRT-PCR 检测乳腺癌组织和血清中 circSIPA1L3 的表达，并进一步评估其诊断价值。我们还通过分析 238 例乳腺癌患者的队列来评估 circSIPA1L3 的预后潜力。通过 gain- 和 loss-of-function 实验、转录组分析和分子生物学实验，探讨 circSIPA1L3 的生物学功能和调控机制。
利用 RNA-seq 分析，鉴定出 circSIPA1L3 是能量应激时代谢适应的关键调节因子。Gain- 和 loss-of-function 实验表明，circSIPA1L3 对乳腺癌的进展和糖酵解具有刺激作用，circSIPA1L3 还可以通过外泌体转运，并促进乳腺癌细胞之间的恶性行为。重要的是，circSIPA1L3 介导的糖酵解增强导致的乳酸分泌增加促进了肿瘤相关巨噬细胞的募集及其促进肿瘤的作用。机制上，EIF4A3 诱导 circSIPA1L3 的环化和细胞质输出，通过增强 UPS7-IGF2BP3 相互作用抑制泛素介导的 IGF2BP3 降解。此外，circSIPA1L3 通过增强与 IGF2BP3 的相互作用或海绵 miR-665 增加乳酸输出载体 SLC16A1 和葡萄糖摄取增强剂 RAB11A 的 mRNA 稳定性，从而增强糖酵解代谢。临床方面，根据 238 例乳腺癌患者的队列，circSIPA1L3 的高表达预示着不良预后。此外，circSIPA1L3 在乳腺癌患者的血清中高表达，对乳腺癌患者具有较高的诊断价值。
我们的研究通过调节葡萄糖代谢强调了 circSIPA1L3 的致癌作用，circSIPA1L3 可能成为有前途的诊断和预后生物标志物以及乳腺癌的潜在治疗靶点。
