Department of Thoracic Surgery, Peking University People's Hospital, No. 11 Xizhimen South Street, Beijing, 100044, China.
Thoracic Oncology Institute, Peking University People's Hospital, Beijing, 100044, China.
Respir Res. 2023 Oct 25;24(1):252. doi: 10.1186/s12931-023-02563-7.
Emerging evidence indicates that circular RNAs (circRNAs) play vital roles in tumor progression, including lung adenocarcinomas (LUAD). However, the mechanisms by which circRNAs promote the progression of LUAD still require further investigation.
Quantitative real-time PCR was performed to detect the expression of circP4HB in LUAD tissues and cells. Then, Kaplan-Meier analysis was used to determine the prognostic value of circP4HB expression. We employed RNA pull-down, RNA immunoprecipitation, mass spectrometry, cells fraction, glucose consumption, lactate production, pyruvate kinase M2 (PKM2) activity, and macrophage polarization assays to uncover the underlying mechanisms of circP4HB in LUAD.
We found that circP4HB is upregulated in LUAD tissues and correlated with advanced TNM stages and lymph node metastasis. LUAD patients with high circP4HB expression had poor prognoses. Functionally, circP4HB promoted LUAD progression in vivo and in vitro. Upregulated circP4HB increased glucose consumption, lactate production and accelerated aerobic glycolysis in LUAD cells. Mechanically, circP4HB mainly accumulated in the cytoplasm of LUAD cells and bound with PKM2 and subsequently upregulating PKM2 enzymatic activity by increasing its tetramer formation. Additionally, circP4HB promoted M2 macrophage phenotype shift via targeting PKM2. Finally, rescue assays further confirmed that circP4HB could promote LUAD cell progression through its interaction with PKM2.
These results demonstrate that circP4HB could promote LUAD progression, indicating circP4HB might be a potential therapeutic target of LUAD.
新兴证据表明，环状 RNA（circRNA）在肿瘤进展中发挥重要作用，包括肺腺癌（LUAD）。然而，circRNA 促进 LUAD 进展的机制仍需要进一步研究。
采用定量实时 PCR 检测 LUAD 组织和细胞中 circP4HB 的表达。然后，采用 Kaplan-Meier 分析确定 circP4HB 表达的预后价值。我们采用 RNA 下拉、RNA 免疫沉淀、质谱、细胞分馏、葡萄糖消耗、乳酸生成、丙酮酸激酶 M2（PKM2）活性和巨噬细胞极化测定来揭示 circP4HB 在 LUAD 中的潜在机制。
我们发现 circP4HB 在 LUAD 组织中上调，并与晚期 TNM 分期和淋巴结转移相关。circP4HB 高表达的 LUAD 患者预后不良。功能上，circP4HB 在体内和体外促进 LUAD 的进展。上调的 circP4HB 增加了 LUAD 细胞的葡萄糖消耗、乳酸生成和加速有氧糖酵解。机制上，circP4HB 主要在 LUAD 细胞的细胞质中积累，并与 PKM2 结合，随后通过增加其四聚体形成来上调 PKM2 酶活性。此外，circP4HB 通过靶向 PKM2 促进 M2 巨噬细胞表型转变。最后，挽救实验进一步证实，circP4HB 可以通过与 PKM2 的相互作用促进 LUAD 细胞的进展。
这些结果表明，circP4HB 可以促进 LUAD 的进展，表明 circP4HB 可能是 LUAD 的潜在治疗靶点。
