缺氧诱导的外泌体 circPDK1 通过调节 miR-628-3p/BPTF 轴和降解 BIN1 来激活 c-myc 促进胰腺癌糖酵解。

Hypoxia-induced exosomal circPDK1 promotes pancreatic cancer glycolysis via c-myc activation by modulating miR-628-3p/BPTF axis and degrading BIN1.

机构信息

Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Research Institute of Pancreatic Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

出版信息

J Hematol Oncol. 2022 Sep 6;15(1):128. doi: 10.1186/s13045-022-01348-7.

BACKGROUND

circRNA has been established to play a pivotal role in tumorigenesis development in a variety of cancers; nevertheless, the biological functions and molecular mechanisms of hypoxia-induced exosomal circRNAs in pancreatic cancer remain largely unknown.

METHODS

Differentially expressed circRNAs in exosomes between hypoxic exosomes and normoxic exosomes in PC cells were verified by RNA sequencing. The expression of circPDK1 in PC tumors and PC patients was evaluated by qRT-PCR and ISH, and the biological functions of circPDK1 in PC were verified through a series of in vitro and in vivo experiments. Using Western blotting, Co-IP, RNA pull-down, ChIP, RIP, dual-luciferase assays, and rescue experiments, the underlying mechanism of circPDK1 was verified.

RESULTS

CircPDK1 was highly abundant in PC tumor tissues and serum exosomes and was associated with poor survival. Exosomal circPDK1 significantly promoted PC cell proliferation, migration, and glycolysis both in vitro and in vivo. Mechanistically, circPDK1 could be activated by HIF1A at the transcriptional level and sponges miR-628-3p to activate the BPTF/c-myc axis. In addition, circPDK1 serves as a scaffold that enhances the interaction between UBE2O and BIN1, inducing the UBE2O-mediated degradation of BIN1.

CONCLUSIONS

We found that circPDK1 was activated by HIF1A at the transcriptional level by modulating the miR-628-3p/BPTF axis and degrading BIN1. Exosomal circPDK1 is a promising biomarker for PC diagnosis and prognosis and represents a potential therapeutic target for PC.

背景

circRNA 已被证明在多种癌症的肿瘤发生发展中发挥关键作用；然而，缺氧诱导的胰腺癌细胞外泌体 circRNAs 的生物学功能和分子机制在很大程度上仍然未知。

方法

通过 RNA 测序验证 PC 细胞中缺氧外泌体和常氧外泌体之间差异表达的 circRNA。通过 qRT-PCR 和原位杂交评估 circPDK1 在 PC 肿瘤和 PC 患者中的表达，通过一系列体外和体内实验验证 circPDK1 在 PC 中的生物学功能。通过 Western blot、Co-IP、RNA 下拉、ChIP、RIP、双荧光素酶报告基因实验和挽救实验验证 circPDK1 的潜在机制。

结果

circPDK1 在 PC 肿瘤组织和血清外泌体中高度丰富，与不良预后相关。外泌体 circPDK1 显著促进 PC 细胞在体外和体内的增殖、迁移和糖酵解。机制上，circPDK1 可被 HIF1A 在转录水平激活，并通过海绵 miR-628-3p 激活 BPTF/c-myc 轴。此外，circPDK1 作为一种支架，增强了 UBE2O 和 BIN1 之间的相互作用，诱导 UBE2O 介导的 BIN1 降解。