circRNA已被证实在多种癌症的发生发展中发挥关键作用;然而，在胰腺癌中缺氧诱导的外泌体环状rna的生物学功能和分子机制仍不清楚。

通过RNA测序证实了PC细胞中低氧和常氧外泌体外泌体中环状RNA的差异表达。采用qRT-PCR和ISH检测circPDK1在PC肿瘤和PC患者中的表达，并通过一系列体内外实验验证circPDK1在PC中的生物学功能。通过Western blotting、Co-IP、RNA下拉、ChIP、RIP、双荧光素酶分析和拯救实验，验证了circPDK1的潜在机制。

CircPDK1在PC肿瘤组织和血清外泌体中高度丰富，与较差的生存率相关。外泌体circPDK1在体内外均显著促进PC细胞增殖、迁移和糖酵解。机制上，circPDK1可以在转录水平上被HIF1A激活，并通过海绵miR-628-3p激活BPTF/c-myc轴。此外，circPDK1作为支架，增强UBE2O与BIN1的相互作用，诱导UBE2O介导的BIN1降解。我们发现circPDK1通过调节miR-628-3p/BPTF轴和降解BIN1在转录水平被HIF1A激活。外泌体circPDK1是PC诊断和预后的一个很有前途的生物标志物，是PC潜在的治疗靶点。

Abstract

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.

原文链接

https://pubmed.ncbi.nlm.nih.gov/36068586/

百度浏览   来源 : 医微客   

版权声明：本网站所有注明来源“医微客”的文字、图片和音视频资料，版权均属于医微客所有，非经授权，任何媒体、网站或个人不得转载，授权转载时须注明来源：”医微客”。本网所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，转载仅作观点分享，版权归原作者所有。不希望被转载的媒体或个人可与我们联系，我们将立即进行删除处理。 本站拥有对此声明的最终解释权。