CircRREB1 Mediates Metabolic Reprogramming and Stemness Maintenance to Facilitate Pancreatic Ductal Adenocarcinoma Progression

IF 12.5 1区医学 Q1 ONCOLOGY

Cancer research Pub Date : 2024-09-17 DOI:10.1158/0008-5472.can-23-3596

Zeyin Rong, Jin Xu, Jianhui Yang, Wei Wang, Rong Tang, Zifeng Zhang, Zhen Tan, Qingcai Meng, Jie Hua, Jiang Liu, Bo Zhang, Chen Liang, Xianjun Yu, Si Shi

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Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal tumor with limited treatment options and poor patient survival. Circular RNAs (circRNAs) play crucial regulatory roles in the occurrence and development of various cancers, including PDAC. Here, using circRNA sequencing of diverse PDAC samples, we identified circRREB1 as an oncogenic circRNA that is significantly upregulated in PDAC and is correlated with an unfavorable patient prognosis. Functionally, loss of circRREB1 markedly inhibited glycolysis and stemness, while elevated circRREB1 elicited the opposite effects. Mechanistically, circRREB1 interacted with PGK1, disrupting the association between PTEN and PGK1 and increasing PGK1 phosphorylation to activate glycolytic flux. Moreover, circRREB1 promoted WNT7B transcription by directly interacting with YBX1 and facilitating its nuclear translocation, consequently activating the Wnt/β-catenin signaling pathway to maintain PDAC stemness. Overall, these results highlight circRREB1 as a key regulator of metabolic and stemness properties of PDAC.

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CircRREB1 介导代谢重编程和干性维持，促进胰腺导管腺癌进展

胰腺导管腺癌（PDAC）是一种致死率极高的肿瘤，治疗方案有限，患者生存率低。环状 RNA（circRNA）在包括 PDAC 在内的各种癌症的发生和发展过程中发挥着至关重要的调控作用。在此，我们通过对不同的 PDAC 样本进行 circRNA 测序，发现 circRREB1 是一种致癌 circRNA，它在 PDAC 中显著上调，并与患者的不良预后相关。从功能上讲，circRREB1 的缺失会明显抑制糖酵解和干性，而 circRREB1 的升高则会产生相反的效果。从机理上讲，circRREB1与PGK1相互作用，破坏了PTEN与PGK1之间的关联，增加了PGK1的磷酸化，从而激活了糖酵解通量。此外，circRREB1通过直接与YBX1相互作用并促进其核转位，从而促进WNT7B的转录，进而激活Wnt/β-catenin信号通路，维持PDAC的干性。总之，这些结果凸显了circRREB1是PDAC代谢和干性特性的关键调控因子。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cancer research 医学-肿瘤学

CiteScore

16.10

自引率

0.90%

发文量

7677

审稿时长

2.5 months

期刊介绍： Cancer Research, published by the American Association for Cancer Research (AACR), is a journal that focuses on impactful original studies, reviews, and opinion pieces relevant to the broad cancer research community. Manuscripts that present conceptual or technological advances leading to insights into cancer biology are particularly sought after. The journal also places emphasis on convergence science, which involves bridging multiple distinct areas of cancer research. With primary subsections including Cancer Biology, Cancer Immunology, Cancer Metabolism and Molecular Mechanisms, Translational Cancer Biology, Cancer Landscapes, and Convergence Science, Cancer Research has a comprehensive scope. It is published twice a month and has one volume per year, with a print ISSN of 0008-5472 and an online ISSN of 1538-7445. Cancer Research is abstracted and/or indexed in various databases and platforms, including BIOSIS Previews (R) Database, MEDLINE, Current Contents/Life Sciences, Current Contents/Clinical Medicine, Science Citation Index, Scopus, and Web of Science.