The m6A reader IGF2BP2 promotes pancreatic cancer progression through the m6A-SLC1A5-mTORC1 axis.

IF 5.3 2区医学 Q1 ONCOLOGY

Cancer Cell International Pub Date : 2025-03-29 DOI:10.1186/s12935-025-03736-8

Xi Pu, Yuting Wu, Weiguo Long, Xinyu Sun, Xiao Yuan, Deqiang Wang, Xu Wang, Min Xu

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引用次数: 0

Abstract

Background: Pancreatic cancer is a highly malignant digestive tumor. Glutamine metabolism is one of the important sources of tumors. N6-methyladenosine (m6A) modification plays a key role in regulating tumor metabolism and holds promise as a therapeutic target in various cancers, including pancreatic cancer. Disrupting m6A regulation of glutamine metabolism could impair tumor growth, offering potential new therapeutic strategies. However, the functional role of m6A modifications in pancreatic cancer, especially in glutamine metabolism, remains poorly understood.

Methods: The Cancer Genome Atlas (TCGA) dataset and GEPIA bioinformatics tool were used to identify the relationship between m6A related proteins and the glutamine metabolism-associated genes, respectively. The biological effects of insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) were investigated using in vitro and in vivo models. Methylated RNA immunoprecipitation sequencing (MeRIP-seq), MeRIP-PCR and RNA immunoprecipitation (RIP) were used to identify solute carrier family 1 member 5 (SLC1A5) as a direct target of IGF2BP2.

Results: We found that IGF2BP2 expression and SLC1A5 were significantly correlated and both highly expressed in pancreatic cancer could predict poor prognosis in patients with pancreatic cancer. Functionally, silencing IGF2BP2 suppressed tumor growth and also inhibited glutamine uptake by tumor cells. Mechanistically, IGF2BP2 induced the m6A-SLC1A5-mTORC1 axis, facilitating the uptake of glutamine by pancreatic cancer cells and accelerate the progress of pancreatic cancer. Furthermore, silencing IGF2BP2 can enhance the sensitivity of pancreatic cancer to radiotherapy and chemotherapy.

Conclusion: Our findings suggest that IGF2BP2 promotes pancreatic cancer by activating the m6A-SLC1A5 -mTORC1 axis. Targeting the m6A machinery, particularly IGF2BP2, offers a novel therapeutic avenue for pancreatic cancer treatment. By disrupting the regulation of glutamine metabolism, we provide new insights into how m6A-based therapies could enhance the efficacy of current treatments and offer hope for improving patient outcomes in this difficult-to-treat cancer.

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m6A 阅读器 IGF2BP2 通过 m6A-SLC1A5-mTORC1 轴促进胰腺癌的进展。

背景：胰腺癌是一种高度恶性的消化道肿瘤。谷氨酰胺代谢是肿瘤发生的重要来源之一。n6 -甲基腺苷（m6A）修饰在调节肿瘤代谢中起关键作用，有望成为包括胰腺癌在内的多种癌症的治疗靶点。破坏m6A对谷氨酰胺代谢的调节可能会损害肿瘤的生长，从而提供潜在的新治疗策略。然而，m6A修饰在胰腺癌中的功能作用，特别是在谷氨酰胺代谢中的作用，仍然知之甚少。方法：利用癌症基因组图谱（Cancer Genome Atlas， TCGA）数据集和GEPIA生物信息学工具，分别鉴定m6A相关蛋白与谷氨酰胺代谢相关基因的关系。采用体外和体内模型研究胰岛素样生长因子2 mrna结合蛋白2 （IGF2BP2）的生物学效应。采用甲基化RNA免疫沉淀测序（MeRIP-seq）、MeRIP-PCR和RNA免疫沉淀（RIP）技术鉴定溶质载体家族1成员5 （SLC1A5）是IGF2BP2的直接靶点。结果：我们发现IGF2BP2与SLC1A5表达显著相关，且在胰腺癌中均高表达，可预测胰腺癌患者预后不良。在功能上，沉默IGF2BP2抑制肿瘤生长，也抑制肿瘤细胞对谷氨酰胺的摄取。机制上，IGF2BP2诱导m6A-SLC1A5-mTORC1轴，促进胰腺癌细胞对谷氨酰胺的摄取，加速胰腺癌的进展。此外，沉默IGF2BP2可以增强胰腺癌对放疗和化疗的敏感性。结论：我们的研究结果表明IGF2BP2通过激活m6A-SLC1A5 -mTORC1轴促进胰腺癌。靶向m6A机制，特别是IGF2BP2，为胰腺癌治疗提供了新的治疗途径。通过破坏谷氨酰胺代谢的调节，我们为基于m6的疗法如何提高当前治疗的疗效提供了新的见解，并为改善这种难以治疗的癌症患者的预后提供了希望。

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 Cell International ONCOLOGY-

CiteScore

10.90

自引率

1.70%

发文量

360

审稿时长

1 months

期刊介绍： Cancer Cell International publishes articles on all aspects of cancer cell biology, originating largely from, but not limited to, work using cell culture techniques. The journal focuses on novel cancer studies reporting data from biological experiments performed on cells grown in vitro, in two- or three-dimensional systems, and/or in vivo (animal experiments). These types of experiments have provided crucial data in many fields, from cell proliferation and transformation, to epithelial-mesenchymal interaction, to apoptosis, and host immune response to tumors. Cancer Cell International also considers articles that focus on novel technologies or novel pathways in molecular analysis and on epidemiological studies that may affect patient care, as well as articles reporting translational cancer research studies where in vitro discoveries are bridged to the clinic. As such, the journal is interested in laboratory and animal studies reporting on novel biomarkers of tumor progression and response to therapy and on their applicability to human cancers.