复旦大学张波等研究人员合作发现，G3BP2通过调控PDIA3-DKC1-hENT并依赖于应激颗粒的方式促进PDAC的肿瘤进展和吉西他滨耐药性。2024年9月17日，《中国药理学报》杂志在线发表了这项成果。

研究人员表示，胰腺导管腺癌（PDAC）以其侵袭性恶性、治疗手段有限以及化疗耐药性倾向为特征，这突显了开展深入研究以发现新治疗方法的迫切需求。应激颗粒（SG）作为一种涉及细胞自我保护机制的结构，其相关家族分子显示出促癌作用，并与肿瘤化疗耐药性密切相关。

研究人员探讨了SG核心成分——Ras GTP酶激活蛋白结合蛋白2（G3BP2）与PDAC恶性及其对化疗药物吉西他滨的耐药性之间的关系。通过分析TCGA数据集，研究人员发现G3BP1和G3BP2在PDAC中的表达显著上调，与邻近正常胰腺组织相比，高表达的G3BP2而非G3BP1与PDAC患者较差的总生存期（OS）显著相关。

研究人员证明了G3BP2的敲低抑制了PANC-1和CFPAC-1细胞在体内外的增殖和侵袭。通过分析G3BP2敲低和过表达的PANC-1细胞中差异表达的基因，研究人员确定了与RNA稳定性和调控相关的DKC1作为G3BP2的靶点。

研究人员证明G3BP2与PDIA3 mRNA结合并将其招募到SG中，增加了PDIA3 mRNA的稳定性并降低了其翻译效率，从而促进了DKC1的表达。此外，DKC1能够结合hENT mRNA并抑制其表达，这增强了PDAC对吉西他滨的耐药性。因此，研究人员提出了一种新机制，其中G3BP2通过以SG依赖的方式调节PDIA3-DKC1-hENT促进PDAC对化疗的耐药性，建议G3BP2及其SG作为PDAC治疗的潜在治疗靶点。

附：英文原文

Title: G3BP2 promotes tumor progression and gemcitabine resistance in PDAC via regulating PDIA3-DKC1-hENT in a stress granules-dependent manner

Author: Xing, Fa-liang, Li, Bo-rui, Fang, Ying-jin, Liang, Chen, Liu, Jiang, Wang, Wei, Xu, Jin, Yu, Xian-jun, Qin, Yi, Zhang, Bo

Issue&Volume: 2024-09-17

Abstract: Pancreatic ductal adenocarcinoma (PDAC) is distinguished by its aggressive malignancy, limited treatment avenues and a tendency towards chemotherapy resistance, underscoring the critical need for advanced research to uncover new therapeutic approaches. Stress granules (SGs) that is implicated in cellular self-protection mechanism, along with its associated family molecules have shown pro-cancer effects and are closely related to tumor chemotherapy resistance. In this study we investigated the relationship between Ras GTPase-activating protein-binding proteins 2 (G3BP2), a core component of SGs, and the malignancy of PDAC as well as its resistance to the chemotherapy drug gemcitabine. Analyzing TCGA dataset revealed that the expression of G3BP1 and G3BP2 was significantly upregulated in PDAC compared with adjacent normal pancreatic tissues, and the high expression of G3BP2 rather than G3BP1 was significantly associated with poorer overall survival (OS) in PDAC patients. We demonstrated that knockdown of G3BP2 inhibited the proliferation and invasion of PANC‐1 and CFPAC-1 cells in vitro and in vivo. By analyzing the differentially expressed genes in G3BP2 knockdown and overexpressed PANC‐1 cells, we identified DKC1 that was associated with RNA stability and regulation as the target of G3BP2. We demonstrated that G3BP2 bound to PDIA3 mRNA and recruited them into SGs, increasing the stability of PDIA3 mRNA and attenuating its translation efficiency, thereby promoting DKC1 expression. Furthermore, DKC1 could bind to hENT mRNA and inhibited its expression, which enhanced gemcitabine resistance of PDAC. Therefore, we propose a novel mechanism wherein G3BP2 facilitates PDAC’s resistance to chemotherapy by modulating PDIA3-DKC1-hENT in a SGs-dependent way, suggesting G3BP2 SGs a protentional therapeutic target for the treatment in PDAC.

DOI: 10.1038/s41401-024-01387-5

Source: https://www.nature.com/articles/s41401-024-01387-5