胰腺导管腺癌 (PDAC) 的特点是侵袭性恶性肿瘤、有限的治疗途径以及化疗耐药的趋势，这凸显了迫切需要开展高级研究来发现新的治疗方法。参与细胞自我保护机制的应激颗粒（SG）及其相关家族分子已显示出促癌作用，并与肿瘤化疗耐药密切相关。在本研究中，我们研究了SGs的核心成分Ras GTP酶激活蛋白结合蛋白2（G3BP2）与PDAC的恶性及其对化疗药物吉西他滨的耐药性之间的关系。分析 TCGA 数据集显示，与邻近正常胰腺组织相比，PDAC 中 G3BP1 和 G3BP2 的表达显着上调，并且 G3BP2 而不是 G3BP1 的高表达与 PDAC 患者较差的总生存期 (OS) 显着相关。我们证明，G3BP2 的敲低可在体外和体内抑制 PANC-1 和 CFPAC-1 细胞的增殖和侵袭。通过分析G3BP2敲低和过表达PANC-1细胞中的差异表达基因，我们确定了与RNA稳定性和调节相关的DKC1作为G3BP2的靶点。我们证明G3BP2与PDIA3 mRNA结合并将其招募到SG中，增加PDIA3 mRNA的稳定性并减弱其翻译效率，从而促进DKC1表达。此外，DKC1可以与hENT mRNA结合并抑制其表达，从而增强PDAC的吉西他滨耐药性。因此，我们提出了一种新机制，其中 G3BP2 通过以 SG 依赖性方式调节 PDIA3-DKC1-hENT 来促进 PDAC 对化疗的耐药性，表明 G3BP2 SG 是 PDAC 治疗的潜在治疗靶点。© 2024。作者，经中国科学院上海药物研究所和中国药理学会独家授权。

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.© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.