Abstract

Pancreatic ductal adenocarcinoma (PDAC) is recognized as the most aggressive and fatal malignancy. A previous study reported that PDAC patients who exhibit elevated levels of DDX3X have a poor prognosis and low overall survival rate. However, the underlying molecular mechanism remains unclear. This study aimed to investigate the specific roles of DDX3X in PDAC. Multiple bioinformatics analyses were used to evaluate DDX3X expression and its potential role in PDAC. In vitro and in vivo studies were performed to assess the effects of DDX3X on PDAC cell growth. Furthermore, Western blotting, quantitative PCR, immunohistochemistry, immunofluorescence, mass spectrometry, coimmunoprecipitation and multiplexed immunohistochemical staining were conducted to identify the specific regulatory mechanism in PDAC. The results verified that DDX3X expression is notably upregulated in the tumor tissue vs. normal tissue of PDAC patients. DDX3X knockdown markedly suppressed the proliferation, invasion and migration of PDAC cells in vitro and inhibited tumor growth in vivo. Conversely, overexpression of DDX3X induced the opposite effect. Further studies supported that the DDX3X protein can associate with sirtuin 7 (SIRT7) to stimulate PDAC carcinogenesis and progression. Furthermore, SIRT7 inhibition significantly impeded DDX3X-mediated tumor growth both ex vivo and in vivo. The results also revealed that programmed death ligand 1 (PD-L1) expression is positively correlated with DDX3X expression. These results reveal significant involvement of the DDX3X-SIRT7 axis in the initiation and advancement of PDAC and offer previously undiscovered therapeutic options for PDAC management.

中文翻译：

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DDX3X 与 SIRT7 相互作用促进 PD-L1 表达，促进 PDAC 进展

摘要

胰腺导管腺癌（PDAC）被认为是最具侵袭性和致命性的恶性肿瘤。先前的一项研究报告称，DDX3X 水平升高的 PDAC 患者预后较差，总生存率较低。然而，潜在的分子机制仍不清楚。本研究旨在探讨DDX3X在PDAC中的具体作用。使用多种生物信息学分析来评估 DDX3X 表达及其在 PDAC 中的潜在作用。进行体外和体内研究以评估 DDX3X 对 PDAC 细胞生长的影响。此外，还通过Western blotting、定量PCR、免疫组化、免疫荧光、质谱、免疫共沉淀和多重免疫组化染色来鉴定PDAC的具体调控机制。结果证实，与 PDAC 患者的正常组织相比，DDX3X 表达在肿瘤组织中显着上调。 DDX3X敲低在体外显着抑制PDAC细胞的增殖、侵袭和迁移，并在体内抑制肿瘤生长。相反，DDX3X 的过度表达会产生相反的效果。进一步的研究表明，DDX3X 蛋白可以与 Sirtuin 7 (SIRT7) 结合，刺激 PDAC 癌变和进展。此外，SIRT7 抑制显着阻止 DDX3X 介导的离体和体内肿瘤生长。结果还显示程序性死亡配体1（PD-L1）的表达与DDX3X的表达呈正相关。这些结果揭示了 DDX3X-SIRT7 轴在 PDAC 的启动和进展中的重要参与，并为 PDAC 管理提供了以前未被发现的治疗选择。