Liu Wenbo, Li Yong, Fan Liqiao, Zhang Mingming, Zhao Xiaohan, Song Yanru, Huo Bingjie, Wang Bingyu, Wang Yingying, Song Chao, Song Buyun, Tan Bibo
Third Department of Surgery, The Fourth Hospital of Hebei Medical University Shijiazhuang 050011, Hebei, China.
Clinical Medicine Research Center, Hebei General Hospital Shijiazhuang 050051, Hebei, China.
Am J Cancer Res. 2024 Nov 15;14(11):5286-5303. doi: 10.62347/BVFO4627. eCollection 2024.
The emergence of immune resistance and a lack of effective therapeutic targets have become significant challenges in immunotherapy, highlighting the urgent need for new molecular markers and treatment targets. Moreover, the significance and mechanisms of PGRN (Progranulin) in gastric cancer remain ambiguous.
To identify differentially expressed proteins in gastric cancer and elucidate the function and mechanism of PGRN.
The data-independent acquisition proteomics was used to identify the differentially expressed proteins in gastric adenocarcinoma and the corresponding paraneoplastic tissues, providing a comprehensive dataset of gastric cancer-related proteins. The function and mechanism of PGRN in gastric cancer were further explored using a series of experiments, including RT-qPCR (Real Time-Quantitative Polymerase Chain Reaction), cell transfection, cell viability assays, cell scratch, immunohistochemistry and Transwell assays, Western blot, and a mouse tumor-bearing model. These investigations were combined with bioinformatics analyses to examine the relationship between PGRN expression and clinical-pathological characteristics, confirming its high expression of PGRN in gastric cancer tissues.
We identified a large number of differentially expressed proteins between gastric cancer and adjacent tissues and conducted an initial functional analysis. Further studies on PGRN showed that it was associated with gastric cancer prognosis and lymph node metastasis. The inhibition of PGRN expression led to reduced cell viability, migration, and invasion, with corresponding changes in related genes and proteins. In a mouse tumor-bearing model, the tumor growth of the subcutaneously transplanted tumors in nude mice was reduced after the inhibition of PGRN expression. An in-depth functional analysis of PGRN was performed using bioinformatics to predict protein interactions, miRNA regulation, and relationships with multiple immune cell types. Enrichment analysis indicated that PGRN is involved in multiple signaling pathways, with the MAPK (Mitogen-Activated Protein Kinase) pathway selected for validation. In AGS and HGC27 cells, PGRN inhibition led to increased expression of phosphorylated p38 (p-p38) in the MAPK pathway, suggesting that PGRN may promote gastric cancer development by regulating p-p38.
This study identified significant differences in protein expression between gastric adenocarcinoma and adjacent tissues, with PGRN emerging as a key protein influencing gastric cancer proliferation, migration, and invasion. These findings suggest that PGRN could serve as a potential therapeutic target for gastric cancer.
免疫抗性的出现以及缺乏有效的治疗靶点已成为免疫治疗中的重大挑战，凸显了对新分子标志物和治疗靶点的迫切需求。此外，颗粒蛋白前体（Progranulin，PGRN）在胃癌中的意义和机制仍不明确。
鉴定胃癌中差异表达的蛋白质，并阐明PGRN的功能和机制。
采用数据非依赖采集蛋白质组学技术鉴定胃腺癌及相应癌旁组织中差异表达的蛋白质，提供一个全面的胃癌相关蛋白质数据集。使用一系列实验进一步探究PGRN在胃癌中的功能和机制，包括实时定量聚合酶链反应（RT-qPCR）、细胞转染、细胞活力测定、细胞划痕实验、免疫组织化学和Transwell实验、蛋白质免疫印迹法以及小鼠荷瘤模型。这些研究结合生物信息学分析来检测PGRN表达与临床病理特征之间的关系，证实其在胃癌组织中高表达。
我们鉴定出胃癌组织与相邻组织之间大量差异表达的蛋白质，并进行了初步的功能分析。对PGRN的进一步研究表明，它与胃癌预后和淋巴结转移相关。抑制PGRN表达导致细胞活力、迁移和侵袭能力降低，相关基因和蛋白质也发生相应变化。在小鼠荷瘤模型中，抑制PGRN表达后裸鼠皮下移植瘤的肿瘤生长减缓。利用生物信息学对PGRN进行深入的功能分析，以预测蛋白质相互作用、微小RNA调控以及与多种免疫细胞类型的关系。富集分析表明，PGRN参与多个信号通路，选择丝裂原活化蛋白激酶（MAPK）通路进行验证。在AGS和HGC27细胞中，抑制PGRN导致MAPK通路中磷酸化p38（p-p38）表达增加，提示PGRN可能通过调节p-p38促进胃癌发展。
本研究鉴定出胃腺癌与相邻组织之间蛋白质表达的显著差异，PGRN成为影响胃癌增殖、迁移和侵袭的关键蛋白质。这些发现表明，PGRN可能成为胃癌的潜在治疗靶点。
