Identification of basement membrane-related prognostic model associated with the immune microenvironment and synthetic therapy response in pancreatic cancer: integrated bioinformatics analysis and clinical validation.
IF 4.3 3区 材料科学Q1 ENGINEERING, ELECTRICAL & ELECTRONIC
{"title":"Identification of basement membrane-related prognostic model associated with the immune microenvironment and synthetic therapy response in pancreatic cancer: integrated bioinformatics analysis and clinical validation.","authors":"Biao Zhang, Xu Chen, Huiyi Song, Xue Gao, Shurong Ma, Hongying Ji, Huixian Qu, Shilin Xia, Dong Shang","doi":"10.7150/jca.100891","DOIUrl":null,"url":null,"abstract":"<p><p>Pancreatic cancer (PC) is a common and highly malignant tumor. Basement membrane (BM) is formed by the crosslinking of extracellular matrix macromolecules and acts as a barrier against tumor cell metastasis. However, the role of BM in PC prognosis, immune infiltration, and treatment remains unclear. This study collected transcriptome and clinical survival data of PC via TCGA, GEO, and ICGC databases. PC patients (PCs) from the First Affiliated Hospital of Dalian Medical University were obtained as the clinical validation cohort. BM-related genes (BMRGs) were acquired from GeneCards and basement membraneBASE databases. A total of 46 differential-expressed BMRGs were identified. Then the BM-related prognostic model (including DSG3, MET, and PLAU) was built and validated. PCs with a low BM-related score had a better outcome and were more likely to benefit from oxaliplatin, irinotecan, and KRAS(G12C) inhibitor-12, and immunotherapy. Immune analysis revealed that BM-related score was positively correlated with neutrophils, cancer-associated fibroblasts, and macrophages infiltration, but negatively correlated with CD8+ T cells, NK cells, and B cells infiltration. PCs from the clinical cohort further verified that BM-related model could accurately predict PCs' outcomes. DSG3, MET, and PLAU were notably up-regulated within PC tissues and linked to a poor prognosis. <i>In vitro</i> experiments showed that DSG3 knockdown markedly suppressed the proliferation, migration, and invasion of PC cells. Molecular docking indicated that epigallocatechin gallate had a strong binding activity with DSG3, MET, and PLAU and may be used as a potential therapeutic agent for PC. In conclusion, this study developed a BM-related model associated with PC prognosis, immune infiltration, and treatment, which provided new insights into PC stratification and drug intervention.</p>","PeriodicalId":3,"journal":{"name":"ACS Applied Electronic Materials","volume":null,"pages":null},"PeriodicalIF":4.3000,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11540510/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"ACS Applied Electronic Materials","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.7150/jca.100891","RegionNum":3,"RegionCategory":"材料科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/1/1 0:00:00","PubModel":"eCollection","JCR":"Q1","JCRName":"ENGINEERING, ELECTRICAL & ELECTRONIC","Score":null,"Total":0}
引用次数: 0
Abstract
Pancreatic cancer (PC) is a common and highly malignant tumor. Basement membrane (BM) is formed by the crosslinking of extracellular matrix macromolecules and acts as a barrier against tumor cell metastasis. However, the role of BM in PC prognosis, immune infiltration, and treatment remains unclear. This study collected transcriptome and clinical survival data of PC via TCGA, GEO, and ICGC databases. PC patients (PCs) from the First Affiliated Hospital of Dalian Medical University were obtained as the clinical validation cohort. BM-related genes (BMRGs) were acquired from GeneCards and basement membraneBASE databases. A total of 46 differential-expressed BMRGs were identified. Then the BM-related prognostic model (including DSG3, MET, and PLAU) was built and validated. PCs with a low BM-related score had a better outcome and were more likely to benefit from oxaliplatin, irinotecan, and KRAS(G12C) inhibitor-12, and immunotherapy. Immune analysis revealed that BM-related score was positively correlated with neutrophils, cancer-associated fibroblasts, and macrophages infiltration, but negatively correlated with CD8+ T cells, NK cells, and B cells infiltration. PCs from the clinical cohort further verified that BM-related model could accurately predict PCs' outcomes. DSG3, MET, and PLAU were notably up-regulated within PC tissues and linked to a poor prognosis. In vitro experiments showed that DSG3 knockdown markedly suppressed the proliferation, migration, and invasion of PC cells. Molecular docking indicated that epigallocatechin gallate had a strong binding activity with DSG3, MET, and PLAU and may be used as a potential therapeutic agent for PC. In conclusion, this study developed a BM-related model associated with PC prognosis, immune infiltration, and treatment, which provided new insights into PC stratification and drug intervention.
胰腺癌（PC）是一种常见的高度恶性肿瘤。基底膜（BM）由细胞外基质大分子交联形成，是防止肿瘤细胞转移的屏障。然而，基底膜在 PC 预后、免疫浸润和治疗中的作用仍不清楚。本研究通过TCGA、GEO和ICGC数据库收集了PC的转录组和临床生存数据。大连医科大学附属第一医院的 PC 患者作为临床验证队列。基底膜相关基因（BMRGs）来自 GeneCards 和 basement membraneBASE 数据库。共鉴定出 46 个差异表达的 BMRGs。然后建立并验证了BM相关预后模型（包括DSG3、MET和PLAU）。BM相关评分低的PC预后较好，更有可能从奥沙利铂、伊立替康、KRAS（G12C）抑制剂-12和免疫疗法中获益。免疫分析显示，BM相关评分与中性粒细胞、癌相关成纤维细胞和巨噬细胞浸润呈正相关，但与CD8+ T细胞、NK细胞和B细胞浸润呈负相关。临床队列中的 PC 进一步验证了 BM 相关模型可以准确预测 PC 的预后。DSG3、MET和PLAU在PC组织中明显上调，并与不良预后有关。体外实验表明，敲除DSG3能明显抑制PC细胞的增殖、迁移和侵袭。分子对接表明，表没食子儿茶素没食子酸酯与DSG3、MET和PLAU有很强的结合活性，可作为治疗PC的潜在药物。总之，本研究建立了一个与PC预后、免疫浸润和治疗相关的BM相关模型，为PC分层和药物干预提供了新的见解。
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号
