Background/Objectives: Pancreatic ductal adenocarcinoma is a lethal malignancy, necessitating an understanding of its molecular mechanisms for the development of new therapeutic strategies. The tight junction protein claudin-1, known to influence cellular functions in various cancers and is considered a therapeutic target, remains unclear in pancreatic cancer. Methods: This study assessed claudin-1 expression in resected pancreatic cancer samples, public databases, and pancreatic cancer cell lines.Claudin-1knockout with CRISPR/Cas9 on poorly differentiated pancreatic cancer cell lines and a proteome analysis were performed to investigate the intracellular mechanisms of claudin-1. Results: Claudin-1 was markedly overexpressed in pancreatic ductal adenocarcinoma and intraepithelial neoplasia compared to normal ducts, and high claudin-1 levels were an independent predictor of poor prognosis.Claudin-1knockout diminished cell proliferation, migration, invasion, and chemoresistance in pancreatic ductal adenocarcinoma. Proteome analysis revealed the significant downregulation of aldo-keto reductase family proteins (AKR1C2, AKR1C3, and AKR1B1) inclaudin-1knockout cells, which are linked to metabolic pathways. Aldo-keto reductase knockdown reduced chemoresistance, proliferation, and invasion in these cell lines. Conclusions: These findings indicate that the abnormal expression of claudin-1 promotes tumor progression and drug resistance through its interaction with aldo-keto reductase proteins, highlighting claudin-1 and aldo-keto reductase family proteins as potential biomarkers and therapeutic targets for pancreatic cancer.
背景/目的：胰腺导管腺癌是一种致命性恶性肿瘤，亟需阐明其分子机制以开发新的治疗策略。紧密连接蛋白claudin-1已知在多种癌症中影响细胞功能，被视为潜在治疗靶点，但其在胰腺癌中的作用尚不明确。方法：本研究通过检测手术切除的胰腺癌样本、公共数据库及胰腺癌细胞系中claudin-1的表达水平，利用CRISPR/Cas9技术敲除低分化胰腺癌细胞系中的claudin-1基因，并结合蛋白质组学分析探究claudin-1的细胞内作用机制。结果：与正常导管组织相比，claudin-1在胰腺导管腺癌及导管内瘤变组织中显著过表达，且高表达水平是患者不良预后的独立预测因子。claudin-1敲除可抑制胰腺导管腺癌细胞的增殖、迁移、侵袭及化疗耐药性。蛋白质组学分析显示，敲除细胞中醛酮还原酶家族蛋白（AKR1C2、AKR1C3和AKR1B1）显著下调，这些蛋白与代谢通路密切相关。敲低醛酮还原酶可降低细胞系的化疗耐药性、增殖及侵袭能力。结论：本研究表明claudin-1通过调控醛酮还原酶蛋白促进肿瘤进展和耐药性，提示claudin-1及醛酮还原酶家族蛋白可作为胰腺癌潜在的生物标志物和治疗靶点。
肿瘤(癌症)患者之家