Objectives: Mesothelin (MSLN) is overexpressed in pancreatic ductal adenocarcinoma (PDAC), promoting cell proliferation, migration, and inhibiting apoptosis. While its oncogenic properties have been documented, the role of MSLN in regulating cellular senescence—a tumor-suppressive mechanism—has remained unexplored. This study is the first to identify and characterize a novel mesothelin-associated anti-senescence (MAAS) effect in PDAC.Methods: A proteogenomic analysis of PDAC tissue samples from the Clinical Proteomic Tumor Analysis Consortium (CPTAC) was performed to evaluate MSLN-associated senescence pathways using WebGestalt. Human and murine PDAC cell lines with modified MSLN expression were analyzed for senescence phenotypes via SA-β-gal staining, Western blotting of key regulators (P53, P21waf1, and P16ink4a), γH2AX immunoblotting, and IL-8 quantification using ELISA.Results: The CPTAC analysis revealed an inverse correlation between MSLN expression and DNA damage/repair pathways. MSLN-deficient cells exhibited classic senescence features—growth arrest, an enlarged morphology, and elevated SA-β-gal activity. The expression of P53, P21waf1, and P16ink4awas upregulated, alongside increased γH2AX levels, indicating the activation of the DNA damage response. IL-8 secretion was significantly higher in the MSLN knockdown cells and reduced in the MSLN-overexpressing cells, consistent with the modulation of the SASP. Notably, MSLN deficiency impaired cell viability without inducing overt cytotoxicity, supporting a shift toward senescence.Conclusions: Our findings uncover a previously unrecognized mechanism through which MSLN promotes tumor progression by suppressing senescence via P53-associated pathways. Targeting the MAAS pathway may offer a novel therapeutic strategy to restore tumor-suppressive senescence and enhance treatment efficacy in PDAC.
目的：间皮素（MSLN）在胰腺导管腺癌（PDAC）中过度表达，可促进细胞增殖、迁移并抑制细胞凋亡。尽管其致癌特性已有文献记载，但MSLN在调控细胞衰老（一种肿瘤抑制机制）中的作用尚未被探索。本研究首次在PDAC中发现并鉴定了一种新型的间皮素相关抗衰老（MAAS）效应。 方法：利用WebGestalt对来自临床蛋白质组肿瘤分析联盟（CPTAC）的PDAC组织样本进行蛋白质组学分析，以评估MSLN相关的衰老通路。通过SA-β-gal染色、关键调控因子（P53、P21waf1和P16ink4a）的Western blotting、γH2AX免疫印迹以及ELISA法检测IL-8水平，分析了MSLN表达被修饰的人源和鼠源PDAC细胞系的衰老表型。 结果：CPTAC分析显示MSLN表达与DNA损伤/修复通路呈负相关。MSLN缺陷细胞表现出典型的衰老特征——生长停滞、形态增大以及SA-β-gal活性升高。P53、P21waf1和P16ink4a的表达上调，同时γH2AX水平增加，表明DNA损伤反应被激活。在MSLN敲低细胞中IL-8分泌显著升高，而在MSLN过表达细胞中则降低，这与衰老相关分泌表型（SASP）的调节一致。值得注意的是，MSLN缺陷会损害细胞活力，但未引起明显的细胞毒性，支持其向衰老转变。 结论：我们的研究结果揭示了一种先前未被认识的机制，即MSLN通过P53相关通路抑制衰老，从而促进肿瘤进展。靶向MAAS通路可能为恢复肿瘤抑制性衰老并提高PDAC治疗效果提供一种新的治疗策略。
Mesothelin-Associated Anti-Senescence Through P53 in Pancreatic Ductal Adenocarcinoma
肿瘤(癌症)患者之家