Department of Biochemistry, School of Medicine, Wakayama Medical University, Wakayama, Japan.
Unité de Glycobiologie Structurale et Fonctionnelle, UMR 8576 CNRS, Université de Lille, Villeneuve d'Ascq, France.
Cancer Sci. 2024 Sep;115(9):2947-2960. doi: 10.1111/cas.16252. Epub 2024 Jun 21.
The tumor suppressor TP53 gene, the most frequently mutated gene in human cancers, produces the product tumor protein p53, which plays an essential role in DNA damage. p53 protein mutations may contribute to tumorigenesis by loss of tumor suppressive functions and malignancy of cancer cells via gain-of-oncogenic functions. We previously reported that mutant p53 proteins form aggregates and that cytoplasmic p53 aggregates were associated with poor prognosis in human ovarian cancer. However, the prognostic impact of p53 aggregation in other tumors including lung squamous cell carcinoma (SCC) is poorly understood. Here, we demonstrated that lung SCC cases with cytoplasmic p53 aggregates had a significantly poor clinical prognosis. Analysis via patient-derived tumor organoids (PDOs) established from lung SCC patients and possessing cytoplasmic p53 aggregates showed that eliminating cytoplasmic p53 aggregates suppressed cell proliferation. RNA sequencing and transcriptome analysis of p53 aggregate-harboring PDOs indicated multiple candidate pathways involved in p53 aggregate oncogenic functions. With lung SCC-derived cell lines, we found that cytoplasmic p53 aggregates contributed to cisplatin resistance. This study thus shows that p53 aggregates are a predictor of poor prognosis in lung SCC and suggests that detecting p53 aggregates via p53 conventional immunohistochemical analysis may aid patient selection for platinum-based therapy.
抑癌基因 TP53 是人类癌症中最常发生突变的基因，其产物肿瘤蛋白 p53 在 DNA 损伤中发挥着重要作用。p53 蛋白突变可能通过丧失抑癌功能和获得致癌功能导致肿瘤发生和癌细胞的恶性转化。我们之前曾报道过突变型 p53 蛋白形成聚集体，细胞质 p53 聚集体与人类卵巢癌的不良预后相关。然而，p53 聚集在包括肺鳞状细胞癌（SCC）在内的其他肿瘤中的预后影响尚不清楚。在这里，我们证明了具有细胞质 p53 聚集体的肺 SCC 病例具有明显不良的临床预后。通过从肺 SCC 患者建立的具有细胞质 p53 聚集体的患者来源肿瘤类器官（PDO）进行分析表明，消除细胞质 p53 聚集体可抑制细胞增殖。对具有 p53 聚集体的 PDO 进行 RNA 测序和转录组分析表明，多个候选途径参与了 p53 聚集体的致癌功能。通过肺 SCC 衍生的细胞系，我们发现细胞质 p53 聚集体有助于顺铂耐药。因此，本研究表明 p53 聚集体是肺 SCC 不良预后的预测因子，并提示通过 p53 常规免疫组织化学分析检测 p53 聚集体可能有助于为铂类治疗选择患者。
