Impacts of cytoplasmic p53 aggregates on the prognosis and the transcriptome in lung squamous cell carcinoma

Sep 21, 2026

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The tumor suppressor TP53 produces p53, a central mediator of DNA-damage responses. While TP53 mutations commonly drive loss of tumor-suppressive activity and oncogenic gain of function, p53 can also form cytoplasmic aggregates. Prior work linked cytoplasmic p53 aggregates to poor outcomes in ovarian cancer, but their prognostic role in lung squamous cell carcinoma (SCC) remained unclear. Here, lung SCC cases with cytoplasmic p53 aggregates showed significantly worse clinical prognosis. Patient-derived tumor organoids (PDOs) retaining cytoplasmic p53 aggregates exhibited reduced proliferation upon aggregate elimination. RNA sequencing and transcriptome analysis implicated multiple candidate pathways in aggregate-driven oncogenic functions, and lung SCC cell lines demonstrated aggregate-associated cisplatin resistance. The findings position p53 aggregates as a predictor of poor prognosis and suggest immunohistochemical detection to support platinum-based therapy selection.

LanguageEnglish

CategoryResearch & Report

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Abstract

Introduction

Received: 3 October 2023 | Revised: 31 May 2024 | Accepted: 4 June 2024 DOI: 10. 1111/cas.16252 OR I G I NAL ART I C L E Impacts of cytoplasmic p53 aggregates on the prognosis and the transcriptome in lung squamous cell carcinoma Kazuchika Nishitsuji1,2 | Remi Mito3,4 | Midori Ikezaki1 | Hiromu Yano3 | Yukio Fujiwara3 | Eri Matsubara3,5 | Taro Nishikawa1 | Yoshito Ihara1 | Kenji Uchimura2 | Naoyuki Iwahashi6 | Takuro Sakagami4 | Makoto Suzuki5 | Yoshihiro Komohara3,7 1Department of Biochemistry, School of Medicine, Wakayama Medical University, Wakayama, Japan 2Unité de Glycobiologie Structurale et Fonctionnelle, UMR 8576 CNRS, Université de Lille, Villeneuve d'Ascq, France 3 Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan 4Department of Respiratory Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan 5Department of Thoracic and Breast Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan 6Department of Obstetrics and Gynecology, School of Medicine, Wakayama Medical University, Wakayama, Japan 7Center for Metabolic Regulation of Healthy Aging, Kumamoto University, Kumamoto, Japan Correspondence Kazuchika Nishitsuji, Department of Biochemistry, School of Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama 641-8509, Japan. Email: [nishit@wakayama-med.ac.jp](nishit@wakayama-med.ac.jp) Yoshihiro Komohara, Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto Chuo-ku, Kumamoto 860-8556, Japan. [Email:](Email: ycomo@kumamoto-u.ac.jp)[ ycomo@kumamoto-u.ac.jp](Email: ycomo@kumamoto-u.ac.jp) Funding information Japan Society for the Promotion of Science, Grant/Award Number: 20H03459, 20K09605, 20KK0371 and 22K09623; Wakayama Medical University, Grant/Award Number: Tokutei-kenkyuzyosei 2019 and Tokutei-kenkyu-zyosei 2020; Mochida Memorial Foundation for Medical and Pharmaceutical Research; Suzuken Memorial Foundation; Princess Takamatsu Cancer Research Fund, Grant/ Award Number: 23-255025 Abstract 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. Kazuchika Nishitsuji, Remi Mito and Midori Ikezaki contributed equally to this work. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. © 2024 The Author(s) . Cancer Science published by John W

FAQs

What clinical impact do cytoplasmic p53 aggregates have in lung squamous cell carcinoma?

Lung SCC cases with cytoplasmic p53 aggregates show a significantly poor clinical prognosis compared with cases lacking these aggregates.

How were cytoplasmic p53 aggregates studied experimentally in this work?

Patient-derived tumor organoids (PDOs) retaining cytoplasmic p53 aggregates were used, and aggregate elimination was tested alongside RNA sequencing and transcriptome analysis. Lung SCC cell lines were also employed to assess treatment response.

How do p53 aggregates influence chemotherapy sensitivity in lung SCC?

Cytoplasmic p53 aggregates contribute to cisplatin resistance in lung SCC-derived cell lines.

Sep 21, 2026

Uploaded by Rowan