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PSMA2通过调节线粒体自噬途径促进口腔鳞状细胞癌的化疗和放疗抗性。

PSMA2 promotes chemo- and radioresistance of oral squamous cell carcinoma by modulating mitophagy pathway.

作者信息

Wang Chun-I, Chen Cheng-Yi, Chen Ting-Wen, Cheng Chun-Chia, Hong Shu-Wen, Tsai Tsung-You, Chang Kai-Ping

机构信息

Department of Biochemistry, School of Medicine, China Medical University, Taichung, Taiwan.

Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

出版信息

Cell Death Discov. 2025 Jan 10;11(1):2. doi: 10.1038/s41420-025-02286-2.

DOI:10.1038/s41420-025-02286-2
PMID:39794329
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11724067/
Abstract

Oral cavity squamous cell carcinoma (OSCC) represents the most prevalent malignancy among head and neck squamous cell carcinomas (HNSCCs). Standard treatment modalities include surgical resection combined with radiation and chemotherapy. However, locoregional failure remains a critical issue affecting the prognosis of OSCC patients, largely due to tumor resistance against radiation or chemotherapy. In this study, we established a gene database related to OSCC recurrence and identified PSMA2 as a novel molecule influencing prognosis in OSCC patients. An independent Taiwanese cohort confirmed that elevated PSMA2 transcript levels were associated with poorer prognosis and contributed to the chemo- and radioresistance phenotype in OSCC. Furthermore, we confirmed that PSMA2 regulates cell cycle, mitochondrial dysfunction, and mitophagy, thereby contributing to carcinogenesis and resistance. Notably, mitophagy inducer exhibit antitumor effects in PSMA2-overexpressing OSCC xenograft mouse model. Collectively, our results provide a mechanistic understanding of the atypical function of PSMA2 in promoting OSCC recurrence.

摘要

口腔鳞状细胞癌（OSCC）是头颈部鳞状细胞癌（HNSCC）中最常见的恶性肿瘤。标准治疗方式包括手术切除联合放疗和化疗。然而，局部区域复发仍然是影响OSCC患者预后的关键问题，这主要是由于肿瘤对放疗或化疗具有抗性。在本研究中，我们建立了一个与OSCC复发相关的基因数据库，并确定PSMA2是影响OSCC患者预后的一种新分子。一个独立的台湾队列证实，PSMA2转录水平升高与较差的预后相关，并导致OSCC出现化疗和放疗抗性表型。此外，我们证实PSMA2调节细胞周期、线粒体功能障碍和线粒体自噬，从而促进肿瘤发生和抗性。值得注意的是，线粒体自噬诱导剂在PSMA2过表达的OSCC异种移植小鼠模型中表现出抗肿瘤作用。总体而言，我们的结果为PSMA2促进OSCC复发的非典型功能提供了机制上的理解。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e2b/11724067/c4c41d6c2695/41420_2025_2286_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e2b/11724067/067daedc25fd/41420_2025_2286_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e2b/11724067/5334ff005eb8/41420_2025_2286_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e2b/11724067/eeed30e95f82/41420_2025_2286_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e2b/11724067/eb1ffbccaba8/41420_2025_2286_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e2b/11724067/2cbbe519da1d/41420_2025_2286_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e2b/11724067/ee272f22009f/41420_2025_2286_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e2b/11724067/c4c41d6c2695/41420_2025_2286_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e2b/11724067/067daedc25fd/41420_2025_2286_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e2b/11724067/5334ff005eb8/41420_2025_2286_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e2b/11724067/eeed30e95f82/41420_2025_2286_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e2b/11724067/eb1ffbccaba8/41420_2025_2286_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e2b/11724067/2cbbe519da1d/41420_2025_2286_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e2b/11724067/ee272f22009f/41420_2025_2286_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e2b/11724067/c4c41d6c2695/41420_2025_2286_Fig7_HTML.jpg

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引用本文的文献

[1]
Mitophagy-Related Gene CHDH Predicts Prognosis and Immune Response and Inhibits Proliferation and Migration in vitro and in vivo of Oral Squamous Cell Carcinoma.

J Inflamm Res. 2025-5-26

本文引用的文献

[1]
Targeting cellular mitophagy as a strategy for human cancers.

Front Cell Dev Biol. 2024-7-5

[2]
PSMA2 promotes glioma proliferation and migration via EMT.

Pathol Res Pract. 2024-4

[3]
Characterization of the m6A/m1A/m5C/m7G-related regulators on the prognosis and immune microenvironment of glioma by integrated analysis of scRNA-seq and bulk RNA-seq data.

J Gene Med. 2024-2

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Unravelling the heterogeneity of oral squamous cell carcinoma by integrative analysis of single-cell and bulk transcriptome data.

J Cell Mol Med. 2024-2

[5]
An immune-related exosome signature predicts the prognosis and immunotherapy response in ovarian cancer.

BMC Womens Health. 2024-1-18

[6]
The inner mitochondrial membrane fission protein MTP18 serves as a mitophagy receptor to prevent apoptosis in oral cancer.

J Cell Sci. 2023-7-1

[7]
Analysis of prognostic biomarker models and immune microenvironment in acute myeloid leukemia by integrative bioinformatics.

J Cancer Res Clin Oncol. 2023-9

[8]
Integrative Single-Cell and Bulk Transcriptomes Analyses Identify Intrinsic HNSCC Subtypes with Distinct Prognoses and Therapeutic Vulnerabilities.

Clin Cancer Res. 2023-8-1

[9]
PSMA2 knockdown impacts expression of proteins involved in immune and cellular stress responses in human lung cells.

Biochim Biophys Acta Mol Basis Dis. 2023-2

[10]
Mitophagy Induced by Metal Nanoparticles for Cancer Treatment.

Pharmaceutics. 2022-10-24

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