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Mutant TP53 promotes invasion of lung cancer cells by regulating desmoglein 3

Yu Feng^1,2, Rulin Qian¹, Dong Cui³

¹Department of Thoracic Surgery, Henan Provincial Chest Hospital, Zhengzhou University, No. 1 Weiwu Road, Zhengzhou, 450000, People's Republic of China.

Journal of Cancer Research and Clinical Oncology

|June 20, 2024

Abstract

Purpose:

Targeted therapies have markedly improved the prognosis of lung cancer patients; nevertheless, challenges persist, including limited beneficiary populations and the emergence of drug resistance. This study investigates the molecular mechanisms of mutant TP53 in lung cancer, aiming to contribute to novel strategies for targeted therapy.

Methods:

The TCGA database was employed to delineate the mutational landscape of TP53 in lung cancer patients. Differential gene expression between TP53-mutant and wild-type patients was analyzed, followed by functional enrichment. DSG3 protein expression in lung cancer patients was assessed using IHC, and its impact on prognosis was analyzed in the TCGA database. The influence of TP53 on the downstream gene DSG3 was investigated using qPCR, ChIP-qPCR, and luciferase reporter gene assays. Protein enrichment in the DSG3 promoter region was examined through IP-MS, and the regulatory role of the HIF1-α/TP53 complex on DSG3 was explored using Co-IP, luciferase assays, and ChIP-qPCR. Molecular interactions between TP53 (R273H) and HIF1-α were detected through immunoprecipitation and molecular docking. The effects and mechanisms of DSG3 on lung cancer phenotypes were assessed through WB, transwell, and wound healing assays.

Results:

TP53 mutations were present in 47.44% of patients, predominantly as missense mutations. DSG3 exhibited high expression in TP53-mutant lung cancer patients, and this elevated expression correlated with a poorer prognosis. TP53 interference led to a reduction in DSG3 mRNA expression, with TP53 mutant P53 enriching at the P2 site of the DSG3 promoter region, a recruitment facilitated by HIF1-α. The DBD region of TP53 (R273H) demonstrated interaction with HIF1-α. DSG3, activated through Ezrin phosphorylation, played a role in promoting invasion and metastasis.

Conclusions:

Mutant TP53 facilitates lung cancer cell invasion by modulating desmoglein 3.

Insights

Mutant TP53 in lung cancer drives invasion by increasing desmoglein 3 (DSG3) expression. This study reveals the molecular mechanism involving HIF1-α, offering new therapeutic targets for lung cancer treatment.

Area of Science:

Oncology
Molecular Biology
Genetics

Background:

Targeted therapies have improved lung cancer outcomes, but drug resistance and limited patient populations remain challenges.
The TP53 tumor suppressor gene is frequently mutated in various cancers, including lung cancer, impacting disease progression.
Understanding the molecular mechanisms of mutant TP53 is crucial for developing effective targeted therapies.

Purpose of the Study:

To investigate the molecular mechanisms by which mutant TP53 influences lung cancer progression.
To identify novel therapeutic targets for lung cancer by elucidating the role of TP53 mutations.
To explore the relationship between TP53 mutations and the expression of desmoglein 3 (DSG3) in lung cancer.

Main Methods:

Utilized TCGA database for mutational landscape and differential gene expression analysis.
Assessed DSG3 protein expression via IHC and analyzed its prognostic impact.
Employed qPCR, ChIP-qPCR, luciferase assays, Co-IP, and Western blotting to investigate TP53-DSG3 regulatory pathways.
Examined protein interactions using IP-MS and molecular docking.

Main Results:

TP53 mutations were identified in 47.44% of lung cancer patients, primarily missense mutations.
Elevated DSG3 expression in TP53-mutant tumors correlated with a poorer prognosis.
TP53 mutations led to increased DSG3 expression, mediated by HIF1-α recruitment to the DSG3 promoter.
DSG3 promotes lung cancer cell invasion and metastasis through Ezrin phosphorylation.

Conclusions:

Mutant TP53 directly facilitates lung cancer cell invasion and metastasis.
The modulation of desmoglein 3 (DSG3) by mutant TP53 is a key mechanism driving tumor aggressiveness.
Targeting the TP53-HIF1-α-DSG3 axis presents a potential therapeutic strategy for lung cancer.

Read full analysis

Keywords:

Invasion Lung cancer Molecular interaction TP53

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