Dataset Information

Elevated TAB182 enhances the radioresistance of esophageal squamous cell carcinoma through G2-M checkpoint modulation.

ABSTRACT:

Background

Radiotherapy is one of the main strategies for the treatment of esophageal squamous cell carcinoma (ESCC). However, treatment failure often occurs due to the emergence of radioresistance. In this study, we report a key regulator of radiation sensitivity, termed TAB182 that may become an ideal biomarker and therapeutic target to overcome radioresistance.

Materials and methods

By applying qRT-PCR and immunohistochemical staining, the expression of TAB182 was detected in patient tissues. We next assessed the influence of TAB182 downregulation to radiosensitivity using clonogenic survival assay and γ-H2A.X foci analysis in TE-1, TE-10, and radioresistant TE-1R cell lines after ionizing radiation. To unveil the mechanism underlying, TAB182 interacting proteins were identified by mass spectrometry following co-immunoprecipitation. Furthermore, flow cytometry and western blot assay were applied to validate the identified proteins.

Results

Our results demonstrated that the expression of TAB182 is higher in cancer tissues than normal tissues and elevated expression of TAB182 correlates with poor outcomes of postoperative radiotherapy. Downregulation of TAB182 sensitized cancer cells to ionizing radiation, particularly in radioresistant TE-1R cells that spontaneously overexpress TAB182. Mechanically, TAB182 interacts with FHL2 to induce G2-M arrest through wiring the CHK2/CDC25C/CDC2 signaling pathway. Finally, overexpression of shRNA-resistant TAB182 restored the checkpoint and radioresistance.

Conclusion

TAB182 potentiates the radioresistance of ESCC cells by modulating the G2-M checkpoint through its interaction with FHL2. Thus, TAB182 may become an ideal biomarker and therapeutic target of ESCC radiotherapy.

SUBMITTER: Cao Y

PROVIDER: S-EPMC8085956 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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Publications

Elevated TAB182 enhances the radioresistance of esophageal squamous cell carcinoma through G2-M checkpoint modulation.

Cao Yuandong Y Gao Aidi A Li Xiaoqing X Min Han H He Chao C Sun Xinchen X Ding Wei-Qun WQ Zhou Jundong J

Cancer medicine 20210330 9

<h4>Background</h4>Radiotherapy is one of the main strategies for the treatment of esophageal squamous cell carcinoma (ESCC). However, treatment failure often occurs due to the emergence of radioresistance. In this study, we report a key regulator of radiation sensitivity, termed TAB182 that may become an ideal biomarker and therapeutic target to overcome radioresistance.<h4>Materials and methods</h4>By applying qRT-PCR and immunohistochemical staining, the expression of TAB182 was detected in p ...[more]

PMID: 33787085

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Project description:Simple Summary Sex biases in cancer incidence and cancer mortality exist in the majority of cancer types. Esophageal squamous cell carcinoma (ESCC) is a typical malignancy with higher mortality rates and worse responses to treatment in males versus females. To overcome the male predominance in ESCC, more therapeutic targets need to be identified. Meanwhile, age is also an important contributor that should be included when we consider sex bias in cancer. In this study, we used multi-omics data from 663 ESCC patients and found that G2/M checkpoint pathway-related sex bias and age bias were significantly present in genomics, transcriptomics, and epigenomics. Our findings suggest that G2/M targets may be included in combination therapy for male patients to improve the efficacy of ESCC treatment. Abstract Esophageal squamous cell carcinoma (ESCC) is strongly characterized by a male predominance with higher mortality rates and worse responses to treatment in males versus females. Despite the role of sex hormones, other causes that may contribute to sex bias in ESCC remain largely unknown, especially as age increases and the hormone difference begins to diminish between sexes. In this study, we analyzed genomics, transcriptomics, and epigenomics from 663 ESCC patients and found that G2/M checkpoint pathway-related sex bias and age bias were significantly present in multi-omics data. In accordance with gene expression patterns across sexes, ten compounds were identified by applying drug repurposing from three drug sensitivity databases: The Connective Map (CMap), Genomics of Drug Sensitivity in Cancer (GDSC), and The Cancer Therapeutic Response Portal (CTRP). MK1775 and decitabine showed better efficacy in two male ESCC cell lines in vitro and in vivo. The drugs’ relevance to the transition between G2 and M was especially evident in male cell lines. In our study, we first validated the sex bias of the G2/M checkpoint pathway in ESCC and then determined that G2/M targets may be included in combination therapy for male patients to improve the efficacy of ESCC treatment.

Project description:BackgroundEsophageal squamous cell carcinoma (ESCC) is a highly prevalent and aggressive cancer with poor treatment outcomes. Despite the critical role of tight junction proteins in tumorigenesis, the involvement of Claudin5 in ESCC remains poorly understood. Thus, this study aimed to investigate the role of Claudin5 in ESCC malignant progression and radioresistance, as well as the underlying regulatory mechanisms.MethodsThe expression of Claudin5 was evaluated in esophageal cancer tissue using both public databases and 123 clinical samples. CCK-8, transwell invasion, wound healing and clonogenic survival assays were used to examine the proliferation, invasion, migration and radiosensitivity of ESCC cells in vitro. Xenograft and animal lung metastasis experiments were conducted to examine the impact of Claudin5 on tumor growth and lung metastasis in vivo. The effect of Claudin5 on autophagy was detected via transmission electron microscopy, western blotting and autophagy flux. Immunohistochemical staining was used to detect Claudin5 expression in ESCC patient samples. The statistical difference was assessed with Student t test or one-way ANOVA. The correlation between Claudin5 expression and radiotherapy response rate was performed by the Chi-square test. The significance of Kaplan-Meier curves was evaluated by the Logrank test.ResultsClaudin5 expression was downregulated in ESCC tissues. Downregulation of Claudin5 promoted ESCC cell proliferation, invasion, and migration both in vitro and in vivo. Downregulation of Claudin5 decreased the radiosensitivity of ESCC cells. Moreover, downregulation of Claudin5 promoted autophagy and the expression of Beclin1. Beclin1 knockdown reversed the effect of Claudin5 downregulation on autophagy induction and the promotion of ESCC cell malignant progression and radioresistance. Additionally, low expression of Claudin5 in ESCC cancer tissues was associated with poor radiotherapy response and prognosis.ConclusionsIn summary, these findings suggest that downregulation of Claudin5 promotes ESCC malignant progression and radioresistance via Beclin1-autophagy activation and may serve as a promising biomarker for predicting radiotherapy response and patient outcome in ESCC.

Dataset Information

Elevated TAB182 enhances the radioresistance of esophageal squamous cell carcinoma through G2-M checkpoint modulation.

Background

Materials and methods

Results

Conclusion

Publications

Elevated TAB182 enhances the radioresistance of esophageal squamous cell carcinoma through G2-M checkpoint modulation.

Similar Datasets

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