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Identify MTDH as a Key Gene of Radio-Resistance in Colorectal Cancer Based on Multi-Omics and Experimental Validation
Wei Xu1, Yuanyuan Zhang2, Yizhi Ge2
1Department of Oncology, Suqian Hospital of Traditional Chinese Medicine, Suqian, China.
Objectives:
Radio-resistance hinders the effectiveness of radiotherapy for treating colorectal cancer (CRC) patients. Metadherin (MTDH) is proposed to exert a pivotal role in resistance to radiotherapy in various malignancies. This study aims to investigate the precise impact of MTDH on CRC radio-resistance.
Methods:
Through a fusion of 14 machine learning algorithms and SHapley Additive exPlanations (SHAP) interpretability analysis, we pinpointed MTDH as a pivotal gene implicated in radio-resistance mechanisms. Subsequently, we investigated MTDH expression in CRC tissues using single-cell RNA sequencing data (scRNA-seq) and bulk transcriptomic data. MTDH level was also examined in tissues from 82 rectal cancer patients who were responsive or non-responsive to radiotherapy. We established radioresistant variants of SW480 and HT29 cells (designated SW480-R and HT29-R), then evaluated their characteristics using cell viability assays, apoptosis measurements, and γ-H2AX foci immunofluorescence. Then, MTDH silencing in radioresistant cells was applied to further investigate the impact of MTDH on regulating radiosensitivity for CRC cells.
Results:
Machine learning analysis revealed a significant association between MTDH and radio-resistance. Furthermore, multi-omics data confirmed that MTDH expression was significantly upregulated in CRC tissues and, more notably, within the more malignant diploid single-cell subpopulation. Genes associated with MTDH were predominantly enriched in pathways related to damage repair, DNA damage response, epithelial-mesenchymal transition (EMT), and stem cell differentiation, which were known to be critically involved in radio-resistance. Experimental validation confirmed significantly elevated MTDH expression in both radioresistant rectal cancer specimens and corresponding cellular models. High level of MTDH was positively related to several clinicopathological parameters, including tumor stage, differentiation, and lymph node status. Silencing of MTDH inhibited proliferative ability, increased apoptosis, and increased γ-H2AX foci numbers in CRC cells with radiation treatment.
Conclusion:
This study emphasizes the potential of MTDH as a promising prognostic and therapeutic target in response to radiotherapy for treating CRC patients.
Insights
Metadherin (MTDH) drives radio-resistance in colorectal cancer (CRC). Targeting MTDH may improve radiotherapy effectiveness for CRC patients by reducing proliferation and increasing apoptosis.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Radiotherapy resistance is a major challenge in treating colorectal cancer (CRC).
- Metadherin (MTDH) has emerged as a potential factor in radio-resistance across various cancers.
Purpose of the Study:
- To investigate the specific role of Metadherin (MTDH) in the radio-resistance of colorectal cancer (CRC).
Main Methods:
- Utilized 14 machine learning algorithms and SHAP analysis to identify MTDH's role.
- Analyzed MTDH expression in CRC tissues via single-cell and bulk transcriptomics.
- Examined MTDH in rectal cancer patient samples and radioresistant cell models (SW480-R, HT29-R).
- Performed MTDH silencing experiments in radioresistant CRC cells.
Main Results:
- Machine learning confirmed a significant link between MTDH and radio-resistance.
- MTDH was upregulated in CRC tissues, particularly in malignant diploid subpopulations.
- MTDH-associated genes are involved in DNA repair, EMT, and stem cell differentiation.
- Elevated MTDH correlated with advanced tumor stage, differentiation, and lymph node status.
- MTDH silencing reduced proliferation, increased apoptosis, and enhanced DNA damage signaling (γ-H2AX foci) in radioresistant CRC cells.
Conclusions:
- MTDH plays a critical role in colorectal cancer radio-resistance.
- MTDH presents a promising target for improving radiotherapy outcomes in CRC patients.
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