MTMR6基因下调导致口腔鳞状细胞癌对顺铂产生耐药性。

MTMR6 downregulation contributes to cisplatin resistance in oral squamous cell carcinoma.

作者信息

Lee Kah Young, Oh Su Young, Lee Heon-Jin, Kwon Tae-Geon, Kim Jin-Wook, Shin Chang-Geol, Hong Su-Hyung, Choi So-Young

机构信息

Department of Microbiology and Immunology, School of Dentistry, Kyungpook National University, Daegu, South Korea.

Department of Oral and Maxillofacial Surgery, School of Dentistry, Kyungpook National University, Daegu, South Korea.

出版信息

Cancer Cell Int. 2025 Jan 31;25(1):30. doi: 10.1186/s12935-025-03654-9.

DOI:10.1186/s12935-025-03654-9

PMID:39891222

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11783708/

Abstract

BACKGROUND

The therapeutic effectiveness of cisplatin, a widely used chemotherapy drug for oral squamous cell carcinoma (OSCC), is often compromised by resistance, making it difficult to predict treatment outcomes. The role of myotubularin and myotubularin-related (MTMR) genes in cisplatin resistance remains unclear. We aimed to elucidate the molecular mechanisms underlying MTMR6 with cisplatin resistance in OSCC.

METHODS

MTMR6 expression was compared between UMSCC1 and cisplatin-resistant UM-Cis cells. Gain- and loss-of-function experiments involving MTMR6 was performed to evaluate its impact on cisplatin resistance. The regulatory role of hsa-miR-544a on MTMR6 expression was explored via antagomir and miRNA mimic assays. The relationship between MTMR6 protein levels and cisplatin sensitivity was assessed in OSCC patient tissues classified as sensitive or resistant to cisplatin monotherapy. A survival analysis based on The Cancer Genome Atlas (TCGA) head and neck squamous cell carcinoma (HNSCC) dataset was performed to evaluate the correlation between MTMR6 expression and patient outcomes following cisplatin treatment. In vivo cisplatin resistance was examined using mouse xenografts derived from MTMR6-knockdown UMSCC1 cells.

RESULTS

MTMR6 expression was markedly reduced in cisplatin-resistant UM-Cis cells compared to UMSCC1 cells. Functional analyses revealed that modulating MTMR6 activity alters cisplatin resistance. A luciferase assay confirmed that hsa-miR-544a regulates MTMR6 gene expression. Additionally, antagomir and miRNA mimics demonstrated that hsa-miR-544a enhances cisplatin resistance by suppressing MTMR6 expression. In OSCC patient tissues, higher MTMR6 protein levels were associated with cisplatin sensitivity, while cisplatin-resistant tissues had lower MTMR6 expression. Survival analysis of the TCGA HNSCC dataset indicated that low MTMR6 expression correlates with poorer outcomes in cisplatin-treated patients compared to those with high MTMR6 expression. Mouse xenografts derived from MTMR6-knockdown UMSCC1 cells exhibited increased resistance to cisplatin compared to controls.

CONCLUSION

Assessing mRNA levels of MTMR6 and has-miR-544a in biopsy samples could help predict cisplatin responsiveness in OSCC.

摘要

背景

顺铂是一种广泛用于口腔鳞状细胞癌（OSCC）的化疗药物，其治疗效果常因耐药性而受到影响，使得难以预测治疗结果。肌管蛋白和肌管蛋白相关（MTMR）基因在顺铂耐药中的作用仍不清楚。我们旨在阐明MTMR6在OSCC顺铂耐药中的分子机制。

方法

比较了UMSCC1细胞和顺铂耐药的UM-Cis细胞中MTMR6的表达。进行了涉及MTMR6的功能获得和功能缺失实验，以评估其对顺铂耐药性的影响。通过拮抗剂和miRNA模拟物实验探究了hsa-miR-544a对MTMR6表达的调控作用。在被分类为对顺铂单药治疗敏感或耐药的OSCC患者组织中，评估了MTMR6蛋白水平与顺铂敏感性之间的关系。基于癌症基因组图谱（TCGA）头颈鳞状细胞癌（HNSCC）数据集进行了生存分析，以评估MTMR6表达与顺铂治疗后患者预后之间的相关性。使用源自MTMR6敲低的UMSCC1细胞的小鼠异种移植物检测体内顺铂耐药性。

结果

与UMSCC1细胞相比，顺铂耐药的UM-Cis细胞中MTMR6表达明显降低。功能分析表明，调节MTMR6活性会改变顺铂耐药性。荧光素酶实验证实hsa-miR-544a调节MTMR6基因表达。此外，拮抗剂和miRNA模拟物表明，hsa-miR-544a通过抑制MTMR6表达增强顺铂耐药性。在OSCC患者组织中，较高的MTMR6蛋白水平与顺铂敏感性相关，而顺铂耐药组织中MTMR6表达较低。TCGA HNSCC数据集的生存分析表明，与MTMR6高表达的患者相比，MTMR6低表达与顺铂治疗患者的较差预后相关。与对照相比，源自MTMR6敲低的UMSCC1细胞的小鼠异种移植物对顺铂的耐药性增加。