NAT10 as a potential prognostic biomarker and therapeutic target for HNSCC
Abstract Background Increasing evidence has demonstrated the critical roles of mRNA modification regulators on multiple types of cancers. However, it is still poorly known about the prognostic and therapeutic value of mRNA modification regulators in HNSCC. Methods The gene expression profile of 36 m...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2021-08-01
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| Series: | Cancer Cell International |
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| Online Access: | https://doi.org/10.1186/s12935-021-02124-2 |
| _version_ | 1818904996496801792 |
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| author | Wenjie Tao Guocai Tian Shengming Xu Jiayi Li Zhiyuan Zhang Jiang Li |
| author_facet | Wenjie Tao Guocai Tian Shengming Xu Jiayi Li Zhiyuan Zhang Jiang Li |
| author_sort | Wenjie Tao |
| collection | DOAJ |
| description | Abstract Background Increasing evidence has demonstrated the critical roles of mRNA modification regulators on multiple types of cancers. However, it is still poorly known about the prognostic and therapeutic value of mRNA modification regulators in HNSCC. Methods The gene expression profile of 36 mRNA modification regulators and their corresponding clinical data were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). Stepwise regression in R with both directions was used to construct a model for the prognosis of HNSCC. Univariate Cox regression survival analysis was performed to identify the most significant risk gene. Gene set enrichment analysis (GSEA) was applied to determine the cancer-associated pathways with NAT10. Immunohistochemistry (IHC) staining was performed to evaluate the expression of NAT10 in formalin fixed paraffin-embedded (FFPE) samples of HNSCC. Univariate and multivariate Cox regression survival analysis performed to identify the independent risk factors associated with the OS of patients with HNSCC. HNSCC cell lines (Cal-27, FaDu, and Detroit-562) were transfected with short interfering RNA (siRNA) targeting NAT10 or treated with Remodelin, a small-molecule inhibitor of NAT10. Knockdown efficiency of siRNA was assessed by quantitative real-time PCR (qRT-PCR) and western blotting. In addition, CCK-8 assay, scratch assay and transwell assay were used to examine the proliferation, migration, and invasion abilities of the three HNSCC cell lines after NAT10 was inhibited genetically and pharmaceutically. Cell cycle and cell apoptosis assays were performed by flow cytometry. Finally, the therapeutic value of Remodelin in HNSCC was evaluated via a patient-derived xenograft (PDX) model. The statistical analysis was performed with SPSS 23.0. Results A risk prediction model containing 10 mRNA modification regulators was constructed and showed prognostic value in HNSCC. NAT10 was further identified as a key risk gene and independent prognostic factor in TCGA HNSCC dataset. The GSEA analysis suggested that high NAT10 expression was associated with MYC, E2F, G2M checkpoint, mTORC1, DNA repair and oxidative phosphorylation pathways. NAT10 protein expression was significantly up-regulated in tumour cells compared to normal epithelial cells in FFPE samples and increased NAT10 protein expression was correlated with poor overall survival of 267 HNSCC patients. Genetic depletion of NAT10 using siRNA or chemical inhibition of NAT10 using Remodelin resulted in reduced cell proliferation, migration and invasion abilities in Cal-27, FaDu and Detroit-562 cells. Knockdown of NAT10 using siRNA significantly increased cell cycle arrest in S/G2-phase. Remodelin significantly inhibited tumour growth and tumour cell proliferation in the PDX model of HNSCC. Conclusions NAT10 could be a potential prognostic marker and a therapeutic target for HNSCC. |
| first_indexed | 2024-12-19T21:16:19Z |
| format | Article |
| id | doaj.art-677ecd5562f04ecb833a4a0addddb9a3 |
| institution | Directory Open Access Journal |
| issn | 1475-2867 |
| language | English |
| last_indexed | 2024-12-19T21:16:19Z |
| publishDate | 2021-08-01 |
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| series | Cancer Cell International |
| spelling | doaj.art-677ecd5562f04ecb833a4a0addddb9a32022-12-21T20:05:20ZengBMCCancer Cell International1475-28672021-08-0121111810.1186/s12935-021-02124-2NAT10 as a potential prognostic biomarker and therapeutic target for HNSCCWenjie Tao0Guocai Tian1Shengming Xu2Jiayi Li3Zhiyuan Zhang4Jiang Li5Department of Oral and Maxillofacial-Head Neck Oncology, Shanghai Ninth People’s Hospital, College of Stomatology, Shanghai Jiao Tong University School of MedicineDepartment of Oral and Maxillofacial-Head Neck Oncology, Shanghai Ninth People’s Hospital, College of Stomatology, Shanghai Jiao Tong University School of MedicineDepartment of Oral and Maxillofacial-Head Neck Oncology, Shanghai Ninth People’s Hospital, College of Stomatology, Shanghai Jiao Tong University School of MedicineDepartment of Oral and Maxillofacial-Head Neck Oncology, Shanghai Ninth People’s Hospital, College of Stomatology, Shanghai Jiao Tong University School of MedicineDepartment of Oral and Maxillofacial-Head Neck Oncology, Shanghai Ninth People’s Hospital, College of Stomatology, Shanghai Jiao Tong University School of MedicineNational Clinical Research Center for Oral DiseasesAbstract Background Increasing evidence has demonstrated the critical roles of mRNA modification regulators on multiple types of cancers. However, it is still poorly known about the prognostic and therapeutic value of mRNA modification regulators in HNSCC. Methods The gene expression profile of 36 mRNA modification regulators and their corresponding clinical data were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). Stepwise regression in R with both directions was used to construct a model for the prognosis of HNSCC. Univariate Cox regression survival analysis was performed to identify the most significant risk gene. Gene set enrichment analysis (GSEA) was applied to determine the cancer-associated pathways with NAT10. Immunohistochemistry (IHC) staining was performed to evaluate the expression of NAT10 in formalin fixed paraffin-embedded (FFPE) samples of HNSCC. Univariate and multivariate Cox regression survival analysis performed to identify the independent risk factors associated with the OS of patients with HNSCC. HNSCC cell lines (Cal-27, FaDu, and Detroit-562) were transfected with short interfering RNA (siRNA) targeting NAT10 or treated with Remodelin, a small-molecule inhibitor of NAT10. Knockdown efficiency of siRNA was assessed by quantitative real-time PCR (qRT-PCR) and western blotting. In addition, CCK-8 assay, scratch assay and transwell assay were used to examine the proliferation, migration, and invasion abilities of the three HNSCC cell lines after NAT10 was inhibited genetically and pharmaceutically. Cell cycle and cell apoptosis assays were performed by flow cytometry. Finally, the therapeutic value of Remodelin in HNSCC was evaluated via a patient-derived xenograft (PDX) model. The statistical analysis was performed with SPSS 23.0. Results A risk prediction model containing 10 mRNA modification regulators was constructed and showed prognostic value in HNSCC. NAT10 was further identified as a key risk gene and independent prognostic factor in TCGA HNSCC dataset. The GSEA analysis suggested that high NAT10 expression was associated with MYC, E2F, G2M checkpoint, mTORC1, DNA repair and oxidative phosphorylation pathways. NAT10 protein expression was significantly up-regulated in tumour cells compared to normal epithelial cells in FFPE samples and increased NAT10 protein expression was correlated with poor overall survival of 267 HNSCC patients. Genetic depletion of NAT10 using siRNA or chemical inhibition of NAT10 using Remodelin resulted in reduced cell proliferation, migration and invasion abilities in Cal-27, FaDu and Detroit-562 cells. Knockdown of NAT10 using siRNA significantly increased cell cycle arrest in S/G2-phase. Remodelin significantly inhibited tumour growth and tumour cell proliferation in the PDX model of HNSCC. Conclusions NAT10 could be a potential prognostic marker and a therapeutic target for HNSCC.https://doi.org/10.1186/s12935-021-02124-2HNSCCmRNA modification regulatorPrognosisNAT10BiomarkerTherapeutic target |
| spellingShingle | Wenjie Tao Guocai Tian Shengming Xu Jiayi Li Zhiyuan Zhang Jiang Li NAT10 as a potential prognostic biomarker and therapeutic target for HNSCC Cancer Cell International HNSCC mRNA modification regulator Prognosis NAT10 Biomarker Therapeutic target |
| title | NAT10 as a potential prognostic biomarker and therapeutic target for HNSCC |
| title_full | NAT10 as a potential prognostic biomarker and therapeutic target for HNSCC |
| title_fullStr | NAT10 as a potential prognostic biomarker and therapeutic target for HNSCC |
| title_full_unstemmed | NAT10 as a potential prognostic biomarker and therapeutic target for HNSCC |
| title_short | NAT10 as a potential prognostic biomarker and therapeutic target for HNSCC |
| title_sort | nat10 as a potential prognostic biomarker and therapeutic target for hnscc |
| topic | HNSCC mRNA modification regulator Prognosis NAT10 Biomarker Therapeutic target |
| url | https://doi.org/10.1186/s12935-021-02124-2 |
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