SERPINA1 methylation as a novel diagnostic marker for early-stage papillary thyroid carcinoma via MAPK6-AKT/mTOR pathway
Abstract Most thyroid nodules can be diagnosed preoperatively by ultrasonography and fine-needle aspiration biopsy. However, accurately differentiating between benign nodules or indolent thyroid tumors and aggressive thyroid cancers remains a significant clinical challenge when the biopsy results ar...
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BMC
2025-05-01
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| Series: | Clinical Epigenetics |
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| Online Access: | https://doi.org/10.1186/s13148-025-01891-3 |
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| author | Junjie Li Haixia Huang Yifei Yin Yizhu Mao Mengxia Li Hong Li Chenxia Jiang Rongxi Yang |
| author_facet | Junjie Li Haixia Huang Yifei Yin Yizhu Mao Mengxia Li Hong Li Chenxia Jiang Rongxi Yang |
| author_sort | Junjie Li |
| collection | DOAJ |
| description | Abstract Most thyroid nodules can be diagnosed preoperatively by ultrasonography and fine-needle aspiration biopsy. However, accurately differentiating between benign nodules or indolent thyroid tumors and aggressive thyroid cancers remains a significant clinical challenge when the biopsy results are indeterminate. In this study, we aim to explore a novel biomarker to determine the malignancy of thyroid nodules. Fifteen tissue samples from patients with Stage I&II papillary thyroid carcinoma (PTC) and benign thyroid nodule (BTN) were analyzed by EPIC Methylation 850 K and RNA-Sequencing. Altered and inversely correlated methylation and expression in SERPINA1 gene in PTC was found in the discovery study. PTC-associated SERPINA1 hypomethylation was further verified by mass spectrometry in case–control studies from two clinical centers (Validation I: 140 PTCs vs. 182 BTNs, ORs ≥ 2.48, and Validation II: 224 PTCs vs. 217 BTNs, ORs ≥ 2.04; P ≤ 3.07E−15, for all measurable CpG sites). Moreover, SERPINA1 methylation had an outstanding clinical application value to differentiate PTC from BTN (the AUC combining Validation I and Validation II was 0.92). Our study also revealed that the upregulated SERPINA1 could promote cell proliferation, migration and invasion in the PTC cell lines, and thereby facilitate the malignant progression of PTC. Mechanistically, SERPINA1 activated the AKT/mTOR pathway via binding to MAPK6. Intervention targeting either SERPINA1 or MAPK6 has a significant impact on the malignancy of PTC cells. Together, we identified SERPINA1 methylation as a functional and effective diagnostic marker for PTC and provided a novel epigenetic insight into the etiology of PTC. Graphical abstract SERPINA1 is a Tumor-Driven Biomarker in PTC. At the population tissue level, we discovered and verified that the methylation level of SERPINA1 gene was significantly decreased and the protein expression was significantly increased in PTC cases, compared to BTN patients. Mechanistically, SERPINA1 significantly activates the AKT/mTOR signaling pathway through binding with MAPK6, which ultimately promotes the malignancy of tumor cells. |
| format | Article |
| id | doaj-art-fe3e1c8662ca4785a9213a5fc56ad9f3 |
| institution | OA Journals |
| issn | 1868-7083 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Clinical Epigenetics |
| spelling | doaj-art-fe3e1c8662ca4785a9213a5fc56ad9f32025-08-20T02:00:01ZengBMCClinical Epigenetics1868-70832025-05-0117111910.1186/s13148-025-01891-3SERPINA1 methylation as a novel diagnostic marker for early-stage papillary thyroid carcinoma via MAPK6-AKT/mTOR pathwayJunjie Li0Haixia Huang1Yifei Yin2Yizhu Mao3Mengxia Li4Hong Li5Chenxia Jiang6Rongxi Yang7Department of Epidemiology, School of Public Health, Nanjing Medical UniversityDepartment of Epidemiology, School of Public Health, Nanjing Medical UniversityDepartment of Thyroid and Breast Surgery, The Affiliated Huai’an Hospital of Xuzhou Medical University and The Second People’s Hospital of Huai’anDepartment of Epidemiology, School of Public Health, Nanjing Medical UniversityDepartment of Epidemiology, School of Public Health, Nanjing Medical UniversityDepartment of Pathology, The Affiliated Huai’an Hospital of Xuzhou Medical University and The Second People’s Hospital of Huai’anDepartment of Pathology, The Affiliated Hospital of Nantong UniversityDepartment of Epidemiology, School of Public Health, Nanjing Medical UniversityAbstract Most thyroid nodules can be diagnosed preoperatively by ultrasonography and fine-needle aspiration biopsy. However, accurately differentiating between benign nodules or indolent thyroid tumors and aggressive thyroid cancers remains a significant clinical challenge when the biopsy results are indeterminate. In this study, we aim to explore a novel biomarker to determine the malignancy of thyroid nodules. Fifteen tissue samples from patients with Stage I&II papillary thyroid carcinoma (PTC) and benign thyroid nodule (BTN) were analyzed by EPIC Methylation 850 K and RNA-Sequencing. Altered and inversely correlated methylation and expression in SERPINA1 gene in PTC was found in the discovery study. PTC-associated SERPINA1 hypomethylation was further verified by mass spectrometry in case–control studies from two clinical centers (Validation I: 140 PTCs vs. 182 BTNs, ORs ≥ 2.48, and Validation II: 224 PTCs vs. 217 BTNs, ORs ≥ 2.04; P ≤ 3.07E−15, for all measurable CpG sites). Moreover, SERPINA1 methylation had an outstanding clinical application value to differentiate PTC from BTN (the AUC combining Validation I and Validation II was 0.92). Our study also revealed that the upregulated SERPINA1 could promote cell proliferation, migration and invasion in the PTC cell lines, and thereby facilitate the malignant progression of PTC. Mechanistically, SERPINA1 activated the AKT/mTOR pathway via binding to MAPK6. Intervention targeting either SERPINA1 or MAPK6 has a significant impact on the malignancy of PTC cells. Together, we identified SERPINA1 methylation as a functional and effective diagnostic marker for PTC and provided a novel epigenetic insight into the etiology of PTC. Graphical abstract SERPINA1 is a Tumor-Driven Biomarker in PTC. At the population tissue level, we discovered and verified that the methylation level of SERPINA1 gene was significantly decreased and the protein expression was significantly increased in PTC cases, compared to BTN patients. Mechanistically, SERPINA1 significantly activates the AKT/mTOR signaling pathway through binding with MAPK6, which ultimately promotes the malignancy of tumor cells.https://doi.org/10.1186/s13148-025-01891-3SERPINA1Benign thyroid nodulePapillary thyroid carcinomaThyroid cancerDiagnosisDNA methylation |
| spellingShingle | Junjie Li Haixia Huang Yifei Yin Yizhu Mao Mengxia Li Hong Li Chenxia Jiang Rongxi Yang SERPINA1 methylation as a novel diagnostic marker for early-stage papillary thyroid carcinoma via MAPK6-AKT/mTOR pathway Clinical Epigenetics SERPINA1 Benign thyroid nodule Papillary thyroid carcinoma Thyroid cancer Diagnosis DNA methylation |
| title | SERPINA1 methylation as a novel diagnostic marker for early-stage papillary thyroid carcinoma via MAPK6-AKT/mTOR pathway |
| title_full | SERPINA1 methylation as a novel diagnostic marker for early-stage papillary thyroid carcinoma via MAPK6-AKT/mTOR pathway |
| title_fullStr | SERPINA1 methylation as a novel diagnostic marker for early-stage papillary thyroid carcinoma via MAPK6-AKT/mTOR pathway |
| title_full_unstemmed | SERPINA1 methylation as a novel diagnostic marker for early-stage papillary thyroid carcinoma via MAPK6-AKT/mTOR pathway |
| title_short | SERPINA1 methylation as a novel diagnostic marker for early-stage papillary thyroid carcinoma via MAPK6-AKT/mTOR pathway |
| title_sort | serpina1 methylation as a novel diagnostic marker for early stage papillary thyroid carcinoma via mapk6 akt mtor pathway |
| topic | SERPINA1 Benign thyroid nodule Papillary thyroid carcinoma Thyroid cancer Diagnosis DNA methylation |
| url | https://doi.org/10.1186/s13148-025-01891-3 |
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