Frontiers in oncology · 2026
TET1 loss promotes malignant phenotypes in HeLa cells and is associated with altered PTEN-PI3K/AKT/mTOR signaling.
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Liu Yan, Liu Lujia, Wang Lusheng, Ren Juan, Meng Fanle, Chen Mengling, Yao Xiaoyan, Zou Ping, Wu Jingjing, Zhou Xiaoyan, Tang Heng, Ma Weiwei
Аннотация
OBJECTIVE: To investigate the biological significance of ten-eleven translocation 1 (TET1) in cervical cancer and its association with PTEN-PI3K/AKT/mTOR signaling.
METHODS: Publicly available bulk and single-cell transcriptomic datasets were analyzed, with histology-restricted analyses focused on cervical squamous cell carcinoma (SCC). TET1 immunoreactivity was assessed in five paired cervical adenocarcinoma and adjacent non-neoplastic tissues using nuclear H-scores. TET1 loss of function was modeled in HeLa cells by shRNA-mediated knockdown, with Bobcat339 used as a complementary TET-family inhibitor. Cellular metabolic activity, clonogenicity, cell-cycle distribution, apoptosis, migration, and invasion were evaluated using CCK-8, colony-formation, flow-cytometric, wound-healing, and Transwell assays. Protein expression and phosphorylation were examined by western blotting.
RESULTS: SCC-restricted bulk analyses consistently showed lower TET1 expression in cervical SCC than in normal cervical tissues. In TCGA-CESC SCC, TET1 expression was not significantly associated with PTEN expression or the PI3K-AKT-mTOR transcriptional score after multiple-testing correction, whereas an inverse association with the apoptosis score remained significant. Patient-level pseudobulk analysis of 12 SCC cases likewise identified no pathway association that remained significant after false-discovery-rate correction. In five paired cervical adenocarcinoma cases, TET1 nuclear H-scores were lower in all tumor samples than in their matched adjacent tissues, although the difference did not reach statistical significance (exact P = 0.0625). In HeLa cells, TET1 depletion increased cellular metabolic activity and clonogenicity, altered cell-cycle distribution, reduced apoptosis, and enhanced migration and invasion. These changes were accompanied by reduced PTEN expression and increased phosphorylation of PI3K, AKT, and mTOR.
CONCLUSION: Reduced TET1 expression was observed in SCC-restricted public cohorts, while TET1 depletion promoted malignant phenotypes in HeLa cells. The accompanying changes in PTEN expression and PI3K/AKT/mTOR phosphorylation identify a candidate signaling association that warrants validation through rescue experiments and locus-specific epigenetic studies.
METHODS: Publicly available bulk and single-cell transcriptomic datasets were analyzed, with histology-restricted analyses focused on cervical squamous cell carcinoma (SCC). TET1 immunoreactivity was assessed in five paired cervical adenocarcinoma and adjacent non-neoplastic tissues using nuclear H-scores. TET1 loss of function was modeled in HeLa cells by shRNA-mediated knockdown, with Bobcat339 used as a complementary TET-family inhibitor. Cellular metabolic activity, clonogenicity, cell-cycle distribution, apoptosis, migration, and invasion were evaluated using CCK-8, colony-formation, flow-cytometric, wound-healing, and Transwell assays. Protein expression and phosphorylation were examined by western blotting.
RESULTS: SCC-restricted bulk analyses consistently showed lower TET1 expression in cervical SCC than in normal cervical tissues. In TCGA-CESC SCC, TET1 expression was not significantly associated with PTEN expression or the PI3K-AKT-mTOR transcriptional score after multiple-testing correction, whereas an inverse association with the apoptosis score remained significant. Patient-level pseudobulk analysis of 12 SCC cases likewise identified no pathway association that remained significant after false-discovery-rate correction. In five paired cervical adenocarcinoma cases, TET1 nuclear H-scores were lower in all tumor samples than in their matched adjacent tissues, although the difference did not reach statistical significance (exact P = 0.0625). In HeLa cells, TET1 depletion increased cellular metabolic activity and clonogenicity, altered cell-cycle distribution, reduced apoptosis, and enhanced migration and invasion. These changes were accompanied by reduced PTEN expression and increased phosphorylation of PI3K, AKT, and mTOR.
CONCLUSION: Reduced TET1 expression was observed in SCC-restricted public cohorts, while TET1 depletion promoted malignant phenotypes in HeLa cells. The accompanying changes in PTEN expression and PI3K/AKT/mTOR phosphorylation identify a candidate signaling association that warrants validation through rescue experiments and locus-specific epigenetic studies.