AKNA serves as a prognostic biomarker and restrains endometrial cancer progression via STING activation and macrophage reprogramming
4 affiliations
- 1Chongqing Key Laboratory of Maternal and Fetal Medicine, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Chongqing Medical University
- 2Department of Gynecology, Chongqing University Qianjiang Hospital (Qianjiang Central Hospital of Chongqing)
- 3International Medical College, Chongqing Medical University
- 4Department of Obstetrics and Gynecology, Women and Children’s Hospital of Chongqing Medical University
Abstract
Background: AKNA, an AT-hook transcription factor, plays a critical role in cancer development. However, its prognostic value and biological function in endometrial cancer (EC) remain unclear.
Methods: To systematically investigate AKNA in EC, we integrated multi-omics data (The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), and single-cell transcriptomics), dual independent clinical cohorts (TCGA-UCEC dataset and two institutional cohorts), and in vitro / in vivo experimental models. Immunohistochemistry, RT-qPCR and Western blotting were used for expression validation. Functional assays, including lentiviral-mediated AKNA knockdown/overexpression, CCK-8, scratch-wound, Transwell, flow cytometry, and colony formation assays were conducted to assess the effects of AKNA modulation on proliferation, migration, invasion, epithelial-mesenchymal transition, chemosensitivity and macrophage polarization. Mechanistically, chromatin immunoprecipitation (ChIP) sequencing (ChIP-seq), ChIP-qPCR, and dual-luciferase reporter assays were employed to define the transcriptional regulation of stimulator of interferon genes (STING) by AKNA. A prognostic nomogram integrating AKNA expression with clinicopathological features was developed and externally validated in independent cohorts.
Results: AKNA was significantly downregulated in EC tissues compared with normal endometrium, which was associated with advanced International Federation of Gynecology and Obstetrics stage, aggressive histological subtypes, and poor prognosis. AKNA knockdown promoted EC cell proliferation, migration, invasion, and epithelial-mesenchymal transition, while enhancing M2 macrophage polarization and reducing sensitivity to paclitaxel and potentially compromising anti-tumor innate immunity. Conversely, AKNA overexpression or STING activation by cyclic GMP–AMP reversed these malignant phenotypes. Mechanistically, AKNA directly bound to the STING promoter and transcriptionally activated STING, thereby inducing TANK-binding kinase 1 and interferon regulatory factor 3 phosphorylation. The nomogram combining AKNA with clinicopathological features demonstrated high accuracy in predicting EC recurrence and outperformed single-variable models in both training and validation cohorts.
Conclusions: AKNA deficiency promotes EC progression by transcriptionally suppressing STING and driving M2 macrophage polarization. AKNA serves as a robust prognostic biomarker and predictive indicator for chemotherapy and innate immune modulation, offering a promising therapeutic target for precision treatment of EC.
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BibTeX
@article{tu2026akna,
title = {{AKNA serves as a prognostic biomarker and restrains endometrial cancer progression via STING activation and macrophage reprogramming}},
author = {Yuan Tu and Lingya Xu and Chengfan Tian and Yuanling Shi and Jiaxin Yu and Chunxia Gong and Tianyu Peng and HangKun Yu and Rui Yuan and Peng Jiang},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1905624},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1905624/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - AKNA serves as a prognostic biomarker and restrains endometrial cancer progression via STING activation and macrophage reprogramming
AU - Yuan Tu
AU - Lingya Xu
AU - Chengfan Tian
AU - Yuanling Shi
AU - Jiaxin Yu
AU - Chunxia Gong
AU - Tianyu Peng
AU - HangKun Yu
AU - Rui Yuan
AU - Peng Jiang
PY - 2026
DA - 2026/10/05
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1905624
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1905624/full
AB - Background: AKNA, an AT-hook transcription factor, plays a critical role in cancer development. However, its prognostic value and biological function in endometrial cancer (EC) remain unclear. Methods: To systematically investigate AKNA in EC, we integrated multi-omics data (The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), and single-cell transcriptomics), dual independent clinical cohorts (TCGA-UCEC dataset and two institutional cohorts), and in vitro / in vivo experimental models. Immunohistochemistry, RT-qPCR and Western blotting were used for expression validation. Functional assays, including lentiviral-mediated AKNA knockdown/overexpression, CCK-8, scratch-wound, Transwell, flow cytometry, and colony formation assays were conducted to assess the effects of AKNA modulation on proliferation, migration, invasion, epithelial-mesenchymal transition, chemosensitivity and macrophage polarization. Mechanistically, chromatin immunoprecipitation (ChIP) sequencing (ChIP-seq), ChIP-qPCR, and dual-luciferase reporter assays were employed to define the transcriptional regulation of stimulator of interferon genes (STING) by AKNA. A prognostic nomogram integrating AKNA expression with clinicopathological features was developed and externally validated in independent cohorts. Results: AKNA was significantly downregulated in EC tissues compared with normal endometrium, which was associated with advanced International Federation of Gynecology and Obstetrics stage, aggressive histological subtypes, and poor prognosis. AKNA knockdown promoted EC cell proliferation, migration, invasion, and epithelial-mesenchymal transition, while enhancing M2 macrophage polarization and reducing sensitivity to paclitaxel and potentially compromising anti-tumor innate immunity. Conversely, AKNA overexpression or STING activation by cyclic GMP–AMP reversed these malignant phenotypes. Mechanistically, AKNA directly bound to the STING promoter and transcriptionally activated STING, thereby inducing TANK-binding kinase 1 and interferon regulatory factor 3 phosphorylation. The nomogram combining AKNA with clinicopathological features demonstrated high accuracy in predicting EC recurrence and outperformed single-variable models in both training and validation cohorts. Conclusions: AKNA deficiency promotes EC progression by transcriptionally suppressing STING and driving M2 macrophage polarization. AKNA serves as a robust prognostic biomarker and predictive indicator for chemotherapy and innate immune modulation, offering a promising therapeutic target for precision treatment of EC.
SN - 1664-3224
ER -