Knockdown of DNAJC12 slows tumor progression and affects tumor radiosensitivity in esophageal squamous cell carcinoma
Abstract
Purpose: To look into the influence of DNAJC12 knockdown on the progression and radio-sensitivity of esophageal squamous cell carcinoma (ESCC), with a focus on cellular mechanics and tumor microenvironment interactions. Methods: The TCGA database combined with immunohistochemical staining was used to validate the DNAJC12 expression in ESCC patients from the perspective of the clinic. DNAJC12 knockdown was performed in TE-1 and KYSE-150 cell lines to assess changes in proliferation, migration, invasion, apoptosis, and cellular mechanical properties (e.g., stiffness, adhesion, and contractility). The downstream molecule regulated by DNAJC12 was explored using Western blotting and biomechanical assays. The effect of DNAJC12 knockdown on tumor radiosensitivity was evaluated in vivo, with a focus on tumor stiffness and extracellular matrix (ECM) remodeling under irradiated conditions. Results: Upon analyzing the TCGA database and examining tumor tissue samples from patients, it was discovered that DNAJC12 exhibited high expression levels in tissues of ESCC. Vitro experiments showed that DNAJC12 knockdown significantly decreased cellular proliferation and migration (P < 0.05). Biomechanical assays revealed that DNAJC12 knockdown decreased cellular stiffness and contractility, suggesting a role in regulating cytoskeletal dynamics. Molecular analysis showed downregulation of P-ERK, MMP-2, N-Cadherin, P-P38, Snail, Vimentin, β-Catenin, Fibronectin, and Twist alongside upregulation of E-Cadherin (P < 0.05). Overexpression of SNAI1 could restore the proliferative and migratory capabilities of cells with downregulated DNAJC12. In vivo experiments, knockdown of DNAJC12 resulted in faster tumor growth under irradiated conditions (P < 0.05). Conclusion: DNAJC12 knockdown slows ESCC progression by modulating cellular biomechanical properties and molecular pathways. However, it enhances tumor growth post-radiotherapy, potentially due to altered mechanosensitive signaling and ECM remodeling. These findings highlight the interplay between molecular biology and biomechanics in ESCC progression and treatment response.
References
1. Cao W, Chen HD, Yu YW, et al. Changing profiles of cancer burden worldwide and in China: a secondary analysis of the global cancer statistics 2020. Chinese Medical Journal. 2021; 134(7): 783-791. doi: 10.1097/cm9.0000000000001474
2. Procopio F, Marano S, Gentile D, et al. Management of Liver Oligometastatic Esophageal Cancer: Overview and Critical Analysis of the Different Loco-Regional Treatments. Cancers. 2019; 12(1): 20. doi: 10.3390/cancers12010020
3. Puhr HC, Prager GW, Ilhan-Mutlu A. How we treat esophageal squamous cell carcinoma. ESMO Open. 2023; 8(1): 100789. doi: 10.1016/j.esmoop.2023.100789
4. Macario AJ, Conway DME. Molecular chaperones: Multiple functions, pathologies, and potential applications. Frontiers in Bioscience. 2007; 12(1): 2588. doi: 10.2741/2257
5. Liu T, Daniels CK, Cao S. Comprehensive review on the HSC70 functions, interactions with related molecules and involvement in clinical diseases and therapeutic potential. Pharmacology & Therapeutics. 2012; 136(3): 354-374. doi: 10.1016/j.pharmthera.2012.08.014
6. Euhus D, Bu D, Xie XJ, et al. Tamoxifen DownregulatesEtsOncogene Family Members ETV4 and ETV5 in Benign Breast Tissue: Implications for Durable Risk Reduction. Cancer Prevention Research. 2011; 4(11): 1852-1862. doi: 10.1158/1940-6207.capr-11-0186
7. He HL, Lee YE, Chen HP, et al. Overexpression of DNAJC12 predicts poor response to neoadjuvant concurrent chemoradiotherapy in patients with rectal cancer. Experimental and Molecular Pathology. 2015; 98(3): 338-345. doi: 10.1016/j.yexmp.2015.03.029
8. Uno Y, Kanda M, Miwa T, et al. Increased Expression of DNAJC12 is Associated with Aggressive Phenotype of Gastric Cancer. Annals of Surgical Oncology. 2019; 26(3): 836-844. doi: 10.1245/s10434-018-07149-y
9. Cajigas-Du Ross CK, Martinez SR, Woods-Burnham L, et al. RNA sequencing reveals upregulation of a transcriptomic program associated with stemness in metastatic prostate cancer cells selected for taxane resistance. Oncotarget. 2018; 9(54): 30363-30384. doi: 10.18632/oncotarget.25744
10. Lee J, Hahn Y, Yun JH, et al. Characterization of JDP genes, an evolutionarily conserved J domain-only protein family, from human and moths. Biochim Biophys Acta. 2000; 1491(1-3): 355-363. doi: 10.1016/S0167-4781(00)00047-6
11. Choi J, Djebbar S, Fournier A, et al. The co-chaperone DNAJC12 binds to Hsc70 and is upregulated by endoplasmic reticulum stress. Cell Stress and Chaperones. 2014; 19(3): 439-446. doi: 10.1007/s12192-013-0471-6
12. Li Y, Li M, Jin F, et al. DNAJC12 promotes lung cancer growth by regulating the activation of β catenin. International Journal of Molecular Medicine. 2021; 47(6). doi: 10.3892/ijmm.2021.4938
13. Fan YC, Meng ZY, Zhang CS, et al. DNAJ heat shock protein family member C1 can regulate proliferation and migration in hepatocellular carcinoma. Peerj; 2023.
14. Zhong BX, Shen FM, Chen JK. The role of HSP40 in cancer: Recent advances. Histol Histopathol. 2024; 39(7): 845-851. doi: 10.14670/HH-18-693
15. Hanahan D, Weinberg RA. Hallmarks of Cancer: The Next Generation. Cell. 2011; 144(5): 646-674. doi: 10.1016/j.cell.2011.02.013
16. Liu Y, Xiong Z, Beasley A, et al. Personalized and targeted therapy of esophageal squamous cell carcinoma: an update. Annals of the New York Academy of Sciences. 2016; 1381(1): 66-73. doi: 10.1111/nyas.13144
17. Olson MF. Mechanisms of tumour cell invasion and metastasis. Journal of Molecular Medicine. 2007; 85(6): 543-544. doi: 10.1007/s00109-007-0189-y
18. Dong B, Wu Y. Epigenetic Regulation and Post-Translational Modifications of SNAI1 in Cancer Metastasis. International Journal of Molecular Sciences. 2021; 22(20): 11062. doi: 10.3390/ijms222011062
19. Ma T, Zhao Y, Lu Q, et al. MicroRNA-30c functions as a tumor suppressor via targeting SNAI1 in esophageal squamous cell carcinoma. Biomedicine & Pharmacotherapy. 2018; 98: 680-686. doi: 10.1016/j.biopha.2017.12.095
20. Abudureheman A, Ainiwaer J, Hou Z, et al. High MLL2 expression predicts poor prognosis and promotes tumor progression by inducing EMT in esophageal squamous cell carcinoma. Journal of Cancer Research and Clinical Oncology. 2018; 144(6): 1025-1035. doi: 10.1007/s00432-018-2625-5
21. Li F, Lv JH, Liang L, et al. Downregulation of microRNA-21 inhibited radiation-resistance of esophageal squamous cell carcinoma. Cancer Cell International. 2018; 18(1). doi: 10.1186/s12935-018-0502-6
22. Cho EJ, Kim JK, Baek HJ, et al. Preclinical evaluation of radiation therapy of BRCA1-associated mammary tumors using a mouse model. International Journal of Biological Sciences. 2021; 17(3): 689-701. doi: 10.7150/ijbs.53667
23. Jing S, Guo H, Qi Y, et al. A portable fast neutron irradiation system for tumor therapy. Applied Radiation and Isotopes. 2020; 160: 109138. doi: 10.1016/j.apradiso.2020.109138
24. van Spronsen FJ, Himmelreich N, Rüfenacht V, et al. Heterogeneous clinical spectrum of DNAJC12-deficient hyperphenylalaninemia: from attention deficit to severe dystonia and intellectual disability. Journal of Medical Genetics. 2017; 55(4): 249-253. doi: 10.1136/jmedgenet-2017-104875
Copyright (c) 2025 Author(s)
This work is licensed under a Creative Commons Attribution 4.0 International License.
Copyright on all articles published in this journal is retained by the author(s), while the author(s) grant the publisher as the original publisher to publish the article.
Articles published in this journal are licensed under a Creative Commons Attribution 4.0 International, which means they can be shared, adapted and distributed provided that the original published version is cited.
Submit a Paper
