AccScience Publishing / EJMO / Online First / DOI: 10.36922/EJMO025150096
Submit to EJMO
Cite this article
3
Download
14
Views
Journal Browser
Volume | Year
Issue
Search
Forthcoming Issue
Current Issue
View All
News and Announcements
View All
ORIGINAL RESEARCH ARTICLE

Vitamin D/Vitamin D receptor signaling suppresses gastric cancer metastasis through autophagy-related protein 13/Beclin1-mediated autophagy

Jinrui Yang1,2 ,  Linyun Tan3 ,  Ruolin Shi1,2 ,  Qian Hu1,2 ,  Yinhong Gu4 ,  Chao Du1,2*
Show Less
1 Institute of Biomedical Engineering, College of Medicine, Southwest Jiaotong University, Chengdu, Sichuan, China
2 Department of Gastroenterology, The General Hospital of Western Theater Command, College of Medicine, Chengdu, Sichuan, China
3 Department of Orthopedics, Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, Sichuan, China
4 Department of Clinical Medicine, College of Clinical Medicine, Chengdu Medical College, Chengdu, Sichuan, China
EJMO, 025150096 https://doi.org/10.36922/EJMO025150096
Received: 8 April 2025 | Revised: 12 May 2025 | Accepted: 22 May 2025 | Published online: 13 August 2025
© 2025 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution -Noncommercial 4.0 International License (CC-by the license) ( https://creativecommons.org/licenses/by-nc/4.0/ )
Download PDF
Cite
XML
Abstract

Introduction: Gastric cancer (GC) exhibits a poor prognosis with high metastasis rates. This study investigates Vitamin D receptor’s (VDRs) role in suppressing GC metastasis through autophagy.

Objective: To elucidate the molecular mechanism by which VDR suppresses GC invasion and metastasis through autophagy regulation.

Methods: VDR expression was assessed in 91 paired GC and adjacent normal tissues using immunohistochemistry. The effects of Vitamin D on GC cell proliferation, cell cycle, migration, and invasion were evaluated using Cell Counting Kit-8, flow cytometry, wound healing, and Transwell assays. The autophagic activity was examined through LysoTracker Red staining, monomeric red fluorescent protein-green fluorescent protein-LC3 fluorescence, and transmission electron microscopy. The roles of VDR, autophagy-related protein 13 (ATG13), and Beclin1 in autophagy regulation were investigated through gene knockdown and silencing. A nude mouse peritoneal metastasis model was used to validate the anti-metastatic effects of the Vitamin D/VDR pathway.

Results: VDR expression was significantly downregulated in GC tissues, correlating with lymph node metastasis and poor prognosis (p<0.001). Vitamin D treatment upregulated VDR, ATG13, and Beclin1 expression, enhancing autophagosome and autolysosome formation without altering cell proliferation or apoptosis, likely due to a cytostatic autophagic response. Silencing ATG13 or BECN1 abolished the inhibitory effects of Vitamin D/VDR signaling on cell migration and invasion. VDR knockdown promoted peritoneal metastasis, whereas Vitamin D treatment suppressed it.

Conclusion: This study provides novel evidence that Vitamin D/VDR signaling inhibits GC metastasis by influencing ATG13/Beclin1-mediated autophagy, offering potential therapeutic targets for GC management.

Keywords
Vitamin D signaling
Gastric cancer metastasis
Autophagy regulation
Vitamin D receptor
Autophagy-related protein 13
Beclin1
Funding
This work was supported by the Military Medical Science and Technology Youth Program (Grant No. 21QNPY121) and the National Natural Science Foundation of China (Grant No. 81702931).
Conflict of interest
The authors declare no conflict of interest.
References
  1. Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209-249. doi: 10.3322/caac.21660

 

  1. Cao W, Chen HD, Yu YW, Li N, Chen WQ. Changing profiles of cancer burden worldwide and in China: A secondary analysis of the global cancer statistics 2020. Chin Med J (Engl). 2021;134(7):783-791. doi: 10.1097/cm9.0000000000001474

 

  1. He Y, Wang Y, Luan F, et al. Chinese and global burdens of gastric cancer from 1990 to 2019. Cancer Med. 2021;10(10):3461-3473. doi: 10.1002/cam4.3892

 

  1. Seeneevassen L, Bessède E, Mégraud F, Lehours P, Dubus P, Varon C. Gastric cancer: Advances in carcinogenesis research and new therapeutic strategies. Int J Mol Sci. 2021;22(7):3418. doi: 10.3390/ijms22073418

 

  1. Haussler MR, Whitfield GK, Kaneko I, et al. Molecular mechanisms of vitamin D action. Calcif Tissue Int. 2013;92(2):77-98. doi: 10.1007/s00223-012-9619-0

 

  1. Pike JW, Meyer MB. Fundamentals of vitamin D hormone-regulated gene expression. J Steroid Biochem Mol Biol. 2014;144 Pt A:5-11. doi: 10.1016/j.jsbmb.2013.11.004

 

  1. Zella LA, Kim S, Shevde NK, Pike JW. Enhancers located within two introns of the vitamin D receptor gene mediate transcriptional autoregulation by 1,25-dihydroxyvitamin D3. Mol Endocrinol. 2006;20(6):1231-1247. doi: 10.1210/me.2006-0015

 

  1. Haussler MR, Whitfield GK, Haussler CA, et al. The nuclear vitamin D receptor: Biological and molecular regulatory properties revealed. J Bone Miner Res. 1998;13(3):325-349. doi: 10.1359/jbmr.1998.13.3.325

 

  1. Li H, Stampfer MJ, Hollis JB, et al. A prospective study of plasma vitamin D metabolites, vitamin D receptor polymorphisms, and prostate cancer. PLoS Med. 2007;4(3):e103. doi: 10.1371/journal.pmed.0040103

 

  1. Gross M, Kost SB, Ennis B, Stumpf W, Kumar R. Effect of 1,25-dihydroxyvitamin D3 on mouse mammary tumor (GR) cells: Evidence for receptors, cellular uptake, inhibition of growth and alteration in morphology at physiologic concentrations of hormone. J Bone Miner Res. 1986;1(5):457-467. doi: 10.1002/jbmr.5650010510

 

  1. Moossavi M, Parsamanesh N, Mohammadoo-Khorasani M, et al. Positive correlation between vitamin D receptor gene FokI polymorphism and colorectal cancer susceptibility in South-Khorasan of Iran. J Cell Biochem. 2018;119(10):8190-8194. doi: 10.1002/jcb.26826

 

  1. Xu Y, He B, Pan Y, et al. Systematic review and meta-analysis on vitamin D receptor polymorphisms and cancer risk. Tumour Biology. 2014;35(5):4153-4169. doi: 10.1007/s13277-013-1544-y

 

  1. Gnagnarella P, Pasquali E, Serrano D, Raimondi S, Disalvatore D, Gandini S. Vitamin D receptor polymorphism FokI and cancer risk: A comprehensive meta-analysis. Carcinogenesis. 2014;35(9):1913-1619. doi: 10.1093/carcin/bgu150

 

  1. Chen WY, Bertone-Johnson ER, Hunter DJ, Willett WC, Hankinson SE. Associations between polymorphisms in the vitamin D receptor and breast cancer risk. Cancer Epidemiol Biomarkers Prev. 2005;14(10):2335-2339. doi: 10.1158/1055-9965.Epi-05-0283

 

  1. Bid HK, Kumar A, Kapoor R, Mittal RD. Association of vitamin D receptor-gene (FokI) polymorphism with calcium oxalate nephrolithiasis. J Endourol. 2005;19(1):111-115. doi: 10.1089/end.2005.19.111

 

  1. Jurutka PW, Whitfield GK, Hsieh JC, Thompson PD, Haussler CA, Haussler MR. Molecular nature of the vitamin D receptor and its role in regulation of gene expression. Rev Endocr Metab Disord. 2001;2(2):203-216. doi: 10.1023/a:1010062929140

 

  1. Colin EM, Weel AE, Uitterlinden AG, et al. Consequences of vitamin D receptor gene polymorphisms for growth inhibition of cultured human peripheral blood mononuclear cells by 1, 25-dihydroxyvitamin D3. Clin Endocrinol (Oxf). 2000;52(2):211-216. doi: 10.1046/j.1365-2265.2000.00909.x

 

  1. Galluzzi L, Pietrocola F, Bravo-San Pedro JM, et al. Autophagy in malignant transformation and cancer progression. EMBO J. 2015;34(7):856-880. doi: 10.15252/embj.201490784

 

  1. Debnath J, Gammoh N, Ryan KM. Autophagy and autophagy-related pathways in cancer. Nat Rev Mol Cell Biol. 2023;24(8):560-575. doi: 10.1038/s41580-023-00585-z

 

  1. Li W, Zhou C, Yu L, et al. Tumor-derived lactate promotes resistance to bevacizumab treatment by facilitating autophagy enhancer protein RUBCNL expression through histone H3 lysine 18 lactylation (H3K18la) in colorectal cancer. Autophagy. 2024;20(1):114-130. doi: 10.1080/15548627.2023.2249762

 

  1. Dong Y, Jin Q, Sun M, et al. CLDN6 inhibits breast cancer metastasis through WIP-dependent actin cytoskeleton-mediated autophagy. J Exp Clin Cancer Res. 2023;42(1):68. doi: 10.1186/s13046-023-02644-x

 

  1. Li Y, Cook KL, Yu W, et al. Inhibition of antiestrogen-promoted pro-survival autophagy and tamoxifen resistance in breast cancer through vitamin D receptor. Nutrients. 2021;13(5):1715. doi: 10.3390/nu13051715

 

  1. Sharma K, Goehe RW, Di X, et al. A novel cytostatic form of autophagy in sensitization of non-small cell lung cancer cells to radiation by vitamin D and the vitamin D analog, EB 1089. Autophagy. 2014;10(12):2346-2361. doi: 10.4161/15548627.2014.993283

 

  1. Amin MB, Greene FL, Edge SB, et al. The eighth edition AJCC cancer staging manual: Continuing to build a bridge from a population-based to a more “personalized” approach to cancer staging. CA Cancer J Clin. 2017;67(2):93-99. doi: 10.3322/caac.21388

 

  1. Tavera-Mendoza LE, Westerling T, Libby E, et al. Vitamin D receptor regulates autophagy in the normal mammary gland and in luminal breast cancer cells. Proc Natl Acad Sci U S A. 2017;114(11):E2186-E2194. doi: 10.1073/pnas.1615015114

 

  1. Gao JP, Xu W, Liu WT, Yan M, Zhu ZG. Tumor heterogeneity of gastric cancer: From the perspective of tumor-initiating cell. World J Gastroenterol. 2018;24(24):2567-2581. doi: 10.3748/wjg.v24.i24.2567

 

  1. Ho SWT, Tan P. Dissection of gastric cancer heterogeneity for precision oncology. Cancer Sci. 2019;110(11):3405-3414. doi: 10.1111/cas.14191

 

  1. Zhang Y, Li Y, Wei Y, Cong L. Molecular mechanism of vitamin D receptor modulating wnt/β-catenin signaling pathway in gastric cancer. J Cancer. 2023;14(17):3285-3294. doi: 10.7150/jca.81034

 

  1. Wen Y, Da M, Zhang Y, Peng L, Yao J, Duan Y. Alterations in vitamin D signaling pathway in gastric cancer progression: A study of vitamin D receptor expression in human normal, premalignant, and malignant gastric tissue. Int J Clin Exp Pathol. 2015;8(10):13176-13184.

 

  1. Parsamanesh N, Moossavi M, Tavakkoli T, et al. Positive correlation between vitamin D receptor gene TaqI variant and gastric cancer predisposition in a sample of Iranian population. J Cell Physiol. 2019;234(9):15044-15047. doi: 10.1002/jcp.28145

 

  1. Cong L, Wang WB, Liu Q, Du JJ. FokI polymorphism of the vitamin D receptor gene is associated with susceptibility to gastric cancer: A case-control study. Tohoku J Exp Med. 2015;236(3):219-224. doi: 10.1620/tjem.236.219

 

  1. Chen Y, Du J, Zhang Z, et al. MicroRNA-346 mediates tumor necrosis factor α-induced downregulation of gut epithelial vitamin D receptor in inflammatory bowel diseases. Inflamm Bowel Dis. 2014;20(11):1910-1918. doi: 10.1097/mib.0000000000000158

 

  1. Wang J, Gong M, Fan X, Huang D, Zhang J, Huang C. Autophagy-related signaling pathways in non-small cell lung cancer. Mol Cell Biochem. 2022;477(2):385-393. doi: 10.1007/s11010-021-04280-5

 

  1. Pangilinan C, Klionsky DJ, Liang C. Emerging dimensions of autophagy in melanoma. Autophagy. 2024;20(8):1700-1711. doi: 10.1080/15548627.2024.2330261

 

  1. Kimmelman AC, White E. Autophagy and tumor metabolism. Cell Metab. 2017;25(5):1037-1043. doi: 10.1016/j.cmet.2017.04.004

 

  1. Kung CP, Budina A, Balaburski G, Bergenstock MK, Murphy M. Autophagy in tumor suppression and cancer therapy. Crit Rev Eukaryot Gene Expr. 2011;21(1):71-100. doi: 10.1615/critreveukargeneexpr.v21.i1.50

 

  1. Zhang QY, Wu LQ, Zhang T, Han YF, Lin X. Autophagy-mediated HMGB1 release promotes gastric cancer cell survival via RAGE activation of extracellular signal-regulated kinases 1/2. Oncol Rep. 2015;33(4):1630-1638. doi: 10.3892/or.2015.3782

 

  1. Qin W, Li C, Zheng W, et al. Inhibition of autophagy promotes metastasis and glycolysis by inducing ROS in gastric cancer cells. Oncotarget. 2015;6(37):39839-39854. doi: 10.18632/oncotarget.5674

 

  1. Onorati AV, Dyczynski M, Ojha R, Amaravadi RK. Targeting autophagy in cancer. Cancer. 2018;124(16):3307-3318. doi: 10.1002/cncr.31335

 

  1. Gugnoni M, Sancisi V, Manzotti G, Gandolfi G, Ciarrocchi A. Autophagy and epithelial-mesenchymal transition: An intricate interplay in cancer. Cell Death Dis. 2016;7(12):e2520. doi: 10.1038/cddis.2016.415

 

  1. Zhang Z, Yu X, Cheng G. Vitamin D sensitizes cervical cancer to radiation-induced apoptosis by inhibiting autophagy through degradation of ambra1. Cell Death Discov. 2025;11(1):1. doi: 10.1038/s41420-024-02279-7

 

  1. Seuter S, Neme A, Carlberg C. Epigenome-wide effects of vitamin D and their impact on the transcriptome of human monocytes involve CTCF. Nucleic Acids Res. 2016;44(9):4090-4104. doi: 10.1093/nar/gkv1519

 

  1. DeSmet ML, Fleet JC. Constitutively active RAS signaling reduces 1,25 dihydroxyvitamin D-mediated gene transcription in intestinal epithelial cells by reducing vitamin D receptor expression. J Steroid Biochem Mol Biol. 2017;173:194-201. doi: 10.1016/j.jsbmb.2017.01.008

 

  1. Manson JE, Cook NR, Lee IM, et al. Vitamin D supplements and prevention of cancer and cardiovascular disease. N Engl J Med. 2019;380(1):33-44. doi: 10.1056/NEJMoa1809944
Share
Back to top
Eurasian Journal of Medicine and Oncology, Electronic ISSN: 2587-196X Print ISSN: 2587-2400, Published by AccScience Publishing
We use cookies on our website to ensure you get the best experience.
Read more about our cookies here
Accept