The Journal of Practical Medicine >

2025 , Vol. 41 >Issue 20: 3135 - 3144

DOI: https://doi.org/10.3969/j.issn.1006-5725.2025.20.001

Basic Research

The role of GPNMB in hypoxia induced epithelial-mesenchymal transition in human chorionic trophoblast cells

  • Tian TIAN ,
  • Ping CAO ,
  • Xuhong ZHANG ,
  • Xiaohong MA ,
  • Jingrui LI ,
  • Xueqin DING ,
  • Xiaoming. YANG
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  • *.National Health Commission Key Laboratory of Metabolic Cardiovascular Disease Research，Yinchuan 750004，Ningxia，China

Received date: 2025-07-08

  Online published: 2025-11-05

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Abstract

Objective To investigate the role of Glycoprotein non-metastatic melanoma protein B （GPNMB） in hypoxia-induced epithelial–mesenchymal transition （EMT） in human chorionic trophoblast HTR-8/SVneo cells. Methods HTR-8/SVneo cells were cultured in vitro to investigate the effect of hypoxia on GPNMB expression. The cells were transfected with either a GPNMB overexpression plasmid （pcDNA3.1-GPNMB）， small interfering RNA targeting GPNMB （si-GPNMB-1/2）， or their respective negative controls （pcDNA3.1-NC or si-NC）， and were also treated with the autophagy agonist rapamycin （Rap）. The experimental groups were categorized as follows： Normoxia， Hypoxia， Normoxia/Hypoxia + si-NC or si-GPNMB， Normoxia/Hypoxia + pcDNA3.1-NC or pcDNA3.1-GPNMB， Normoxia/Hypoxia + Rap， and Hypoxia + Rap + pcDNA3.1-NC or pcDNA3.1-GPNMB. GPNMB expression levels were evaluated using qRT-PCR， Western blotting， and immunofluorescence staining. The expression of autophagy-related proteins （LC3B Ⅱ/Ⅰ， p62） and epithelial-mesenchymal transition （EMT） markers （E-cadherin， N-cadherin） was analyzed by Western blotting. Cell migration and invasion capacities were assessed using wound healing and Transwell assays. Results Compared with the Normoxia group， the mRNA and protein levels of GPNMB were downregulated in the Hypoxia group. Additionally， the protein levels of p62 and N-cadherin were reduced， while LC3B Ⅱ/Ⅰ and E-cadherin expression levels were increased （P < 0.05）. Compared with the Hypoxia + si-NC group， the Hypoxia + si-GPNMB-2 group showed significantly decreased protein levels of p62 and N-cadherin， along with elevated levels of LC3B Ⅱ/Ⅰ and E-cadherin （P < 0.05）. Compared with the Hypoxia + pcDNA3.1-NC group， the Hypoxia + pcDNA3.1-GPNMB group exhibited opposite trends. Notably， compared with the Hypoxia group， the Hypoxia + Rap group showed increased LC3B Ⅱ/Ⅰ and E-cadherin levels， accompanied by reduced p62 and N-cadherin levels （P < 0.05）. However， compared with the Hypoxia + pcDNA3.1-GPNMB group， the Hypoxia + Rap + pcDNA3.1-GPNMB group attenuated the promoting effect of GPNMB overexpression on EMT in HTR-8/SVneo cells， as evidenced by decreased p62 and N-cadherin protein expression levels and increased LC3B Ⅱ/Ⅰ and E-cadherin protein expression levels （P < 0.05）. Conclusion In hypoxia-induced HTR-8/SVneo cells， GPNMB inhibits autophagy， promotes the epithelial-mesenchymal transition， and enhances cell migration and invasion.

Key words： glycoprotein nonmetastatic melanoma protein B; human chorionic trophoblast cells; autophagy; epithelial-mesenchymal transition; migration; invasion

Cite this article

Tian TIAN , Ping CAO , Xuhong ZHANG , Xiaohong MA , Jingrui LI , Xueqin DING , Xiaoming. YANG . The role of GPNMB in hypoxia induced epithelial-mesenchymal transition in human chorionic trophoblast cells[J]. The Journal of Practical Medicine, 2025 , 41(20) : 3135 -3144 . DOI: 10.3969/j.issn.1006-5725.2025.20.001

References

[1] INVERSETTI A， PIVATO C A， CRISTODORO M， et al. Update on long-term cardiovascular risk after pre-eclampsia： A systematic review and meta-analysis［J］. Eur Heart J Qual Care， 2024， 10（1）： 4-13. doi:10.1093/ehjqcco/qcad065
[2] KIM S， SHIM S， KWON J， et al. Publisher Correction： Alleviation of preeclampsia-like symptoms through PlGF and eNOS regulation by hypoxia- and NF-κB-responsive miR-214-3p deletion［J］. Exp Mol Med， 2024， 56（7）： 1682. doi:10.1038/s12276-024-01275-2
[3] 李蕊， 林靓， 胡绪洋， 等. circIRAK3靶向miR-942-5p/LITAF轴调控滋养层细胞的增殖、迁移、侵袭和EMT［J］.华中科技大学学报（医学版）， 2023， 52（5）： 603-609.
[4] 胡琴，张晨曦，柯少瑞.细胞自噬调控上皮间质转化在肺纤维化中的作用机制［J］.实用医学杂志，2022，38（1）：38-44.
[5] TSOU P S， SAWALHA A H. Glycoprotein nonmetastatic melanoma protein B： A key mediator and an emerging therapeutic target in autoimmune diseases［J］. FASEB J， 2020， 34（7）： 8810-8823. doi:10.1096/fj.202000651
[6] VAN DER LIENDEN M J C， GASPAR P， BOOT R， et al. Glycoprotein Non-Metastatic Protein B： An Emerging Biomarker for Lysosomal Dysfunction in Macrophages［J］. Int J Mo Sci， 2018， 20（1）： 66. doi:10.3390/ijms20010066
[7] LIN Y， QI Y， JIANG M， et al. Lactic acid-induced M2-like macrophages facilitate tumor cell migration and invasion via the GPNMB/CD44 axis in oral squamous cell carcinoma［J］. Int Immunopharmacol， 2023， 124（Pt B）： 110972. doi:10.1016/j.intimp.2023.110972
[8] 刘惠娜，王一鸣，杨明磊，等.子痫前期风险预测基因的筛选［J］.郑州大学学报（医学版），2024，59（6）：816-820.
[9] 杨晓涛，韩顶立， N.Baker Philip， 等.体外缺氧诱导子痫前期滋养细胞模型优化及代谢组学鉴定［J］. 重庆医科大学学报， 2017， 42（8）： 1045-1052.
[10] SATO Y. Endovascular trophoblast and spiral artery remodeling［J］. Mol Cell Endocrinol， 2020， 503： 110699. doi:10.1016/j.mce.2019.110699
[11] CAI J， HAN X， PENG S， et al. Chemerin facilitates placental trophoblast invasion and spiral artery remodeling through the pentose phosphate pathway［J］. Life Sci， 2025， 373： 123645. doi:10.1016/j.lfs.2025.123645
[12] BARRAGáN-Zú?IGA L J， ESCALONA-RIVANO R， CORDERO-TIRADO C， et al. PLAC8 Expression Regulates Trophoblast Invasion and Conversion into an Endothelial Phenotype （eEVT）［J］. Int J Mol Sci， 2025， 26（11）： 5371. doi:10.3390/ijms26115371
[13] GAO Y， ZHANG X， MENG T. Overexpression of let-7b exerts beneficial effects on the functions of human placental trophoblasts by activating the ERK1/2 signaling pathway［J］. Mol Reprod Dev， 2022， 89（1）： 39-53. doi:10.1002/mrd.23535
[14] CHEN J， SONG T， YANG S， et al. Snail mediates GDF-8-stimulated human extravillous trophoblast cell invasion by upregulating MMP2 expression［J］. Cell Commun Signal， 2023， 21（1）： 93. doi:10.1186/s12964-023-01107-2
[15] LIU J， WANG Y， ZHANG S， et al. ADAM9 deubiquitination induced by USP22 suppresses proliferation， migration， invasion， and epithelial-mesenchymal transition of trophoblast cells in preeclampsia［J］. Placenta， 2024， 146： 50-57. doi:10.1016/j.placenta.2023.12.008
[16] LIU Y， WANG S， ZHANG X， et al. Circ_0001861 facilitates trophoblast cell proliferation， migration， invasion and epithelial-mesenchymal transition via the miR-296-5p/forkhead box protein 1 pathway in preeclampsia［J］. J Hypertens， 2024， 42（3）： 546-556. doi:10.1097/hjh.0000000000003634
[17] NAKASHIMA A， AOKI A， KUSABIRAKI T， et al. Autophagy regulation in preeclampsia： Pros and cons［J］. J Reprod Immunol， 2017， 123： 17-23. doi:10.1016/j.jri.2017.08.006
[18] WANG A， LI Z， ZHANG D， et al. Excessive ER-phagy mediated by FAM134B contributes to trophoblast cell mitochondrial dysfunction in preeclampsia［J］. Acta Biochim Biophys Sin， 2024， 56（10）： 1446-1459. doi:10.3724/abbs.2024065
[19] STRIPPOLI R， NIAYESH-MEHR R， ADELIPOUR M， et al. Contribution of Autophagy to Epithelial Mesenchymal Transition Induction during Cancer Progression［J］. Cancers， 2024， 16（4）： 807. doi:10.3390/cancers16040807
[20] WANG Y， PING Z， GAO H， et al. LYC inhibits the AKT signaling pathway to activate autophagy and ameliorate TGFB-induced renal fibrosis［J］. Autophagy， 2024， 20（5）： 1114-1133. doi:10.1080/15548627.2023.2287930
[21] ZHOU Z， WANG H， ZHANG X， et al. Defective autophagy contributes to endometrial epithelial-mesenchymal transition in intrauterine adhesions［J］. Autophagy， 2022， 18（10）： 2427-2442. doi:10.1080/15548627.2022.2038994
[22] GAO L， QI H B， KAMANA K C， et al. Excessive autophagy induces the failure of trophoblast invasion and vasculature： Possible relevance to the pathogenesis of preeclampsia［J］. J Hypertens， 2015， 33（1）： 106-117. doi:10.1097/hjh.0000000000000366
[23] YAN Z， HAN J， MI Z， et al. GPNMB disrupts SNARE complex assembly to maintain bacterial proliferation within macrophages［J］. Cell Mol Immunol， 2025， 22（5）： 512-526. doi:10.1038/s41423-025-01272-z
[24] WALLINGS R L， GILLETT D A， STALEY H A， et al. ASO-mediated knock-down of GPNMB in mutant-GRN and in Grn-deficient peripheral myeloid cells disrupts lysosomal function and immune responses［J］. Mol Neurodegener， 2025， 20（1）： 41. doi:10.1186/s13024-025-00829-w
[25] XU Y， WANG M， ZHANG L， et al. Glycoprotein Non-Metastatic Melanoma Protein B Restricts PRRSV Replication by Inhibiting Autophagosome-Lysosome Fusion［J］. Viruses， 2023， 15（4）： 920. doi:10.3390/v15040920
[26] YANG S， SUN Y， LONG M， et al. Single-cell transcriptome sequencing-based analysis： Probing the mechanisms of glycoprotein NMB regulation of epithelial cells involved in silicosis［J］. Part Fibre Toxicol， 2023， 20（1）： 29. doi:10.1186/s12989-023-00543-9
[27] ELHINNAWI M A， OKITA Y， SHIGEMATSU K， et al. GPNMB is a novel binding partner of FGFR1 that affects tumorigenic potential through AKT phosphorylation in TNBC［J］. Cancer Sci， 2025， 116（2）： 432-443. doi:10.1111/cas.16419
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