Advances in the Pathogenesis of Fetal Growth Restriction by HMGA2

doi:10.12280/gjfckx.20241066

Abstract

Abstract:

Fetal growth restriction (FGR) is one of the major pregnancy complications leading to stillbirth and adverse outcomes in newborns, with complex pathogenesis and limited clinical treatment. High-mobility group protein A2 (HMGA2), a non-histone chromatin protein, plays a key role in embryonic development, angiogenesis and apoptosis regulation. Recent studies have shown that HMGA2 may be involved in the pathological process of FGR by regulating angiogenesis, endothelial cell function and multi-organ development-related signalling pathways. This article reviews the research progress of HMGA2 in the pathogenesis of FGR and explores its potential role in placental function, foetal hypoxia tolerance and organ development, with aim of providing a new theoretical basis and intervention strategy for the early prediction, diagnosis and targeted treatment of FGR. The in-depth study of the function of HMGA2 and its regulatory network will not only helps to reveal the molecular mechanism of FGR, but also lays an important foundation for the development of precision medicine therapeutic solutions in the future.

Key words: Fetal growth retardation, Fetal development, HMGA2 protein, Signal transduction, Vascular endothelial growth factors

HOU Chun-yan, DU Xiu-ping, WANG Hong-hong, HOU Yue-yang. Advances in the Pathogenesis of Fetal Growth Restriction by HMGA2[J]. Journal of International Obstetrics and Gynecology, 2025, 52(2): 127-131.

References 31

[1]	Giouleka S, Tsakiridis I, Mamopoulos A, et al. Fetal Growth Restric-tion: A Comprehensive Review of Major Guidelines[J]. Obstet Gynecol Surv, 2023, 78(11):690-708. doi: 10.1097/OGX.0000000000001203. pmid: 38134339
[2]	Sehgal A, Murthi P, Dahlstrom JE. Vascular changes in fetal growth restriction: clinical relevance and future therapeutics[J]. J Perinatol, 2019, 39(3):366-374. doi: 10.1038/s41372-018-0287-4. pmid: 30518801
[3]	Fetal Growth Restriction: ACOG Practice Bulletin, Number 227[J]. Obstet Gynecol, 2021, 137(2):e16-e28. doi: 10.1097/AOG.0000000000004251. pmid: 33481528
[4]	Naik VD, Lee J, Wu G, et al. Effects of nutrition and gestational alcohol consumption on fetal growth and development[J]. Nutr Rev, 2022, 80(6):1568-1579. doi: 10.1093/nutrit/nuab119.
[5]	Burton GJ, Jauniaux E. Pathophysiology of placental-derived fetal growth restriction[J]. Am J Obstet Gynecol, 2018, 218(2S):S745-S761. doi: 10.1016/j.ajog.2017.11.577.
[6]	Atallah A, Butin M, Moret S, et al. Fetal growth restriction: underdiagnosed condition with non-optimal screening[J]. J Matern Fetal Neonatal Med, 2022, 35(25):8237-8244. doi: 10.1080/14767058.2021.1967924.
[7]	Mecacci F, Avagliano L, Lisi F, et al. Fetal Growth Restriction: Does an Integrated Maternal Hemodynamic-Placental Model Fit Better?[J]. Reprod Sci, 2021, 28(9):2422-2435. doi: 10.1007/s43032-020-00393-2. pmid: 33211274
[8]	Mansoori B, Mohammadi A, Ditzel HJ, et al. HMGA2 as a Critical Regulator in Cancer Development[J]. Genes(Basel), 2021, 12(2):269. doi: 10.3390/genes12020269.
[9]	Zhang S, Mo Q, Wang X. Oncological role of HMGA2 (Review)[J]. Int J Oncol, 2019, 55(4):775-788. doi: 10.3892/ijo.2019.4856. pmid: 31432151
[10]	Ferrero H. HMGA2 involvement in uterine leiomyomas development through angiogenesis activation[J]. Fertil Steril, 2020, 114(5):974-975. doi: 10.1016/j.fertnstert.2020.07.044. pmid: 32943224
[11]	Lee MO, Li J, Davis BW, et al. Hmga2 deficiency is associated with allometric growth retardation, infertility, and behavioral abnormalities in mice[J]. G3(Bethesda), 2022, 12(2):jkab417. doi: 10.1093/g3journal/jkab417.
[12]	Wang J, Chen Y, Zeng Z, et al. HMGA2 contributes to vascular development and sprouting angiogenesis by promoting IGFBP2 production[J]. Exp Cell Res, 2021, 408(1):112831. doi: 10.1016/j.yexcr.2021.112831.
[13]	Li T, Forbes ME, Fuller GN, et al. IGFBP2: integrative hub of developmental and oncogenic signaling network[J]. Oncogene, 2020, 39(11):2243-2257. doi: 10.1038/s41388-020-1154-2. pmid: 31925333
[14]	Khazem F, Zetoune AB. Decoding high mobility group A2 protein expression regulation and implications in human cancers[J]. Discov Oncol, 2024, 15(1):322. doi: 10.1007/s12672-024-01202-x. pmid: 39085703
[15]	Matsumoto T, Claesson-Welsh L. VEGF receptor signal transduction[J]. Sci STKE, 2001, 2001(112):re21. doi: 10.1126/stke.2001.112.re21.
[16]	Su EJ. Role of the fetoplacental endothelium in fetal growth restriction with abnormal umbilical artery Doppler velocimetry[J]. Am J Obstet Gynecol, 2015, 213(Suppl 4):S123-S130. doi: 10.1016/j.ajog.2015.06.038.
[17]	Cai ZL, Liu C, Yao Q, et al. The pro-migration and anti-apoptosis effects of HMGA2 in HUVECs stimulated by hypoxia[J]. Cell Cycle, 2020, 19(24):3534-3545. doi: 10.1080/15384101.2020.1850970.
[18]	Zhao Y, Xing C, Deng Y, et al. HIF-1α signaling: Essential roles in tumorigenesis and implications in targeted therapies[J]. Genes Dis, 2024, 11(1):234-251. doi: 10.1016/j.gendis.2023.02.039. pmid: 37588219
[19]	Xie Y, Shi X, Sheng K, et al. PI3K/Akt signaling transduction pathway, erythropoiesis and glycolysis in hypoxia (Review)[J]. Mol Med Rep, 2019, 19(2):783-791. doi: 10.3892/mmr.2018.9713. pmid: 30535469
[20]	Singh I, Mehta A, Contreras A, et al. Hmga2 is required for canonical WNT signaling during lung development[J]. BMC Biol, 2014, 12:21. doi: 10.1186/1741-7007-12-21. pmid: 24661562
[21]	Vignali R, Marracci S. HMGA Genes and Proteins in Development and Evolution[J]. Int J Mol Sci, 2020, 21(2):654. doi: 10.3390/ijms21020654.
[22]	Negishi T, Mihara N, Chiba T, et al. High mobility group AT-hook 2 regulates osteoblast differentiation and facial bone development[J]. Biochem Biophys Res Commun, 2022, 590:68-74. doi: 10.1016/j.bbrc.2021.12.093.
[23]	Liu J, Xiao Q, Xiao J, et al. Wnt/β-catenin signalling: function, biological mechanisms, and therapeutic opportunities[J]. Signal Transduct Target Ther, 2022, 7(1):3. doi: 10.1038/s41392-021-00762-6.
[24]	Dietrich B, Haider S, Meinhardt G, et al. WNT and NOTCH signaling in human trophoblast development and differentiation[J]. Cell Mol Life Sci, 2022, 79(6):292. doi: 10.1007/s00018-022-04285-3. pmid: 35562545
[25]	Dai FQ, Li CR, Fan XQ, et al. miR-150-5p Inhibits Non-Small-Cell Lung Cancer Metastasis and Recurrence by Targeting HMGA2 and β-Catenin Signaling[J]. Mol Ther Nucleic Acids, 2019, 16:675-685. doi: 10.1016/j.omtn.2019.04.017.
[26]	张文俊, 王明祥, 宋沁哲, 等. HMGA2通过Wnt/β-catenin信号通路促进结直肠癌上皮间质转化的研究[J]. 中国现代普通外科进展, 2023, 26(4):253-257. doi: 10.3969/j.issn.1009-9905.2023.04.001.
[27]	Singh A, Pajni K, Panigrahi I, et al. Clinical and Molecular Heterogeneity of Silver-Russell Syndrome and Therapeutic Challenges: A Systematic Review[J]. Curr Pediatr Rev, 2023, 19(2):157-168. doi: 10.2174/1573396318666220315142542.
[28]	Maharaj AV, Cottrell E, Thanasupawat T, et al. Characterization of HMGA2 variants expands the spectrum of Silver-Russell syndrome[J]. JCI Insight, 2024, 9(6):e169425. doi: 10.1172/jci.insight.169425.
[29]	Abi Habib W, Brioude F, Edouard T, et al. Genetic disruption of the oncogenic HMGA2-PLAG1-IGF2 pathway causes fetal growth restriction[J]. Genet Med, 2018, 20(2):250-258. doi: 10.1038/gim.2017.105. pmid: 28796236
[30]	Tse WT, Bass C, Gurney L, et al. Maternally inherited autosomal dominant PLAG-1 related Silver Russell syndrome in a fetus with intra-uterine growth restriction[J]. Prenat Diagn, 2023, 43(6):724-726. doi: 10.1002/pd.6364.
[31]	Harris LK, Pantham P, Yong H, et al. The role of insulin-like growth factor 2 receptor-mediated homeobox gene expression in human placental apoptosis, and its implications in idiopathic fetal growth restriction[J]. Mol Hum Reprod, 2019, 25(9):572-585. doi: 10.1093/molehr/gaz047. pmid: 31418778