Objective Disruptions to trophoblast infiltration and placental implantation are recognized as pivotal early mechanisms underlying the pathogenesis of preeclampsia. Previous studies have reported the aberrant expression of PTPRN2 in preeclamptic placentas, yet its precise pathological role remains poorly defined. The present study investigated the functional involvement of PTPRN2 in regulating trophoblast invasion.
Methods PTPRN2 expression was detected by qRT-PCR and Western blotting in normal and preeclamptic placentas, as well as in HTR-8/SVneo cells cultured under normoxic or hypoxic conditions. HTR-8/SVneo cells were then transfected with a PTPRN2 overexpression plasmid. Transwell assays were performed to evaluate trophoblast invasion ability. Additionally, the expression of key Wnt/β-catenin signaling components, including β-catenin and GSK-3β was analyzed in PTPRN2-overexpressing HTR-8/SVneo cells and preeclamptic placentas.
Results Our results demonstrated that PTPRN2 was significantly upregulated in preeclamptic placental tissues. In vitro experiments further revealed that hypoxic exposure induced PTPRN2 expression in HTR-8/SVneo cells and that overexpression of PTPRN2 markedly suppressed the invasive ability of these cells. Moreover, hypoxia decreased the protein levels of β‑catenin and GSK‑3β in HTR-8/SVneo cells, and these effects were further exacerbated by PTPRN2 overexpression.
Conclusion Collectively, these findings indicate that hypoxia‑induced upregulation of PTPRN2 contributes to impaired trophoblast invasion via inhibition of the Wnt/β‑catenin signaling pathway.
| [1] |
Poon LC, Shennan A, Hyett JA, et al.. The International federation of gynecology and obstetrics (FIGO) initiative on pre-eclampsia: a pragmatic guide for first-trimester screening and prevention. Int J Gynecol Obstet, 2019, 145(S1): 1-33
|
| [2] |
Tsikouras P, Oikonomou E, Nikolettos K, et al.. The impact of periodontal disease on preterm birth and preeclampsia. J Pers Med, 2024, 14(4): 345
|
| [3] |
Ho L, van Dijk M, Chye STJ, et al.. ELABELA deficiency promotes preeclampsia and cardiovascular malformations in mice. Science, 2017, 357(6352): 707-713
|
| [4] |
Wang J, Han T, Zhu X. Role of maternal–fetal immune tolerance in the establishment and maintenance of pregnancy. Chin Med J, 2024, 137(12): 1399-1406
|
| [5] |
Zur RL, McLaughlin K, Aalto L, et al.. Phenotypes of maternal vascular malperfusion placental pathology and adverse pregnancy outcomes: a retrospective cohort study. BJOG Int J Obstet Gynaecol, 2024, 131(11): 1515-1523
|
| [6] |
Dimitriadis E, Rolnik DL, Zhou W, et al.. Pre-eclampsia. Nat Rev Dis Primers, 2023, 9: 8
|
| [7] |
Cui J, Yang Z, Ma R, et al.. Placenta-targeted treatment strategies for preeclampsia and fetal growth restriction: an opportunity and major challenge. Stem Cell Rev Rep, 2024, 20(6): 1501-1511
|
| [8] |
Wu JL, Jia J, He MZ, et al.. Placental origins of preeclampsia: potential therapeutic targets. Curr Med Sci, 2019, 39(2): 190-195
|
| [9] |
Zhao J, Yang DH, Qieqieke Y, et al.. Regulation of alternative splicing by PARP1 in HTR-8/svneo cells: implications for placental development and spontaneous abortion. Curr Med Sci, 2024, 44(6): 1325-1336
|
| [10] |
Fisher SJ. Why is placentation abnormal in preeclampsia?. Am J Obstet Gynecol, 2015, 213(4): S115-S122
|
| [11] |
Apicella C, Ruano CSM, Méhats C, et al.. The role of epigenetics in placental development and the etiology of preeclampsia. Int J Mol Sci, 2019, 20(11): 45
|
| [12] |
Zhu L, Lv R, Kong L, et al.. Genome-wide mapping of 5mC and 5hmC identified differentially modified genomic regions in late-onset severe preeclampsia: a pilot study. PLoS One, 2015, 10(7 e0134119
|
| [13] |
Suckale J, Solimena M. The insulin secretory granule as a signaling hub. Trends Endocrinol Metab, 2010, 21(10): 599-609
|
| [14] |
Kang T, Ye J, Qin P, et al.. Knockdown of Ptprn-2 delays the onset of puberty in female rats. Theriogenology, 2021, 176: 137-148
|
| [15] |
Pan J, Yan D, Liang Y, et al.. Bioinformatic analysis constructs an optimal prognostic index for survival-related variables (OPISV) based on whole-genome expression data in Glioblastoma. Int J Biol Macromol, 2024, 282 137184
|
| [16] |
Paniagua-Herranz L, Moreno I, Nieto-Jiménez C, et al.. Genomic and immunologic correlates in prostate cancer with high expression of KLK2. Int J Mol Sci, 2024, 25(4): 2222
|
| [17] |
Awamleh Z, Butcher DT, Hanley A, et al.. Exposure to gestational diabetes mellitus (GDM) alters DNA methylation in placenta and fetal cord blood. Diabetes Res Clin Pract, 2021, 174 108690
|
| [18] |
Izquierdo AG, Boughanem H, Diaz-Lagares A, et al.. DNA methylome in visceral adipose tissue can discriminate patients with and without colorectal cancer. Epigenetics, 2022, 17(6): 665-676
|
| [19] |
Yin J, Guo Y. HOXD13 promotes the malignant progression of colon cancer by upregulating PTPRN2. Cancer Med, 2021, 10(16): 5524-5533
|
| [20] |
Sengelaub CA, Navrazhina K, Ross JB, et al.. PTPRN2 and PLCβ1 promote metastatic breast cancer cell migration through PI(4, 5)P2-dependent actin remodeling. EMBO J, 2016, 35(1): 62-76
|
| [21] |
Louwen F, Muschol-Steinmetz C, Reinhard J, et al.. A lesson for cancer research: placental microarray gene analysis in preeclampsia. Oncotarget, 2012, 3(8): 759-773
|
| [22] |
Zheng ZZ, Xu JH, Chen JL, et al.. Integrated DNA methylation analysis reveals a potential role for PTPRN2 in Marfan syndrome scoliosis. JOR Spine, 2024, 7(1 e1304
|
| [23] |
Wu S, Wu Z, Chen M, et al.. Interactions of genetic variations in FAS, GJB2 and PTPRN2 are associated with noise-induced hearing loss: a case-control study in China. BMC Med Genomics, 2024, 17(1): 18
|
| [24] |
Kochmanski J, Kuhn NC, Bernstein AI. Parkinson’s disease-associated, sex-specific changes in DNA methylation at PARK7 (DJ-1), SLC17A6 (VGLUT2), PTPRN2 (IA-2β), and NR4A2 (NURR1) in cortical neurons. NPJ Parkinsons Dis, 2022, 8(1): 120
|
| [25] |
Liang Y, Wang P, Shi Y, et al.. Long noncoding RNA maternally expressed gene 3 improves trophoblast dysfunction and inflammation in preeclampsia through the Wnt/β-Catenin/nod-like receptor pyrin domain-containing 3 axis. Front Mol Biosci, 2022, 9: 1022450
|
| [26] |
Zou Y, Salinas P. Introduction: Wnt signaling mechanisms in development and disease. Dev Neurobiol, 2014, 74(8): 757-758
|
| [27] |
Wang X, Zhang Z, Zeng X, et al.. Wnt/β-catenin signaling pathway in severe preeclampsia. J Mol Histol, 2018, 49(3): 317-327
|
| [28] |
Jiang LL, Yang DL, Han Q, et al.. LncRNA-NEAT1 blocks the Wnt/β-catenin signaling pathway by targeting miR-217 to inhibit trophoblast cell migration and invasion. J Assist Reprod Genet, 2024, 41(8): 2107-2115
|
Funding
Key Technologies Research and Development Program(2022YFC2704500)
Youth Science Foundation of Guangxi Medical University(GXMUYSF202330)
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