2. Academic Validation
  3. miR-196a-5p suppresses the MAPK/ERK pathway by targeting HOXA7 to regulate the proliferation and apoptosis of placental trophoblasts in gestational diabetes

miR-196a-5p suppresses the MAPK/ERK pathway by targeting HOXA7 to regulate the proliferation and apoptosis of placental trophoblasts in gestational diabetes

  • Placenta. 2025 Dec:172:167-178. doi: 10.1016/j.placenta.2025.11.006.
Jianhua Li 1,  Xinping Xie 2,  Lin Lu 3,  Bei Gan 3,  Jianying Yan 4
Affiliations

Affiliations

  • 1 College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, 350001, China; Department of Obstetrics and Gynecology, The First Affiliated Hospital of Fujian Medical University, 350005, China. Electronic address: [email protected].
  • 2 College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, 350001, China; Department of Obstetrics and Gynecology, The First Affiliated Hospital of Fujian Medical University, 350005, China.
  • 3 Department of Obstetrics and Gynecology, The First Affiliated Hospital of Fujian Medical University, 350005, China.
  • 4 College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, 350001, China; Laboratory of Maternal-Fetal Medicine, Fujian Maternity and Child Health Hospital, 350001, China. Electronic address: [email protected].
PMID: 41274131 DOI: 10.1016/j.placenta.2025.11.006
Abstract

Introduction: Gestational diabetes mellitus (GDM) disrupts placental trophoblast function through hyperglycemia-induced Apoptosis and impaired proliferation. Non-coding RNAs, particularly miR-196a-5p, are implicated in GDM pathogenesis, but their mechanistic roles remain unclear. HOXA7, a homeobox transcription factor, and the MAPK/ERK pathway are critical in cellular regulation, however, their interplay in GDM is unexplored.

Methods: Clinical samples (blood and placental tissues) from GDM patients and controls were analyzed via miRNA-seq, qRT-PCR, and Western blot. Bioinformatics (TargetScan, miRDB, miRWalk) identified miR-196a-5p targets. Functional validation used HTR8-Svneo trophoblasts under high-glucose (25 mM) conditions, with miR-196a-5p mimics/inhibitors and HOXA7 overexpression and two key functional rescue assays: co-treatment with a miR-196a-5p mimic and HOXA7 overexpression, and co-treatment with a mimic and a MEK Activator, including CCK-8, Transwell, flow cytometry, and dual-luciferase reporter analysis. miR-196a-5p was upregulated in GDM patients and directly targeted HOXA7 via three conserved 3'UTR binding sites.

Results: Hyperglycemia suppressed MAPK/ERK phosphorylation, reducing trophoblast proliferation, migration, and invasion while increasing Apoptosis. miR-196a-5p-mimic exacerbated these effects, whereas inhibitors or HOXA7 overexpression restored MAPK/ERK activity and cellular functions. Crucially, rescue experiments confirmed that HOXA7 is a necessary mediator for miR-196a-5p's effects and that activating the MAPK/ERK pathway downstream is sufficient to reverse the induced dysfunction. miR-196a-5p suppresses the MAPK/ERK pathway by specifically regulating HOXA7, thereby reducing proliferation and increasing Apoptosis of placental trophoblasts.

Discussion: This study demonstrated that miR-196a-5p with higher expression in GDM suppresses the HOXA7/MAPK/ERK axis to inhibit placental trophoblasts proliferation and promote its Apoptosis.

Keywords

Apoptosis; Gestational diabetes; HOXA7; MAPK/ERK pathway; Proliferation; miR-196a-5p.

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