Dysregulation of Placental Functions and Immune Pathways in Complete Hydatidiform Moles

Int J Mol Sci. 2019 Oct 10;20(20):4999. doi: 10.3390/ijms20204999.


Gene expression studies of molar pregnancy have been limited to a small number of candidate loci. We analyzed high-dimensional RNA and protein data to characterize molecular features of complete hydatidiform moles (CHMs) and corresponding pathologic pathways. CHMs and first trimester placentas were collected, histopathologically examined, then flash-frozen or paraffin-embedded. Frozen CHMs and control placentas were subjected to RNA-Seq, with resulting data and published placental RNA-Seq data subjected to bioinformatics analyses. Paraffin-embedded tissues from CHMs and control placentas were used for tissue microarray (TMA) construction, immunohistochemistry, and immunoscoring for galectin-14. Of the 14,022 protein-coding genes expressed in all samples, 3,729 were differentially expressed (DE) in CHMs, of which 72% were up-regulated. DE genes were enriched in placenta-specific genes (OR = 1.88, p = 0.0001), of which 79% were down-regulated, imprinted genes (OR = 2.38, p = 1.54 × 10-6), and immune genes (OR = 1.82, p = 7.34 × 10-18), of which 73% were up-regulated. DNA methylation-related enzymes and histone demethylases were dysregulated. "Cytokine-cytokine receptor interaction" was the most impacted of 38 dysregulated pathways, among which 17 were immune-related pathways. TMA-based immunoscoring validated the lower expression of galectin-14 in CHM. In conclusion, placental functions were down-regulated, imprinted gene expression was altered, and immune pathways were activated, indicating complex dysregulation of placental developmental and immune processes in CHMs.

Keywords: choriocarcinoma; galectin; gestational trophoblastic disease; hydatidiform mole; placental-specific gene; systems biology; trophoblast differentiation.

MeSH terms

  • Choriocarcinoma
  • Cytokines
  • DNA Methylation
  • Down-Regulation
  • Female
  • Gene Expression
  • Gestational Trophoblastic Disease
  • Humans
  • Hydatidiform Mole / genetics*
  • Hydatidiform Mole / immunology*
  • Immunohistochemistry
  • Placenta / metabolism*
  • Pregnancy / immunology*
  • Pregnancy Trimester, First
  • Systems Biology
  • Up-Regulation


  • Cytokines