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Int J Mol Sci. 2019 Oct 10;20(20). pii: E4999. doi: 10.3390/ijms20204999.

Dysregulation of Placental Functions and Immune Pathways in Complete Hydatidiform Moles.

Author information

1
Department of Obstetrics and Gynecology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA. jennyrenaeking@gmail.com.
2
Department of Preventive Medicine, University of Southern California, Los Angeles, CA 90033, USA. melisslw@usc.edu.
3
Systems Biology of Reproduction Research Group, Institute of Enzymology, Research Centre for Natural Sciences, H-1117 Budapest, Hungary. heteysz@gmail.com.
4
Systems Biology of Reproduction Research Group, Institute of Enzymology, Research Centre for Natural Sciences, H-1117 Budapest, Hungary. peter0kiraly@gmail.com.
5
Department of Obstetrics and Gynecology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA. koji.matsuo@med.usc.edu.
6
Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA. antonio.castaneda@osumc.edu.
7
Systems Biology of Reproduction Research Group, Institute of Enzymology, Research Centre for Natural Sciences, H-1117 Budapest, Hungary. toth.eszter@ttk.hu.
8
First Department of Pathology and Experimental Cancer Research, Semmelweis University, H-1085 Budapest, Hungary. krenacst@gmail.com.
9
Maternity Private Clinic of Obstetrics and Gynecology, H-1126 Budapest, Hungary. hupuczi.petronella@maternity.hu.
10
Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA. pfauceglia@hotmail.com.
11
Systems Biology of Reproduction Research Group, Institute of Enzymology, Research Centre for Natural Sciences, H-1117 Budapest, Hungary. balogh.andrea@ttk.hu.
12
Systems Biology of Reproduction Research Group, Institute of Enzymology, Research Centre for Natural Sciences, H-1117 Budapest, Hungary. szilagyi.andras@ttk.hu.
13
Department of Immunology, Institute of Biology, Eotvos Lorand University, H-1117 Budapest, Hungary. matko@elte.hu.
14
Maternity Private Clinic of Obstetrics and Gynecology, H-1126 Budapest, Hungary. pzorvosihetilap@maternity.hu.
15
Department of Obstetrics and Gynecology, Semmelweis University, H-1088 Budapest, Hungary. pzorvosihetilap@maternity.hu.
16
Department of Obstetrics and Gynecology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA. lroman@usc.edu.
17
Department of Obstetrics and Gynecology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA. victoria.cortessis@med.usc.edu.
18
Department of Preventive Medicine, University of Southern California, Los Angeles, CA 90033, USA. victoria.cortessis@med.usc.edu.
19
Department of Obstetrics and Gynecology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA. than.gabor@ttk.hu.
20
Systems Biology of Reproduction Research Group, Institute of Enzymology, Research Centre for Natural Sciences, H-1117 Budapest, Hungary. than.gabor@ttk.hu.
21
First Department of Pathology and Experimental Cancer Research, Semmelweis University, H-1085 Budapest, Hungary. than.gabor@ttk.hu.
22
Maternity Private Clinic of Obstetrics and Gynecology, H-1126 Budapest, Hungary. than.gabor@ttk.hu.

Abstract

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

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