Downregulation of PDCD4 by deSUMOylation associates with the progression of gestational trophoblastic disease

Ya-Xin Wang; Ling Cui; Wei-Bin Wu; Martin John Quinn; Ramkumar Menon; Jiu-Ru Zhao; Hui-Juan Zhang

doi:10.1016/j.placenta.2022.10.014

Downregulation of PDCD4 by deSUMOylation associates with the progression of gestational trophoblastic disease

Placenta. 2022 Dec:130:17-24. doi: 10.1016/j.placenta.2022.10.014. Epub 2022 Nov 3.

Authors

Ya-Xin Wang¹, Ling Cui², Wei-Bin Wu³, Martin John Quinn², Ramkumar Menon⁴, Jiu-Ru Zhao⁵, Hui-Juan Zhang⁶

Affiliations

¹ Departments of Pathology, International Peace Maternity and Child Health Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China; Department of Ultrasound in Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China.
² Departments of Pathology, International Peace Maternity and Child Health Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China.
³ Department of Biobank, International Peace Maternity and Child Health Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China.
⁴ Division of Basic and Translational Research, Department of Obstetrics and Gynaecology, The University of Texas Medical Branch at Galveston, Galveston, TX, USA.
⁵ Department of Biobank, International Peace Maternity and Child Health Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China. Electronic address: 730001668@shsmu.edu.cn.
⁶ Departments of Pathology, International Peace Maternity and Child Health Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China. Electronic address: zhanghj815@sjtu.edu.cn.

PMID: 36370491
DOI: 10.1016/j.placenta.2022.10.014

Abstract

Introduction: Gestational trophoblastic disease (GTD) encompasses a range of trophoblastic disorders from hydatidiform mole (HM), to malignant gestational trophoblastic neoplasia (GTN). The exact molecular mechanisms of GTN remain unknown. Dysregulation and dysfunction of programmed cell death 4 (PDCD4)have been observed in many cancers. The roles of PDCD4 in GTD have not been previously reported.

Methods: A total of 161 cases of formalin-fixed, paraffin-embedded trophoblast blocks, and 36 cases of fresh trophoblast tissues were collected, including normal first trimester placentas, HM, and invasive HM. Choriocarcinoma cells JAR and JEG-3 were employed. The expressions of PDCD4 and small ubiquitin-like modifier 2/3 (SUMO2/3) were examined by immunohistochemistry, quantitative reverse transcription PCR and Western blotting in trophoblastic tissues and cells. The relationship between SUMOylation and PDCD4 was investigated. The effects of PDCD4 on proliferation, invasion, and migration of choriocarcinoma cells were evaluated by Cell Counting Kit-8 and transwell assays post siRNA transfection. Extracellular Matrix & Adhesion Profiler PCR Array was used to screen the downstream molecules of PDCD4.

Results: PDCD4 was significantly repressed in HM tissues. Loss of PDCD4 expression was demonstrated in 90% invasive HMs. Choriocarcinoma cells also displayed with suppressed PDCD4 expression. The varied expression of PDCD4 was paralleled by SUMO2/3. Inhibition of SUMOylation reduced the expression of PDCD4. Silencing of PDCD4promoted proliferation/migration/invasion, upregulatedMMP3/MMP8/ITGB2, and downregulated TIMP1/TIMP2 in choriocarcinoma cells.

Discussion: Our results suggest that reduced SUMOylation is one reason for suppressed PDCD4 in GTD. Loss of PDCD4 likely determines the malignant phenotype of GTN by dysregulating some members of the MMPs/TIMPs/integrins complex.

Keywords: Gestational trophoblastic disease; Gestational trophoblastic neoplasia; Programmed cell death 4; SUMOylation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Apoptosis Regulatory Proteins / genetics
Apoptosis Regulatory Proteins / metabolism
Cell Line, Tumor
Choriocarcinoma* / pathology
Down-Regulation
Female
Gestational Trophoblastic Disease* / pathology
Humans
Hydatidiform Mole* / pathology
Pregnancy
RNA-Binding Proteins / genetics
RNA-Binding Proteins / metabolism
Uterine Neoplasms* / pathology

Substances

Apoptosis Regulatory Proteins
PDCD4 protein, human
RNA-Binding Proteins