Matrix metalloproteinases and their inhibitors and inducer in gestational trophoblastic diseases and normal placenta

Singh, Margit; Kindelberger, David W.; Nagymanyoki, Zoltan; Ng, Sook Kien; Quick, Charles M.; Elias, Kevin M.; Yamamoto, Hidemi S.; Fichorova, Raina N.; Fülöp, Vilmos; Berkowitz, Ross S.

doi:10.1016/j.ygyno.2011.03.025

Cited by 24 publications

(20 citation statements)

References 26 publications

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“…Such a phenomenon is also observed in metastatic cancers (Nuovo et al www.reproduction-online.org 1995). Our findings are in accordance with the earlier studies correlating high expression of MMPs to the high invasiveness in GTDs (Singh et al 2011) and inverse correlation between invasiveness of human cells and the levels of TIMPs (Hicks et al 1984). Decreased levels of H3K9me3 at MMP9 and increased levels of H3K9me3 at TIMP1 and both H3K9/27me3 at TIMP2 were detected in molar villi, relative to early trimester normal villi.…”

Section: Discussionsupporting

confidence: 93%

Imbalance between matrix metalloproteinases and their tissue inhibitors in preeclampsia and gestational trophoblastic diseases

Rahat¹,

Sharma²,

Bagga³

et al. 2016

Reproduction

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The invasion cascade exhibited by placental trophoblasts and cancerous cells bears many similarities, and it is attributed to extracellular matrix degradation mediated by matrix metalloproteinases (MMPs). Although proper and controlled invasion by trophoblasts into the maternal uterus is an essential requirement for maintenance of normal pregnancy, any abnormality in this phenomenon results in the development of invasion-related disorders such as gestational trophoblastic diseases (GTDs) and preeclampsia. We studied the epigenetic basis of differential expression of two placental MMPs (MMP2 and MMP9) and tissue inhibitors of metalloproteinases (TIMP2 and TIMP1) during normal gestation and invasion-related disorders, i.e., preeclampsia and GTDs. Our study suggests the association of H3K9/27me3 with differential expression of these MMPs and their inhibitors, which regulate the placental invasion during normal pregnancy, whereas no role of CpG methylation was observed in the differential expression of MMPs/TIMPs. Further, development of GTDs was associated with abnormally higher expression of these MMPs and lower levels of their inhibitors, whereas the reverse trends were observed for MMPs and their TIMPs in case of preeclampsia, in association with abnormal changes in H3K9/27me3. These results suggest the involvement of higher levels of MMPs in an aggressive invasive behavior depicted by GTDs, whereas lower levels of these MMPs in shallow and poor invasive phenotype associated with preeclampsia. Thus, our study shows the significance of a proper balance regulated by histone trimethylation between differential expression of MMPs and their TIMPs for maintaining normal pregnancy and its deregulation as a contributing factor for pathogenesis of invasive disorders during pregnancy.

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Section: Discussionsupporting

confidence: 93%

Imbalance between matrix metalloproteinases and their tissue inhibitors in preeclampsia and gestational trophoblastic diseases

Rahat¹,

Sharma²,

Bagga³

et al. 2016

Reproduction

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“…However, very few of these regulatory factors have been investigated in depth. Recent reports have demonstrated that MMP-9 down-regulation and TIMP-1 up-regulation can both lead to reduced trophoblast invasiveness [15,16,17]. We have also investigated the roles of MMP-9 and TIMP-1 in trophoblast invasion.…”

Section: Discussionmentioning

confidence: 99%

“…MMP-9 and TIMP-1 are both closely associated with trophoblast invasion. Down-regulation of MMP-9 and up-regulation of TIMP-1 may both lead to decreased trophoblast invasion [16,17,18]. …”

Section: Introductionmentioning

confidence: 99%

CDX2 Enhances HTR-8/SVneo Trophoblast Cell Invasion by Altering the Expression of Matrix Metalloproteinases

Jia

Ding²,

Gu³

et al. 2014

Cell Physiol Biochem

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Background/Aims: The invasion of trophoblast cells into the maternal uterine decidua is critical for normal placentation, establishment of pregnancy and maintenance of fetal growth in humans. Several growth factors and cytokines have been implicated in trophoblast invasion, but the underlying regulatory mechanisms of invasion are not fully understood. Our earlier studies have found that caudal-related homeobox transcription factor 2 (CDX2) is hypomethylated in human pre-eclampsia placental tissues. However, whether CDX2 is involved in trophoblast invasion was unclear. Methods and Results: In this study, we investigated CDX2 function using a human HTR-8/SVneo cell line that overexpressed CDX2. Cell invasion assays demonstrated that CDX2 enhanced trophoblast cell invasiveness. Meanwhile, MTT assays revealed that CDX2 did not affect cell proliferation. Western blot analysis and quantitative real-time PCR demonstrated that the expression level of matrix metalloproteinase-9 (MMP-9) was significantly increased, whereas the expression of tissue inhibitor of metalloproteinase-1 (TIMP-1) was markedly suppressed in the CDX2-overexpressing trophoblast cells. The phosphoinositide-3-kinase (PI3K)/Akt signaling pathway is involved in proliferation, migration, metastasis and invasion. Our study showed that inhibition of PI3K/Akt signaling led to decreased expression of CDX2. Conclusion: We concluded that CDX2 is likely regulated by the PI3K/Akt signaling pathway during trophoblast cell invasion. Our findings may reveal new insights into the regulatory mechanisms of trophoblast cell invasion and may be an important contributor to the pathogenesis of pregnancy-related diseases.

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“…MMPs and their inhibitors have recently been studied in both GTD and normal placenta [22]. CCA was characterized by high levels of expression of several MMPs (MMP-1, -2, -21, and -28) and low levels of expression of tissue inhibitors of MMPs which may contribute to the invasiveness of CCA.…”

Section: Molecular Biologymentioning

confidence: 99%

Current advances in the management of gestational trophoblastic disease

Berkowitz

Goldstein

2013

Gynecologic Oncology

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Matrix metalloproteinases and their inhibitors and inducer in gestational trophoblastic diseases and normal placenta

Cited by 24 publications

References 26 publications

Imbalance between matrix metalloproteinases and their tissue inhibitors in preeclampsia and gestational trophoblastic diseases

Imbalance between matrix metalloproteinases and their tissue inhibitors in preeclampsia and gestational trophoblastic diseases

CDX2 Enhances HTR-8/SVneo Trophoblast Cell Invasion by Altering the Expression of Matrix Metalloproteinases

Current advances in the management of gestational trophoblastic disease

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