Matrix metalloproteinase-26 (MMP-26) and Tissue inhibitor of metalloproteinases-4 (TIMP-4) in normal, hyperplastic, and malignant endometrium.

Radovan Pilka

Research output: ThesisDoctoral Thesis (compilation)

Abstract

The aim of the thesis was to study matrix metalloproteinase-26 (MMP-26) and tissue inhibitor of metalloproteinases-4 (TIMP-4) in normal, hyperplastic, and malignant endometrium. Most importantnly, both these molecules may be ivolved in the implantation process. Trophoblast tissue from human as well as mouse embryos produces pro-MMP-9. Active MMP-9

(gelatinase B) is a proteolytic enzyme with a broad substrate specificity. MMP-26 is an effective activator of pro-MMP-9, and TIMP-4 is a strong inhibitor of MMP-26.

We found that endometrial expression of MMP-26 mRNA and TIMP-4 mRNA is elevated during the proliferative phase, is maximal in the early, decreases in the mid-, and is low in the late secretory phases (I, III). The expression pattern of both genes suggests their up-regulation by estrogen, and down-regulation by progesterone. This is supported by our findings of potential estrogen response elements upstream the coding sequences of both genes (II, III). In situ hybridization localised MMP-26 mRNA in epithelial and TIMP-4 mRNA in stromal cells (I, III). As expected, using immunohistochemistry we found MMP-26 protein in the epithelium (II). However, the same technique showed only occasional staining for TIMP-4 in the stroma (V). Instead, TIMP-4 protein was localised in granules of the apical part of epithelial cells. This finding suggests that TIMP-4 is produced in and secreted by the stromal cells, taken up by the epithelial cells, stored in apical granules, and finally secreted to the uterine fluid. Analysis of uterine fluid with Western blot technique demonstrated presence of TIMP-4, but not MMP-26 (V). So far, very few proteins of stromal origin have been demonstrated in the uterine fluid. Furthermore, using different antibodies, we have shown that MMP-26 is stored in epithelial cells in its active form, is not released spontaneously, and when released it is controlled by TIMP-4 in both stroma and uterine fluid. Examination of endometrial tissue obtained from IVF patients in an estrogen and progesterone substitution protocol showed that the estrogen sensitive genes MMP-26 and TIMP-4 are over-stimulated by both estrogen and progesterone.

Analysis of MMP-26 and TIMP-4 expression in endometrial hyperplastia showed that both localization and amount of mRNA corresponded to that of the proliferative phase. This is in agreement with estrogen mediated regulation of these genes, as well as hyperplasia being the result of estrogen over-stimulation.

The expression of MMP-26 and TIMP-4 decreases with loss of histological differentiation in endometrial cancer. This is also in agreement with the general loss of differentiated functions during progression to poorly differentiated, and more malignant tumors.
Original languageEnglish
QualificationDoctor
Awarding Institution
  • Obstetrics and Gynaecology (Lund)
Supervisors/Advisors
  • Casslén, Bertil, Supervisor
Award date2006 Apr 28
Publisher
ISBN (Print)91-85481-73-4
Publication statusPublished - 2006

Bibliographical note

Defence details

Date: 2006-04-28
Time: 13:00
Place: Dept. of Obstetrics and Gynecology, Lecture Hall

External reviewer(s)

Name: Marbaix, Etienne
Title: Professor
Affiliation: Department of Pathology, University of Louvain Medical School, Brussels, Belgium

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<div class="article_info">R Pilka, C Whatling, H Domanski, S Hansson, P Eriksson and B Casslen. <span class="article_issue_date">2003</span>. <span class="article_title">Epithelial expression of matrix metalloproteinase-26 (MMP-26) is elevated at midcycle in the human endometrium.</span> <span class="journal_series_title">Mol Human Reprod,</span>, <span class="journal_volume">vol 9</span> <span class="journal_pages">pp 271-7</span>.</div>
<div class="article_info">R Pilka, G D Norata, H Domanski, C Andersson, S Hansson, P Eriksson and B Casslen. <span class="article_issue_date">2004</span>. <span class="article_title">Matrix metalloproteinase-26 (matrilysin-2) expression is high in endometrial hyperplasia and decreases with loss of histological differentiation in endometrial cancer.</span> <span class="journal_series_title">Gynecol Oncol,</span>, <span class="journal_volume">vol 94</span> <span class="journal_pages">pp 661-70</span>.</div>
<div class="article_info">R Pilka, H Domanski, S Hansson, P Eriksson and B Casslen. <span class="article_issue_date">2004</span>. <span class="article_title">Endometrial TIMP-4 mRNA is high at midcycle and in hyperplasia, but downregulated in malignant tumours. Coordinated expression with MMP-26.</span> <span class="journal_series_title">Mol Hum Reprod,</span>, <span class="journal_volume">vol 10</span> <span class="journal_pages">pp 641-50</span>.</div>
<div class="article_info">R Pilka, I Oborna, V Lichnovsky, P Havelka, H Fingerova, P Eriksson, S Hansson and B Casslén. <span class="article_issue_date"></span>. <span class="article_title">Endometrial expression of the estrogen sensitive genes MMP-26 and TIMP-4 is altered by a substitution protocol without down regulation in IVF patients.</span> <span class="journal_series_title">Hum Reprod</span>, (submitted)</div>
<div class="article_info">R Pilka, V Noskova, H Domanski, C Andersson, S Hansson and B Casslén. <span class="article_issue_date"></span>. <span class="article_title">Endometrial TIMP-4 is derived from the stroma, accumulates in the epithelium, and is released to the uterine fluid.</span> <span class="journal_series_title">Mol Hum Reprod</span>, (submitted)</div>

Subject classification (UKÄ)

  • Obstetrics, Gynecology and Reproductive Medicine

Free keywords

  • cancer
  • Obstetrics
  • gynaecology
  • Cytologi
  • onkologi
  • cancerology
  • secretion
  • Biology
  • Biologi
  • Cytology
  • oncology
  • implantation
  • human
  • endometrium
  • mRNA
  • MMP-26
  • TIMP-4
  • reproduktion
  • andrologi
  • gynekologi
  • Obstetrik
  • sexuality
  • reproduction
  • sexualitet
  • andrology

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