The role of relaxin in endometrial cancer

Aparna A. Kamat, Shu Feng, Irina U. Agoulnik, Farrah Kheradmand, Natalia V. Bogatcheva, Donna Coffey, Anil K. Sood, Alexander I. Agoulnik

Research output: Contribution to journalArticle

45 Scopus citations

Abstract

Relaxin (RLN) is a naturally occurring hormone that is known to modulate connective tissue remodeling in the uterus and cervix. Our goal was to investigate the role of RLN in endometrial cancer. RLN expression was evaluated using immunohistochemistry in 57 samples of invasive endometrial carcinoma (EC) and ten benign endometrial tissues. 67% of high-stage (III/IV) tumors demonstrated strong RLN expression compared to 37% of low-stage (I/II) cases. Strong RLN expression associated significantly with high-grade and depth of myometrial invasion. Notably, strong RLN expression was associated with a significantly shorter overall survival (p < 0.005) compared to weak or moderate expression. Using RT-PCR, the expression of RLN and its receptor (LGR7) was detected in EC cell lines (HEC-1B and KLE); in addition, LGR7 was expressed in 86% of 15 primary EC tissue samples. Exogenous RLN stimulation caused a significant increase in migration and invasion in both cell lines, but did not stimulate proliferation in vitro. Addition of the MMP inhibitor, FN439 abolished the stimulatory effect of RLN on invasion in both HEC-1B and KLE cells. RLN stimulation caused a significant increase in levels of activated MMP-2 in KLE cells and activated MMP-9 in HEC-1B cells compared to unstimulated cells. Inhibition of endogenous RLN signaling via siRNA targeted to LGR7 caused a significant reduction of EC cell invasiveness. Our results indicate that RLN overexpression is significantly associated with aggressive features such as high-grade and deep myometrial invasion. We provide the first evidence that overexpression of RLN is associated with poor clinical outcome in women with EC. RLN stimulation enhances the invasive potential of endometrial cancer cells by upregulating MMPs. In turn, downregulation of endogenous RLN signaling decreases invasiveness of endometrial cancer cells. These novel findings may have therapeutic implications in the management of patients with endometrial carcinoma.

Original languageEnglish (US)
Pages (from-to)71-77
Number of pages7
JournalCancer Biology and Therapy
Volume5
Issue number1
DOIs
StatePublished - Jan 2006
Externally publishedYes

Keywords

  • Cancer
  • Endometrium
  • Invasion
  • Migration
  • Relaxin

ASJC Scopus subject areas

  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

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  • Cite this

    Kamat, A. A., Feng, S., Agoulnik, I. U., Kheradmand, F., Bogatcheva, N. V., Coffey, D., Sood, A. K., & Agoulnik, A. I. (2006). The role of relaxin in endometrial cancer. Cancer Biology and Therapy, 5(1), 71-77. https://doi.org/10.4161/cbt.5.1.2289