Abstract
The balanced turnover of collagen is necessary to maintain the mechanical strength of pelvic supportive connective tissues. Homeobox (HOX) A11 is a key transcriptional factor that controls collagen metabolism and homoeostasis in the uterosacral ligaments (USLs), and the deficient HOXA11 signalling may contribute to alterations in the biochemical strength of the USLs, leading to pelvic organ prolapse (POP). However, it is unknown how HOXA11 transcripts are regulated in the USLs. In this study, we found that microRNA (miRNA)-30d and 181a were overexpressed in women with POP, and their expression was inversely correlated with HOXA11 mRNA levels. The overexpression of miR-30d or 181a suppressed HOXA11 mRNA and protein levels in 293T cells, whereas the knockdown of these miRNAs enhanced HOXA11 levels and collagen production. Cotransfection of a luciferase reporter plasmid containing the 3′-untranslated region of HOXA11 with miR-30d or 181a mimic resulted in decreased relative luciferase activity. Conversely, cotransfection with anti-miR-30d or 181a increased luciferase activity. Taken together, these results indicate that both miR-30d and 181a are important posttranscriptional regulators of HOXA11 in the USLs and could be a potential therapeutic target for POP.
Highlights
Previous biochemical studies have demonstrated a decrease in collagen content in the pelvic supportive connective tissues of women with POP compared to women without POP, and this is related to decreased synthesis and increased breakdown by matrix metalloproteinase as well as decreased cellularity, of fibroblasts [9, 19,20,21]
Given its vital role in the control of collagen metabolism and cell proliferation [7,8,9], HOXA11 may serve as a good candidate for the maintenance of collagen homoeostasis in the uterosacral ligaments (USLs)
We provide several lines of evidence to show that the expression of HOXA11 in USLs is regulated by two miRNAs, miR-30d and miR-181a
Summary
Pelvic organ prolapse (POP) is the downward descent of pelvic organs that results in a protrusion of the vagina, uterus or both. While not life-threatening, it often causes bladder, bowel and pelvic symptoms that can have an adverse effect on a woman’s daily activities and quality of life [1]. POP is a significant economic burden to women and healthcare systems. It affects almost half of all women over 50 years of age [2], and one in five women will undergo surgery for POP in their lifetime [3]. In the United States, the direct cost of prolapse surgery is greater than 1 billion dollars per year [4], and as the population is ageing, the demand for POP care is estimated to double over the 40 years [5]. It has been proposed that the biomechanical weakness of pelvic floor supportive a 2015 The Authors
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