HOXA11 Promotes Fibroblast Proliferation and Regulates p53 in Uterosacral Ligaments

Abstract

The uterosacral ligaments (USLs) are key support structures of the uterus and upper vagina. Previously, we have shown that HOXA11 is necessary for the development of the USLs, is deficient in women with pelvic organ prolapse (POP) and regulates expression of extracellular matrix (ECM) proteins. Here we sought to determine if HOXA11 regulates cell proliferation in the USLs in women. Like others, we have found that, there is decreased cellularity in prolapsed USLs compared to USLs in women with normal pelvic support. We have also demonstrated that HOXA11 promotes cell proliferation in murine fibroblasts and primary human USL cells in vitro. These findings support a relationship between HOXA11 expression, rates of proliferation and phenotypic abnormalities in the USL. Based on these findings, we sought to determine if HOXA11 regulates p53, a tumor suppressor gene which controls progression through the cell cycle and regulates ECM genes. We have demonstrated that expression of HOXA11 represses expression of p53, suggesting a mechanism by which HOXA11 regulates of the morphology and integrity of the USLs. A better understanding of the influence of these genes on the homeostasis of the ECM and interactions with each other may prove beneficial in defining the underlying etiologies of the development of POP and aid in the development of new treatment options for women with this disorder.