The regulation of Hh/Gli1 signaling cascade involves Gsk3?- mediated mechanism in estrogen-derived endometrial hyperplasia.

ABSTRACT: The present study was undertaken to explore the functional involvement of Hh signaling and its regulatory mechanism in endometrial hyperplasia. Differential expression of Hh signaling molecules i.e., Ihh, Shh, Gli1 or Gsk3? was observed in endometrial hyperplasial (EH) cells as compared to normal endometrial cells. Estradiol induced the expression of Hh signaling molecules and attenuated the expression of Gsk3? whereas anti-estrogen (K1) or progestin (MPA) suppressed these effects in EH cells. Cyclopamine treatment or Gli1 siRNA knockdown suppressed the growth of EH cells and reduced the expression of proliferative markers. Estradiol also induced the nuclear translocation of Gli1 which was suppressed by both MPA and K1 in EH cells. While exploring non-canonical mechanism, LY-294002 (Gsk3? activator) caused a decrease in Gli1 expression indicating the involvement of Gsk3? in Gli1 regulation. Further, Gsk3? silencing promoted the expression and nuclear translocation of Gli1 demonstrating that Gsk3? serves as a negative kinase regulator of Gli1 in EH cells. Similar attenuation of Hh signaling molecules was observed in rats with uterine hyperplasia undergoing anti-estrogen treatment. The study suggested that Hh/Gli1 cascade (canonical pathway) as well as Gsk3?-Gli1 crosstalk (non-canonical pathway) play crucial role in estrogen-dependent cell proliferation in endometrial hyperplasia.

SUBMITTER: Kaushal JB 

PROVIDER: S-EPMC5529438 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature