Hypo-Expression of Tuberin Promotes Adenomyosis via the mTOR1-Autophagy Axis.

Ni-Hao Gu,Yu Lin,Bing-Xin Yang,Min You,Hong Xu,Feng Sun,Guo-Jing Li

doi:10.3389/fcell.2021.710407

Abstract

Adenomyosis (AM) is a disease in which endometrial tissue invades the myometrium and has a 10–60% prevalence in reproductive-aged women. TSC2 regulates autophagy via mTOR1 signalling in colorectal cancer and endometrial carcinoma. Dysregulation of autophagy is implicated in adenomyosis pathogenesis. However, whether TSC2 participates in adenomyosis via autophagy remains obscure. Here, we found that the expression of TSC2 in adenomyosis was significantly decreased than that in normal endometrium during the secretory phase. Moreover, TSC2 and autophagy marker expression was significantly lower in ectopic lesions than in eutopic samples. TSC2 downregulation inhibited autophagy through mTOR1 signalling pathway activation in endometrial cells, leading to excessive proliferation, migration, and EMT; TSC2 overexpression induced the opposite effects. Rapamycin treatment suppressed cell proliferation, migration and EMT in the absence of TSC2. In parallel, an autophagy-specific inhibitor (SAR-405) restored migration and EMT under rapamycin treatment in TSC2-knockdown Ishikawa cells. Finally, SAR-405 treatment promoted EMT and migration of overexpressing cells. Collectively, our results suggest that TSC2 controls endometrial epithelial cell migration and EMT by regulating mTOR1-autophagy axis activation and that hypo-expression of TSC2 in the endometrium might promote adenomyosis.

Highlights

Adenomyosis (AM) is a benign uterine disorder characterised by the presence of ectopic endometrial tissue in the myometrium with hyperplasia of adjacent smooth muscle (Chapron et al, 2020)
To determine whether the proliferation, epithelial-mesenchymal transition (EMT) and migration of TSC2-overexpressing and TSC2-knockdown cells are mediated by autophagy, we evaluated the effects of rapamycin and SAR405, a specific mTOR1 inhibitor and a specific vacuolar protein sorting 34 (VPS34) inhibitor, respectively, in the presence of E2 or E2/P4
We examined TSC2 expression in human eutopic endometrial tissues according to the phases of the menstrual cycle

Summary

INTRODUCTION

Adenomyosis (AM) is a benign uterine disorder characterised by the presence of ectopic endometrial tissue in the myometrium with hyperplasia of adjacent smooth muscle (Chapron et al, 2020) It is one of the leading disorders causing pelvic pain, abnormal uterine bleeding and subfertility and significantly impacts the quality of life in women of reproductive age (Leyendecker et al, 2002; Vercellini et al, 2014; Yang et al, 2021). Accumulated evidence shows that autophagy participates in the regulation of the endometrial cell cycle and that its dysregulation promotes carcinogenesis in many tissues through augmentation of cellular proliferation, migration and EMT processes (Choi et al, 2014; Gugnoni et al, 2017; Liu et al, 2020; Zhao et al, 2020). Our findings indicate that TSC2 inhibits the abnormal migration and EMT of endometrial cells by regulating the mTORautophagy axis

RESULTS

Ethical Approval

DISCUSSION

ETHICS STATEMENT