Altered p16Ink4a, IL-1β, and Lamin b1 Protein Expression Suggest Cellular Senescence in Deep Endometriotic Lesions

Abstract

Endometriosis causes immunological and cellular alterations. Endometriosis lesions have lower levels of lamin b1 than the endometrium. Moreover, high levels of pro-inflammatory markers are observed in the peritoneal fluid, follicular fluid, and serum in endometriosis lesions. Thus, we hypothesized that the accumulation of senescent cells in endometriosis tissues would facilitate endometriosis maintenance in an inflammatory microenvironment. To study senescent cell markers and the senescence-associated secretory phenotype (SASP) in endometriosis lesions, we conducted a cross-sectional study with 27 patients undergoing video laparoscopy for endometriosis resection and 19 patients without endometriosis. Endometriosis lesions were collected from patients with endometriosis, while eutopic endometrium was collected from patients both with and without endometriosis. Tissues were evaluated for senescence markers (p16Ink4a, lamin b1, and IL-1β) and interleukin concentrations. The expression of p16Ink4a increased in lesions compared to that in eutopic endometrium from endometriosis patients in the secretory phase. In the proliferative phase, lesions exhibited lower lamin b1 expression but higher IL-4 expression than the eutopic endometrium. Further, IL-1β levels were higher in the lesions than in the eutopic endometrium in both the secretory and proliferative phases. We believe that our findings may provide targets for better therapeutic interventions to alleviate the symptoms of endometriosis.

Colocalization of senescent biomarkers in deep, superficial, and ovarian endometriotic lesions: a pilot study

“…Our previous studies revealed a decrease in lamin B1 expression 28 and an increased expression of p16 23 in deep infiltrative endometriosis lesions compared to that in the eutopic endometrium, which could potentially be implicated in the pro-senescence pattern of endometriosis lesions as both lamin b1 and p16 are biomarkers used to assess cellular senescence. However, this study is anyhow intended to highlight this assumption as this aim has been detailed elsewhere.…”

“…In our previous study, higher p16 and depleted lamin b1 concentrations was observed in deep infiltrating endometriosis compared to that in the eutopic endometrium of patients with endometriosis to assess senescence 23 . Senescence is defined as irreversible cell cycle arrest in response to a stimulus, a natural process that occurs in almost every somatic cell in multicellular organisms 24 and despite their inability to duplicate, senescent cells continue to synthesize metabolites with deleterious effect on surrounding cells and tissues 25 , 26 .…”

Higher Oxidative Stress in Endometriotic Lesions Upregulates Senescence-Associated p16ink4a and β-Galactosidase in Stromal Cells

“…MAPK pathways initiate the senescence cascade [ 50 ] and upregulate proteins such as p16 inka4 , which are responsible for maintaining the growth arrest state indefinitely. Previously, we detected a higher expression of p16 inka4 in endometriotic lesions compared to that in the eutopic endometrium [ 13 ]. The upregulation of both MAPKs and p16 inka4 describe a scenario favorable for the establishment of senescence traits in endometriotic lesions.…”

“…There is evidence of the involvement of the MAPK signaling pathway [ 11 ] and senescence [ 12 , 13 , 14 ] in the physiopathogenesis of endometriosis. The extracellular signal-regulated protein kinase (ERK)-mediated pathway modifies cell growth, proliferation, and survival [ 15 , 16 ].…”

“…Furthermore, the c-Jun N-terminal kinase (JNK)-mediated pathway, which is a cellular-stress-activation pathway, controls cell proliferation and apoptosis [ 18 ]. Similarly, senescence markers present in the endometriotic lesion [ 13 ] can alter tissue homeostasis, contributing to the maintenance of lesions and the characteristic inflammatory milieu of the disease. Previous studies have linked the increase in endometrial stromal cells’ senescence to implantation failure and impaired decidualization [ 19 , 20 ], but no association with endometriosis or endometriosis-associated infertility is known.…”