Cianci A

Valenti G

Vitale Salvatore Giovanni

English

Archivio istituzionale della ricerca - Università di Cagliari

Crosstalk betweentransforming growth factor-b3and microRNA-29c inleiomyoma: are westepping forward?Uterine fibroids (UFs) are benign monoclonal neoplasms, rep-resenting the most common solid tumor of the female genitaltract in reproductive-aged women. Despite the incidencebeing generally high worldwide (70%–80% in women bythe age of 50 years), UFs affect %80% of women in someparticular populations (African-American women). Further-more, UFs are relative common in pregnancy andmight nega-tively influence its outcomes (1). Uterine fibroids aregenerally asymptomatic; however, when symptoms occur,they might impair normal functioning and affect quality oflife, most widely causing abnormal uterine bleeding andiron deficiency anemia, abdominal and pelvic pain, andcompression to the surrounding organs thus urologic andgastrointestinal symptoms. However, being typically encoun-tered during the reproductive age, UFs may also have a detri-mental effect on women's fertility. Although submucosal UFscertainly affect fertility, intramural UFs more than a certainsize (>4 cm) may have a negative effect on early pregnancyoutcomes. With regard to the subserosal UFs, the effect onfertility is still on debate. Different mechanisms have beenproposed to explain this effect. Except for the obvious alter-ation of uterine structure, some investigators (1, 2) havebeen focusing on functional changes of the myometriumand endometrium, and the interfering with the endocrineand paracrine signals that play paramount roles in gametesrecognition and encounter, embryo tubal migration, andnidation and its development. These interferences could berelated to the recent conception that UFs arise from aninflammatory background in genetically predisposedwomen. Several uterine irritations, such as ovulation,menstruation, infections, tissue injury (cesarean section,uterine surgery, surrounding peritoneal irritation), talc use,intrauterine device (IUD), male reproductive proteins, stress,mechanical forces, hypoxia, and cellular oxidative stress,may have been the initial triggers for cellular andextracellular modification in UFs formation. Changes in theextracellular matrix (ECM) is a marked sign of UFs. As itoccurs in all fibrotic disease, histopathology analyses reportan increasing number of smooth muscle cells, collagen,proteoglycans, and fibronectin. These triggers can promotemonocytes and macrophages migration and activation andsecondarily, the release of growth factors (transforminggrowth factor [TGF]-b, activin-A, and platelet-derivedgrowth factor) and cytokines (tumor necrosis factor [TNF]-a). This leads to fibroblast activation and differentiationinto myofibroblasts, a process that is increased by steroid hor-mones (estrogen [E] and P). During chronic inflammation,myofibroblasts become resistant to elimination by apoptosisVOL. 112 NO. 6 / DECEMBER 2019and produce excessive amounts of ECM components, leadingto fibrotic transformation. The ECM accumulation is sup-ported not only by growth factors, cytokines, steroid hor-mones, but also by the interaction between cells andmodified ECM, affecting cell behavior and producing epige-netic modifications (2). Among the three main epigeneticsmechanisms in modulating the gene expression in fibroidsformation, and more specifically DNA methylation, histonemodifications and microRNAs (miRNAs) interfering, the lastseems to have a pivotal role in UFs formation and mainte-nance. Among miRNAs (miR-29 family, miR-200c, andmiR-93/106b) that have been shown to affect the regulationof ECM accumulation, the miR-29 family seems to have acentral role. All members of these microRNAs are down-expressed in UFs, acting on a different level of the interactionbetween cells and ECM. Down-expression of miRNA-29a andmiRNA-29b supports the accumulation of collagens,including COL1A1 and COL1A3, whereas down-expressionof miR-29c is associated with high expression of COL3A1,elastin, and matrix metalloproteinases (3). Consistent datahave established that TGF-b and its family of ligands induceabnormal proliferation in UF cells but not in healthy myome-trial cells. This action depends on its concentration and thehigh levels recorded in fibrotic tissues that are able to promotetumor growth. Particularly, TGF-b3 isoform is up to five timesmore expressed in UFs than in surrounding healthy tissues.Through activation of Smad 2/3 and ERK 2/3 signaling path-ways, TGF-b3 increases messenger RNA expression of ECMcomponents and decreases the production of matrix metallo-proteinases (2, 3). Because TGF-b3 is a target of miR-29c andboth promote fibrosis, Chuang and Khorram (4) in an in vitrostudy cultured cells obtained from UFs and surroundingnormal myometrium. They determined not only the expres-sion of miR-29c and TGF-b3, but also the mechanisms of theirreciprocal regulation in healthy and UFs tissues. They showedthat miR-29c expression was lesser whereas TGF-b3 wasincreased in UFs compared with paired healthy myometrium.Interestingly, no significant racial/ethnic differences inexpression of miR-29c and TGF-b3 was noted. This is incontrast with the epidemiological data where UFs are morecommon and have more morbidity in African-Americanwomen, suggesting the presence of other factors that interactat the paracrine/endocrine and epigenetic levels. Moreremarkable, the investigators demonstrated that miR-29cdirectly interacts with the 30 untranslated region of TGF-b3thereby regulating its expression in UF cells. Gain-of-function of miR-29c in UF cells down-regulated the expres-sion of TGF-b3 at protein andmessemger RNA levels, whereasknockdown of miR-29c, using anti-miR-29c, had the oppositeeffect. Culturing UF cells with TGF-b3 (5 ng/mL) for 48 hours,Chuang and Khorram (4) also highlighted how the expressionof miR-29c was inhibited. Assuming the epigenetic effect ofmiR-29c on these cells, they evaluated whether TGF-b3 hadan effect on epigenetic enzymes involved in DNA and histonemethylation (DNMT1, DNMT3A, and EZH2). They demon-strated that TGF-b3 induced DNMT1 expression, but had nosignificant effect on DNMT3A and EZH2 expression.1055REFLECTIONSInterestingly, the DNMT1 suppression resulted in suppressionof TGF-b3 and increase of miR-29c expression. Thats study(4) pointed out the presence of a crosstalk between growthfactors and miRNAs interfering at the epigenetic level. How-ever, this is one of the possible mechanisms of crosstalking,opening new perspectives of similar interactions. Forinstance, an important aspect that should be investigated isthe E and P roles in modulating these possible crosstalkings.New evidence demonstrated that ulipristal acetate (UPA), aselective P receptor (PR) modulator with proven anti-UF effectchanges the ECM production and matrix metalloproteinaseexpression. To better understand this mechanism, Lewis atal. (5) analyzed the effect of UPA on TGF-b3 canonical andnoncanonical signaling pathways in UFs. They proved thatUPA affects ECM protein production through the attenuationof transcription and translation of TGF-b3. After UPA treat-ment significant reductions in canonical pathway throughthe TGF-receptor I and II/Smad-dependent cascade were re-corded, whereas no inhibition of noncanonical (MEK1 andMEK2 signaling) pathway was noted. They (5) also saw adose-dependent reduction of some ECM proteins, includingcollagen 1 after 72 hours of UPA treatment. However, thereis no evidence how the activation of Smad 2/3 leads to up-regulation of collagen 1 gene in UFs because at present, noSmad response elements have been identified within the pro-moter of this gene. Several in vivo and in vitro studies (3) haveshown that miR-29 regulate the messenger RNAs encodingECM proteins, such as collagen type I, alpha 1 and 2, collagentype III alpha 1, elastin, and fibrillin 1. A similar crosstalkmodel between miR-29 family and other growth factors, hor-mones, and paracrine factors could be taken into account to1056elucidate better the fibrotic mechanisms behind UF formationand growth and, for instance, the interracial differences, asnoted in the literature.Salvatore Giovanni Vitale, M.D., Ph.D.Gaetano Valenti, M.D.Antonio Cianci, M.D.Unit of Gynecology and Obstetrics, Department of GeneralSurgery and Medical Surgical Specialties, University ofCatania, Catania, Italyhttps://doi.org/10.1016/j.fertnstert.2019.08.067You can discuss this article with its authors and otherreaders athttps://www.fertstertdialog.com/users/16110-fertility-and-sterility/posts/52537-28830REFERENCES1. Zepiridis LI, Grimbizis GF, Tarlatzis BC. Infertility and uterine fibroids. BestPract Res Clin Obstet Gynaecol 2016;34:66–73.2. IslamMS, Ciavattini A, Petraglia F, Castellucci M, Ciarmela P. Extracellular ma-trix in uterine leiomyoma pathogenesis: a potential target for future therapeu-tics. Hum Reprod Update 2018;24:59–85.3. Kwon JJ, Factora TD, Dey S, Kota J. A systematic review of miR-29 in cancer.Mol Ther Oncolytics 2019;12:173–94.4. Chuang T-D, Khorram O. Cross-talk between MiR-29c and TGF-b3 is medi-ated by an epigenetic mechanism in leiomyoma. Fertil Steril. 2019;112:1180–9.5. Lewis TD, Malik M, Britten J, Parikh T, Cox J, Catherino WH. Ulipristal acetatedecreases active TGF-beta3 and its canonical signaling in uterine leiomyomavia two novel mechanisms. Fertil Steril 2019;111:806–15.e1.VOL. 112 NO. 6 / DECEMBER 2019

Crosstalk between transforming growth factor-β3 and microRNA-29c in leiomyoma: are we stepping forward?

https://iris.unica.it/bitstream/11584/349859/1/Crosstalk%20between%20transforming%20growth%20factor-%ce%b23%20and%20microRNA-29c%20in%20leiomyoma-%20are%20we%20stepping%20forward%3f.pdf

Crosstalk between transforming growth factor-β3 and microRNA-29c in leiomyoma: are we stepping forward?

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Archivio istituzionale della ricerca - Università di Cagliari