Corroborating evidence for platelet-induced epithelial-mesenchymal transition and fibroblast-to-myofibroblast transdifferentiation in the development of adenomyosis

Liu, Xishi; Shen, Minhong; Qi, Qiu-Ming; Zhang, Hongqi; Guo, Sun‐Wei

doi:10.1093/humrep/dew018

Cited by 134 publications

(147 citation statements)

References 85 publications

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“…However, as DNA damage, oxidative stress, hypoxia, and oncogene (such as KRAS and YAP) activation induce cellular senescence and senescence would curtail fibrosis, it is likely that in older and thus more fibrotic lesions may experience less hypoxia and less oxidative stress (due to increased fibrotic content and thus reduced cellularity, less hemorrhage and thus iron overload) and less DNA damage (as seen by reduced γ‐H2AX expression ), the pressure for cellular senescence may be reduced, especially in the stromal compartment. This would be consistent with reduced Caveolin‐1 expression in adenomyosis, which can be highly fibrotic, especially as lesions get older . This also would be consistent with seemingly progressive decrease in CCN1 expression in older lesions .…”

Section: Changing Pressure For Genomic Alteration Due To Oxidative Stsupporting

confidence: 72%

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Cancer driver mutations in endometriosis: Variations on the major theme of fibrogenesis

Guo

2018

Reprod Medicine & Biology

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BackgroundOne recent study reports cancer driver mutations in deep endometriosis, but its biological/clinical significance remains unclear. Since the natural history of endometriosis is essentially gradual progression toward fibrosis, it is thus hypothesized that the six driver genes reported to be mutated in endometriosis (the RP set) may play important roles in fibrogenesis but not necessarily malignant transformation.MethodsExtensive PubMed search to see whether RP and another set of driver genes not yet reported (NR) to be mutated in endometriosis have any roles in fibrogenesis. All studies reporting on the role of fibrogenesis of the genes in both RP and NR sets were retrieved and evaluated in this review.ResultsAll six RP genes were involved in various aspects of fibrogenesis as compared with only three NR genes. These nine genes can be anchored in networks linking with their upstream and downstream genes that are known to be aberrantly expressed in endometriosis, piecing together seemingly unrelated findings.ConclusionsGiven that somatic driver mutations can and do occur frequently in physiologically normal tissues, it is argued that these mutations in endometriosis are not necessarily synonymous with malignancy or premalignancy, but the result of enormous pressure for fibrogenesis.

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Section: Changing Pressure For Genomic Alteration Due To Oxidative Stsupporting

confidence: 72%

“…Both animal and human data lend support for the notion that endometriotic lesions are fundamentally wounds undergoing repeated tissue injury and repair (ReTIAR) . Similar processes also occur in adenomyosis, due to the shared commonality of cyclic bleeding …”

Section: A Primer On the Natural History Of Endometriosismentioning

confidence: 82%

Cancer driver mutations in endometriosis: Variations on the major theme of fibrogenesis

Guo

2018

Reprod Medicine & Biology

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“…Fibrosis is now recognized as a prominent feature of endometriosis 8, 21 as well as of adenomyosis 51, 52 . Remarkably, EZH2 is intimately involved in fibrogenesis 28 .…”

Section: Discussionmentioning

confidence: 99%

Enhancer of Zeste homolog 2 (EZH2) induces epithelial-mesenchymal transition in endometriosis

Zhang

Dong

Liu

et al. 2017

Sci Rep

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EZH2, a subunit of the polycomb repressive complex 2 (PRC2) catalyzing trimethylation of histone H3 lysine 27 (H3K27), induces epithelial-mesenchymal transition (EMT) in cancers. However, whether EZH2 regulates EMT in endometriosis is unclear. Here, we show that EZH2 expression, along with its associated PRC2 proteins, is significantly elevated in ectopic and eutopic endometrium from women with endometriosis as compared with control endometrium. EZH2 knockdown or inhibition restored the epithelial phenotypes of endometriotic epithelial cells, concomitant with the upregulation of E-cadherin and downregulation of vimentin and transcription factors (Snail and Slug) as well as reduced cellular migratory and invasive propensity. Conversely, overexpression of EZH2 induced the expression of Snail, Slug and vimentin and suppresses E-cadherin expression. In vivo administration of 3-Deazaneplanocin A (DZNep), an EZH2 inhibitor, significantly inhibited the growth of endometriotic lesions and improved generalized hyperalgesia, along with attenuated EMT and reduced fibrosis in endometriosis. Notably, platelets induced EZH2 upregulation and increased H3K27 and H3K9 trimethylation levels in endometriotic epithelial cells. These data identify EZH2 as a novel driver of EMT in endometriosis, implicates the link between wound healing and epigenetic changes in the context of endometriosis, and underscore the role of platelets in the development of endometriosis.

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“…[6] Fundamental analysis studies in recent years demonstrated that CA125, PLT, and NEU may related to the development and progression of the inflammatory pathology of endometriosis via the inflammation-associated molecular mechanism. [14,15] It was reported that patients with preoperative CA125 levels higher than 65 IU/mL were at high risk for advanced-stage or severe pelvic adhesion. [16] Numerous studies demonstrated that both PLT and NEU were implicated in the pathogenesis of endometriosis and adenomyosis.…”

Section: Discussionmentioning

confidence: 99%

“…[20] The significant correlations between PLT and NLR and PDA in this study suggest that both of PLT and NLR may be related to the inflammatory pathogenesis of adenomyosis. [14,18] …”

Section: Discussionmentioning

confidence: 99%

CA125 modified by PLT and NLR improves the predictive accuracy of adenomyosis-derived pelvic dense adhesion

et al. 2017

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To explore the value of serum levels of CA125, platelet count (PLT), neutrophil–lymphocyte ratio (NLR), and modified CA125 markers CA125a and CA125b in predicting pelvic dense adhesion (PDA) associated with adenomyosis, CA125a = lg(CA125 × PLT × 109), CA125b = lg(CA125 × NLR).This retrospective study included 304 patients who underwent surgery for adenomyosis. Correlations of serum levels of CA125, PLT, NLR, and modified CA125 markers with adenomyosis-derived PDA were analyzed by Logistic regression. Receiver operating characteristic curve was applied to assess the utility of these parameters for predicting PDA.All the parameters including CA125, PLT, NLR, and modified CA125 markers were positively correlated with PDA (P < .05 or P < .01). More importantly, CA125a was more specific (85.03% vs. 83.00%) and more sensitive (47.56% vs. 47.47%) than CA125 alone for the prediction of PDA, and CA125b could also improve the predictive specificity of PDA (53.13% vs. 47.47%).Serum CA125, PLT, and NLR were all closely correlated with PDA in adenomyosis patients. CA125 modified by PLT and NLR could further improve the predictive accuracy of adenomyosis-derived PDA, thus providing more meaningful references for better-informed decisions about the mode of surgical access for the clinical treatment of adenomyosis.

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Corroborating evidence for platelet-induced epithelial-mesenchymal transition and fibroblast-to-myofibroblast transdifferentiation in the development of adenomyosis

Abstract: Support for data collection and analysis was provided by grants from the National Science Foundation of China. None of the authors has anything to disclose.

Cited by 134 publications

References 85 publications

Cancer driver mutations in endometriosis: Variations on the major theme of fibrogenesis

Cancer driver mutations in endometriosis: Variations on the major theme of fibrogenesis

Enhancer of Zeste homolog 2 (EZH2) induces epithelial-mesenchymal transition in endometriosis

CA125 modified by PLT and NLR improves the predictive accuracy of adenomyosis-derived pelvic dense adhesion

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