Obesity and the Endometrium: Adipocyte-Secreted Proinflammatory TNF<b><i>α</i></b>Cytokine Enhances the Proliferation of Human Endometrial Glandular Cells

Nair, Sangeeta; Nguyen, HoVan; Salama, Salama; Al-Hendy, Ayman

doi:10.1155/2013/368543

Cited by 22 publications

(13 citation statements)

References 41 publications

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“…38 In the hyperkeratosis and IFH cases, 4 (80%) and 2 (25%) samples, respectively, demonstrated positivity in cells located in the basal and parabasal epithelial compartments. Nonetheless, CCND1 expression should be considered as a possible result of inflammation in these cases, as was previously demonstrated by Nair et al 40 In conclusion, comparative analysis of the proteins involved in the HH pathway in the present OED, NNM, IFH, and hyperkeratosis cases strongly suggests that this pathway plays an important role in the biological behavior of OED. Notably, when compared with IFH, the OED samples exhibited higher levels of expression with respect to all the HH molecules involved, substantiating the notion that these proteins may influence carcinogenesis, regardless of the associated inflammatory process.…”

Section: Discussionsupporting

confidence: 75%

Enhanced Expression of Hedgehog Pathway Proteins in Oral Epithelial Dysplasia

Dias

Valverde

Sales

et al. 2016

Applied Immunohistochemistry &Amp; Molecular Morphology

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The aim of this study was to characterize the profile of the proteins involved in the Hedgehog signaling pathway to aid in the understanding of the pathogenesis of oral epithelial dysplasia (OED). The proteins SHH, PTCH1, HHIP, SUFU, GLI1, and cyclin D1 were evaluated by immunohistochemistry in 25 cases of OED, 4 of non-neoplasic oral mucosa, 8 of inflammatory fibrous hyperplasia and 5 of hyperkeratosis. SHH proteins were predominant in OED cases. Although PTCH1 protein was observed in all cases, this molecule was more highly expressed in OED. The inhibitor protein SUFU was present in OED and HHIP protein was overexpressed in OED. GLI1 proteins were predominantly found in the nuclei of epithelial cells in OED. Basal and suprabasal cells in the epithelial lining were positive for cyclin D1 only in OED. In conclusion, comparative analysis of the proteins involved in the Hedgehog pathway suggests that enhanced expression of these proteins can play an important role in the biological behavior of OED.

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Section: Discussionsupporting

confidence: 75%

Enhanced Expression of Hedgehog Pathway Proteins in Oral Epithelial Dysplasia

Dias

Valverde

Sales

et al. 2016

Applied Immunohistochemistry &Amp; Molecular Morphology

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“…Another emerging characteristic of UF is the promotion of inflammation as reported by our group and others. 24 , 25 Furthermore, recent reports connected aberration of autophagy with altered inflammatory state. 26 In order to explore the impact of ATG4D silencing on the inflammatory response of normal human UTSM myometrial cells, we examined the expression level of proinflammatory cytokines such us TNF-a, IL-1b and TGF-b in ATG4D-KD-UTSM versus scramble control cells.…”

Section: Resultsmentioning

confidence: 99%

Defective expression of ATG4D abrogates autophagy and promotes growth in human uterine fibroids

Andaloussi¹,

Habib²,

Soylemes³

et al. 2017

Cell Death Discov.

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Uterine fibroids (UF) are the most common pelvic tumors in women of reproductive-age and they usually cause heavy menstrual bleeding, pain and infertility. Autophagy is a collection of processes that enables the cells to digest and recycle their cytoplasmic contents, such as toxic protein aggregates, defunct or disused organelles and invading microorganisms. Dysregulation in autophagy process were described in neoplasms; however, the contribution of autophagy to the pathogenesis of UF remains unknown. In this study, we demonstrate that autophagy is deregulated in human UF as evidenced by significant accumulation of autophagosome in human UF cells compared to normal myometrium cells. Analysis of the autophagy markers revealed an enhanced initiation of the autophagy in UF tissues compared to their adjacent myometrial tissues (MyoF). However, autophagosome maturation and flux was blocked in UF tissues, as marked by accumulation of LC3-B and P62 protein. This block was associated with defective expression of autophagy-related protein 4 (ATG4) in the UF tissues compared to MyoF in ~90% of patient samples. Silencing of ATG4D in normal human myometrial cells resulted in defective autophagy flux, enhanced cell proliferation and increased extracellular matrix production, which phenocopy UF cell line. This study indicates that impairment of autophagy flux secondary to defective expression of ATG4D expression is a new mechanistic aberration that contributes to UF pathogenesis. Targeting autophagy pathway could provide novel medical therapeutic approach for non-surgical treatment of UF.

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“…2013 ) and increased concentrations of cholesterol have been reported in tumours of various cancer types although they have not been directly measured in EC. 27HC can also promote secretion of TNFA and IL6 from macrophages and TNFA is reported to increase proliferation of human endometrial glandular epithelial cells ( Nair et al . 2013 ).…”

Section: Discussionmentioning

confidence: 99%

The impact of 27-hydroxycholesterol on endometrial cancer proliferation

Gibson¹,

Collins²,

Cousins³

et al. 2018

Endocrine-Related Cancer

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Endometrial cancer (EC) is the most common gynaecological malignancy. Obesity is a major risk factor for EC and is associated with elevated cholesterol. 27-hydroxycholesterol (27HC) is a cholesterol metabolite that functions as an endogenous agonist for Liver X receptor (LXR) and a selective oestrogen receptor modulator (SERM). Exposure to oestrogenic ligands increases risk of developing EC; however, the impact of 27HC on EC is unknown. Samples of stage 1 EC (n = 126) were collected from postmenopausal women undergoing hysterectomy. Expression of LXRs (NR1H3, LXRα; NR1H2, LXRβ) and enzymes required for the synthesis (CYP27A1) or breakdown (CYP7B1) of 27HC were detected in all grades of EC. Cell lines originating from well-, moderate- and poorly-differentiated ECs (Ishikawa, RL95, MFE 280 respectively) were used to assess the impact of 27HC or the LXR agonist GW3965 on proliferation or expression of a luciferase reporter gene under the control of LXR- or ER-dependent promoters (LXRE, ERE). Incubation with 27HC or GW3965 increased transcription via LXRE in Ishikawa, RL95 and MFE 280 cells (P < 0.01). 27HC selectively activated ER-dependent transcription (P < 0.001) in Ishikawa cells and promoted proliferation of both Ishikawa and RL95 cells (P < 0.001). In MFE 280 cells, 27HC did not alter proliferation but selective targeting of LXR with GW3965 significantly reduced cell proliferation (P < 0.0001). These novel results suggest that 27HC can contribute to risk of EC by promoting proliferation of endometrial cancer epithelial cells and highlight LXR as a potential therapeutic target in the treatment of advanced disease.

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Obesity and the Endometrium: Adipocyte-Secreted Proinflammatory TNFαCytokine Enhances the Proliferation of Human Endometrial Glandular Cells

Cited by 22 publications

References 41 publications

Enhanced Expression of Hedgehog Pathway Proteins in Oral Epithelial Dysplasia

Enhanced Expression of Hedgehog Pathway Proteins in Oral Epithelial Dysplasia

Defective expression of ATG4D abrogates autophagy and promotes growth in human uterine fibroids

The impact of 27-hydroxycholesterol on endometrial cancer proliferation

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