Regulation of TIMP-1 in Human Placenta and Fetal Membranes by lipopolysaccharide and demethylating agent 5-aza-2'-deoxycytidine

Vincent, Zoë; Mitchell, Murray D.; Ponnampalam, Anna P.

doi:10.1186/s12958-015-0132-y

Cited by 10 publications

(12 citation statements)

References 75 publications

(71 reference statements)

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“…These findings indicate that TIMP-1 expression might be linked to more aggressive subtypes of breast cancer and are consistent with previous studies reporting that TIMP-1 expression is associated with a poor prognosis in breast cancer [ 40 ], colorectal cancer [ 41 ], laryngeal squamous cell carcinoma [ 42 ] and hepatocellular carcinoma [ 43 ]. An increase in TIMP-1 mRNA levels induced by 5-Aza treatment has also been observed in melanoma [ 44 ] and gestational tissues [ 45 ], indicating that promoter methylation mediates the expression of TIMP-1 in various cell types.…”

Section: Discussionmentioning

confidence: 95%

Higher levels of TIMP-1 expression are associated with a poor prognosis in triple-negative breast cancer

et al. 2016

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BackgroundTissue inhibitor of metalloproteinases-1 (TIMP-1) is a multifunctional protein that can directly regulate apoptosis and metastasis. In this study, we investigated the functional and molecular mechanisms by which TIMP-1 influences triple-negative breast cancer (TNBC).MethodsThe expression level of TIMP-1 in breast cancer tissues was analyzed using the ONCOMINE microarray database. The overall survival of patients with distinct molecular subtypes of breast cancer stratified by TIMP-1 expression levels was evaluated using Kaplan–Meier analysis. Bisulfate sequencing PCR (BSP) was used to analyze the methylation status of the TIMP-1 promoter. Real-time-PCR (RT-PCR), Western blot and ELISA assays were used to evaluate gene and protein expression in cell lines and human tissue specimens. In addition, TIMP-1 function was analyzed using a series of in vitro and in vivo assays with cells in which TIMP-1 was inhibited using RNAi or neutralizing antibodies.ResultsWe found that serum TIMP-1 levels were strongly enhanced in patients with TNBC and that elevated TIMP-1 levels were associated with a poor prognosis in TNBC. However, TIMP-1 levels were not significantly associated with overall survival in other subtypes of breast cancer or in the overall population of breast cancer patients. We also report the first evidence that the TIMP-1 promoter is hypomethylated in TNBC cell lines compared with non-TNBC cell lines, suggesting that aberrant TIMP-1 expression in TNBC results from reduced DNA methylation. RNAi-mediated silencing of TIMP-1 in TNBC cells induced cell cycle arrest at the G1 phase and reduced cyclin D1 expression. In addition, mechanistic analyses revealed that the p-Akt and p-NF-κB signaling pathways, but not the GSK-3β and MAPK1/2 pathways, are associated with TIMP-1 overexpression in TNBC cells. Moreover, neutralizing antibodies against TIMP-1 significantly decreased the rate of tumor growth in vivo.ConclusionsOur findings suggest that TIMP-1 is a biomarker indicative of a poor prognosis in TNBC patients and that targeting TIMP-1 may provide an attractive therapeutic intervention specifically for triple-negative breast cancer patients.

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Section: Discussionmentioning

confidence: 95%

Higher levels of TIMP-1 expression are associated with a poor prognosis in triple-negative breast cancer

et al. 2016

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“…TIMP1 is an important regulator for both testicular development and spermatogenesis [49]. TIMP1 was highly expressed in ZIKVinfected endothelial cells [50], is intimately involved in maintaining fetal membrane integrity until labor [51], and amniotic fluid levels decrease during pregnancy with advancing gestation [52]. Coordinated regulation of MMPs and TIMPs are required to maintain tissue architecture and normal ovarian function [53,54].…”

Section: Zikv Disrupts Proteins Involved In Hserc Functions Related Tmentioning

confidence: 99%

Zika virus dysregulates human Sertoli cell proteins involved in spermatogenesis with little effect on tight junctions

et al. 2020

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Zika virus (ZIKV), a neglected tropical disease until its re-emergence in 2007, causes microcephaly in infants and Guillain-Barré syndrome in adults. Its re-emergence and spread to more than 80 countries led the World Health Organization in 2016 to declare a Public Health Emergency. ZIKV is mainly transmitted by mosquitos, but can persist in infected human male semen for prolonged periods and may be sexually transmitted. Testicular Sertoli cells support ZIKV replication and may be a reservoir for persistent ZIKV infection. Electrical impedance analyses indicated ZIKV infection rapidly disrupted Vero cell monolayers but had little effect upon human Sertoli cells (HSerC). We determined ZIKV-induced proteomic changes in HSerC using an aptamer-based multiplexed technique (SOMAscan) targeting >1300 human proteins. ZIKV infection caused differential expression of 299 proteins during three different time points, including 5 days after infection. Dysregulated proteins are involved in different bio-functions, including cell death and survival, cell cycle, maintenance of cellular function, cell signaling, cellular assembly, morphology, movement, molecular transport, and immune response. Many signaling pathways important for maintenance of HSerC function and spermatogenesis were highly dysregulated. These included IL-6, IGF1, EGF, NF-κB, PPAR, ERK/MAPK, and growth hormone signaling. Down-regulation of the PPAR signaling pathway might impact cellular energy supplies. Upstream molecule analysis also indicated microRNAs involved in germ cell development were downregulated by infection. Overall, this study leads to a better understanding of Sertoli cellular mechanisms used by ZIKV during persistent infection and possible ZIKV impacts on spermatogenesis.

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“…In 2015, the first biochemical evidence that the fetal membranes might be stronger in female pregnancies was published and has provided critical insight into the sex‐specific mechanisms of P‐PROM in human pregnancies . Vincent et al.…”

Section: Maintenance and Rupture Of The Fetal Membranesmentioning

confidence: 99%

“…47 In 2015, the first biochemical evidence that the fetal membranes might be stronger in female pregnancies was published and has provided critical insight into the sex-specific mechanisms of P-PROM in human pregnancies. 49 Vincent et al showed that there is sex-specific expression of tissue inhibitor of metalloproteinase-1 (TIMP-1), an inhibitor of MMPs, and a marker of fetal membrane integrity in amniochorion, where TIMP-1 expression is greater in female amnion at term and is reduced during labour. 49…”

Section: Maintenance and Rupture Of The Fetal Membranesmentioning

confidence: 99%

The intrauterine renin–angiotensin system: Sex‐specific effects on the prevalence of spontaneous preterm birth

Pringle

Zakár

Lumbers

2017

Clin Exp Pharma Physio

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Preterm birth (PTB) is the single largest cause of death in infants and young children. The rate of PTB is significantly higher in male infants, particularly those that are born very preterm. Here we present evidence to suggest that the decidual renin-angiotensin system may play a role in inhibiting inflammation and maintaining the integrity of the fetal membranes during pregnancy, and that sex-specific alterations in the intrauterine RAS could contribute to the increased risk of PTB in male babies. Women carrying female fetuses have high levels of expression of decidual prorenin at term. Decidua from 'female' pregnancies also have greater expression of the anti-inflammatory angiotensin (Ang)-(1-7) pathway, than decidua from 'male' pregnancies, and have lower levels of the pro-inflammatory Ang II pathway. We propose that in 'female' pregnancies, the very high levels of decidual prorenin drive the anti-inflammatory Ang-(1-7) pathway, thus reducing the likelihood of PTB. In addition, the high levels of prorenin produced by the decidua in 'female' pregnancies are able to diffuse into the amnion and bind to the PRR. We postulate that PRR/prorenin interactions, possibly through both angiotensin dependent and independent pathways, stimulate the production of ECM proteins, inhibit ECM degradation and prevent apoptosis, thus strengthening the amnion. Thus control of the inflammatory signature and the integrity of the fetal membranes prior to parturition may partly depend on the sexually determined activity of the decidual and amniotic renin-angiotensin system pathways.

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Regulation of TIMP-1 in Human Placenta and Fetal Membranes by lipopolysaccharide and demethylating agent 5-aza-2'-deoxycytidine

Cited by 10 publications

References 75 publications

Higher levels of TIMP-1 expression are associated with a poor prognosis in triple-negative breast cancer

Higher levels of TIMP-1 expression are associated with a poor prognosis in triple-negative breast cancer

Zika virus dysregulates human Sertoli cell proteins involved in spermatogenesis with little effect on tight junctions

The intrauterine renin–angiotensin system: Sex‐specific effects on the prevalence of spontaneous preterm birth

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