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Relationship: 2971
Title
Expression of factors ruling proliferation, modified leads to Increase, Hyperplasia (glandular epithelial cells of endometrium)
Upstream event
Downstream event
Key Event Relationship Overview
AOPs Referencing Relationship
AOP Name | Adjacency | Weight of Evidence | Quantitative Understanding | Point of Contact | Author Status | OECD Status |
---|---|---|---|---|---|---|
Activation of uterine estrogen receptor-alfa leading to endometrial adenocarcinoma, via epigenetic modulation | adjacent | Barbara Viviani (send email) | Under development: Not open for comment. Do not cite | Under Review |
Taxonomic Applicability
Sex Applicability
Sex | Evidence |
---|---|
Female |
Life Stage Applicability
Term | Evidence |
---|---|
All life stages |
Key Event Relationship Description
Proliferation is under the control of several different factors which promote the entry of cells into cell cycle (growth factors) and/or prevent apoptosis. This KER focuses on those factors that are under epigenetic control and have been found altered in human specimens of endometrial adenocarcinoma, with a particular attention to the estrogen dependent type I.
Evidence Collection Strategy
Evidence Supporting this KER
Biological Plausibility
Overexpression, gain-of-function mutation of factors promoting replication (or repressing apoptosis) and/or downregulation, loss-of-function mutation of factors repressing replication (or triggering apoptosis), promotes an uncontrolled proliferation leading to pathologic hyperplasia. Excessive or inappropriate cells/tissue stimulation by hormones cause most forms of pathologic hyperplasia. Endometrial hyperplasia is an example of pathological hormone-induced hyperplasia (Robbins and Cotran, 2015).
Overexpressed factors in human specimens derived from uterine endometrial carcinoma (protein class as reported in the Human Protein Atlas)
- Transcription factors:
PAX2, Type I endometrial carcinoma (Wu et al. 2005, supported by Kahraman et al. 2012). Differentiation, transcription, transcription regulation (Uniprot). Is a prognostic marker in endometrial cancers: high expression is unfavorable in endometrial cancers (Human Protein Atlas database). PAX2 is also involved in different type of cancers promoting cell proliferation (Maulbecker et al. 1993, Khoubehi 2001).
KLF-1, Type I endometrial carcinoma (previously known as erythroid Kruppel-like factor- EKLF) (Wu et al. 2005). Transcription regulator (activator) of erythrocyte development (Uniprot, McConnell et al. 2010).
- Cancer related genes
TFF3, UA type not specified (Pandey et al. 2017, supported by Bignotti et al. 2008). Involved in the maintenance and repair of intestinal mucosas, promotes the mobility of epithelial cells in healing process (Uniprot). In physiological conditions TFF3 rules transiently increases in the proliferative phase of the endometrium (Borthwick et al. 2003). Is a prognostic marker in endometrial cancer: high expression is favourable in endometrial cancer (Human Protein Atlas database). Beside endometrial tumors, TFF3 expression is increased in colorectal (Chen et al. 2019, Yusufu et al. 2019), gastric (Taniguchi et al. 2018), lung adeno- (Zhang et al. 2019) and pancreatic carcinomas (Cheng et al. 2022) and its overexpression has been correlated to the promotion of proliferation.
NMPI, UA type not specified (Zhou et al. 2014, 2018). Involved in diverse cellular processes such as ribosome biogenesis, centrosome duplication, protein chaperoning, histone assembly, cell proliferation, and regulation of tumor suppressors p53/TP53 and ARF. Negatively regulates the activation of EIF2AK2/PKR and suppresses apoptosis through inhibition of EIF2AK2/PKR autophosphorylation (Uniprot). Antagonizes the inhibitory effect of ATF5 on cell proliferation and relieves ATF5-induced G2/M blockade (Uniprot, Liu et al. 2012). In complex with MYC enhances the transcription of MYC target genes (Uniprot, Kim et al. 2015). NMPI is involved in different type of cancers promoting cell proliferation (Grisendi et al. 2006).
DHODH, UA type not specified (Dai et al. 2021). Plays a crucial role in the de novo synthesis of pyrimidine (Barnes, 1993) necessary to maintain proliferation and is overexpressed in different type of tumors (Zhou et al. 2021)
Downregulated factors in human specimens derived from uterine endometrial carcinoma (protein class as reported in the Human Protein Atlas)
- Transcription factors:
KLF-9, UA ERa positive (Simmons et al. 2011, supported by Simmen et al. 2008, Mutter et al. 2001). Transcription regulator (Uniprot, McConnell et al. 2010).
HOPX, endometrial carcinoma type I (Yamaguchi et al. 2009). Prevents serum response factor (SRF)-dependent transcription by inhibiting SRF binding to DNA or by recruiting histone deacetylase protein preventing transcription of SRF. May act as tumor suppressor (Uniprot). It is silenced or downregulated in different tumors and has a role in the control of proliferation (Mariotto et al. 2016)
Empirical Evidence
Uncertainties and Inconsistencies
Wu et al. 2005 – The chosen exposure paradigm to evaluate PAX2 expression in non-tumoral cells (5mM TAM and 100nM E2 for 3h) is based on pilot experiments done to determine the optimal duration of the treatment in cancer cells. These experiments proved that about 75% of known ER target genes were covered. The lack of exposure of control cells at different time and doses of TAM or E2 hamper the possibility to evaluate whether expression of PAX2 increased at different exposure conditions in controls. These observations would be relevant to identify molecular signs distinctive of endometrial cells transformation.
Known modulating factors
Quantitative Understanding of the Linkage
In vitro studies- TAM increases the expression of different factors promoting proliferation in a range of doses included between 0.1-100 mM. TAM 1-100 mM induced cell proliferation. Both effects have been measured at a single time point.
Two different studies address E2 effect on the expression of factors ruling proliferitation and the proliferative effect. No dose response is provided and both endpoints are modified at the same dose and time point. In particular, these effects are observed at E2 0.001 mM after 24h exposure and at 0.1 mM after 3h exposure.
In vivo studies: uterine increased expression of factors ruling proliferation and hyperplasia is observed after 48h exposure to TAM 500 mg/rat/day and E2 2.5 mg/rat/day after.
Response-response Relationship
Time-scale
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
References
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