Hippo signaling in the ovary and polycystic ovarian syndrome

Maas, K.; Mirabal, Sheyla; Penzias, Alan S.; Sweetnam, Paul M.; Eggan, Kevin; Sakkas, Denny

doi:10.1007/s10815-018-1235-0

Cited by 34 publications

(24 citation statements)

References 47 publications

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“…For example, organ growth depends on a series of cell biological processes, including cell proliferation, cell division, and programmed cell death. Hippo signaling pathway inhibits cell proliferation and induces apoptosis [28], which is becoming increasingly important in the study of uncontrolled cell division in cancer. The notably enriched mRNAs in Hippo signaling pathway included WNT5A, DLG4, LEF1, TEAD2, PARD6G, FZD2, BMP7, WNT6, TCF7L1, FZD7, and BMP6.…”

Section: Resultsmentioning

confidence: 99%

Identification of clinical trait–related lncRNA and mRNA biomarkers with weighted gene co-expression network analysis as useful tool for personalized medicine in ovarian cancer

Zhan

2019

EPMA Journal

109

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Relevance The pathogenesis and biomarkers of ovarian cancer (OC) remain not well-known in diagnosis, effective therapy, and prognostic assessment in OC personalized medicine. The novel identified lncRNA and mRNA biomarkers from gene co-expression modules associated with clinical traits provide new insight for effective treatment of ovarian cancer. Purpose Long non-coding RNAs (lncRNAs) are relevant to tumorigenesis via multiple mechanisms. This study aimed to investigate cancer-specific lncRNAs and mRNAs, and their related networks in OCs. Methods This study comprehensively analyzed lncRNAs and mRNAs with associated competing endogenous RNA (ceRNA) network and lncRNA–RNA binding protein–mRNA network in the OC tissues in the Cancer Genome Atlas, including 2562 cancer-specific lncRNAs ( n = 352 OC tissues) and 5000 mRNAs ( n = 359 OC tissues). The weighted gene co-expression network analysis (WGCNA) was used to construct the co-expression gene modules and their relationship with clinical traits. The statistically significant difference of identified lncRNAs and mRNAs was confirmed with qRT-PCR in OC cells. Results An lncRNA-based co-expression module was significantly correlated with patient age at initial pathologic diagnosis, lymphatic invasion, tissues source site, and vascular invasion, and identified 16 lncRNAs (ACTA2-AS1, CARD8-AS1, HCP5, HHIP-AS1, HOTAIRM1, ITGB2-AS1, LINC00324, LINC00605, LINC01503, LINC01547, MIR31HG, MIR155HG, OTUD6B-AS1, PSMG3-AS1, SH3PXD2A-AS1, and ZBED5-AS1) that were significantly related to overall survival in OC patients. An mRNA-based co-expression module was significantly correlated with patient age at initial pathologic diagnosis, lymphatic invasion, tumor residual disease, and vascular invasion; and identified 21 hub-mRNA molecules and 11 mRNAs (FBN3, TCF7L1, SBK1, TRO, TUBB2B, PLCG1, KIAA1549, PHC1, DNMT3A, LAMA1, and C10orf82) that were closely linked with OC patients’ overall survival. Moreover, the prognostic model of five-gene signature (OTUD6B-AS1, PSMG3-AS1, ZBED5-AS1, SBK1, and PLCG1) was constructed to predict risk score in OC patients. Furthermore, starBase bioinformatics constructed the lncRNA–miRNA–mRNA and lncRNA–RNA binding protein-mRNA networks in OCs. Conclusion These new findings showed that lncRNA-related networks in OCs are a useful resource for identification of biomarkers in OCs. Electronic supplementary material The online version of this article (10.1007/s13167-019-00175-0) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Identification of clinical trait–related lncRNA and mRNA biomarkers with weighted gene co-expression network analysis as useful tool for personalized medicine in ovarian cancer

Zhan

2019

EPMA Journal

109

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“…TAZ also contains a WW domain as the Yes-associated protein (YAP1) 43 and is another gene that was associated with PCOS 12, 13, 16 . WWTR1 and YAP1 are two key molecules of the Hippo signaling pathway, and their expression were significantly altered in PCOS tissues 44 . Insulin resistance affects 50-70% of women with PCOS 45 .…”

Section: Results and Implicationsmentioning

confidence: 99%

A genome-wide association study of polycystic ovary syndrome identified from electronic health records

Zhang¹,

Keaton

et al. 2019

Preprint

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Background: Polycystic ovary syndrome (PCOS) is the most common endocrine disorder affecting women of reproductive age. Previous studies have identified genetic variants associated with PCOS identified by different diagnostic criteria. The Rotterdam Criteria is the broadest and able to identify the most PCOS cases. Objectives: To identify novel associated genetic variants, we extracted PCOS cases and controls from the electronic health records (EHR) based on the Rotterdam Criteria and performed a genome-wide association study (GWAS). Study Design: We developed a PCOS phenotyping algorithm based on the Rotterdam criteria and applied it to three EHR-linked biobanks to identify cases and controls for genetic study. In discovery phase, we performed individual GWAS using the Geisinger's MyCode and the eMERGE cohorts, which were then meta-analyzed. We attempted validation of the significantly association loci (P<1x10-6) in the BioVU cohort. All association analyses used logistic regression, assuming an additive genetic model, and adjusted for principal components to control for population stratification. An inverse-variance fixed effect model was adopted for meta-analyses. Additionally, we examined the top variants to evaluate their associations with each criterion in the phenotyping algorithm. We used STRING to identify protein-protein interaction network. Results: We identified 2,995 PCOS cases and 53,599 controls in total (2,742 cases and 51,438 controls from the discovery phase; 253 cases and 2,161 controls in the validation phase). GWAS identified one novel genome-wide significant variant rs17186366 (OR=1.37 [1.23,1.54], P=2.8x10-8) located near SOD2. Additionally, two loci with suggestive association were also identified: rs113168128 (OR=1.72 [1.42,2.10], P=5.2 x10-8), an intronic variant of ERBB4 that is independent from the previously published variants, and rs144248326 (OR=2.13 [1.52,2.86], P=8.45x10-7), a novel intronic variant in WWTR1. In the further association tests of the top 3 SNPs with each criterion in the PCOS algorithm, we found that rs17186366 was associated with polycystic and hyperandrogenism, while rs11316812 and rs144248326 were mainly associated with oligomenorrhea or infertility. Besides ERBB4, we also validated the association with DENND1A1. Conclusion: Through a discovery-validation GWAS on PCOS cases and controls identified from EHR using an algorithm based on Rotterdam criteria, we identified and validated a novel association with variants within ERBB4. We also identified novel associations nearby SOD2 and WWTR1. These results suggest the eGFR and Hippo pathways in the disease etiology. With previously identified PCOS-associated loci YAP1, the ERBB4-YAP1-WWTR1 network implicates the epidermal growth factor receptor and the Hippo pathway in the multifactorial etiology of PCOS.

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“…In patients with POI, the few existing primordial follicles would be located very close to the medulla ( 36 ). Moreover, in patients with PCOS it has been demonstrated that all pre antral follicles are trapped in cortex which could be explained by an aberrant Hippo-signaling, considered important for adequate follicular growth ( 37 ).…”

Section: Mechanical Signaling In Ovarian Functionmentioning

confidence: 99%

In Vitro Follicular Activation and Stem Cell Therapy as a Novel Treatment Strategies in Diminished Ovarian Reserve and Primary Ovarian Insufficiency

et al. 2021

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Usually poor ovarian response (POR) to gonadotropins reflects a diminished ovarian reserve (DOR) that gives place to few recruitable follicles despite aggressive stimulation. The reduction in the quantity and quality of the oocytes with advanced age is physiological. However, some women experience DOR much earlier and become prematurely infertile, producing an accelerated follicular depletion towards primary ovarian insufficiency (POI). Up to now, egg donation has been commonly used to treat their infertility. In the last thirty years, specialists in assisted reproduction have focused their attention on the final stages of folliculogenesis, those that depend on the action of gonadotrophins. Nevertheless, recently novel aspects have been known to act in the initial phases, with activating and inhibiting elements. In vitro activation (IVA) combining the in vitro stimulation of the ovarian Akt signaling pathway in ovarian cortex fragments with a method named Hippo-signaling disruption. Later, a simplification of the technique designated Drug-Free IVA have shown encouraging results in patients with POI. Another innovative therapeutic option in these patients is the infusion of bone marrow-derived stem cells (BMDSC) in order to supply an adequate ovarian niche to maintain and/or promote follicular rescue in patients with impaired or aged ovarian reserves. In this review, for the first time, both therapeutic options are addressed together in a common clinical setting. The aim of this review is to analyze the physiological aspects on which these innovative techniques are based; the preliminary results obtained up to now; and the possible therapeutic role that they may have in the future with DOR and POI patients.

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Hippo signaling in the ovary and polycystic ovarian syndrome

Cited by 34 publications

References 47 publications

Identification of clinical trait–related lncRNA and mRNA biomarkers with weighted gene co-expression network analysis as useful tool for personalized medicine in ovarian cancer

Identification of clinical trait–related lncRNA and mRNA biomarkers with weighted gene co-expression network analysis as useful tool for personalized medicine in ovarian cancer

A genome-wide association study of polycystic ovary syndrome identified from electronic health records

In Vitro Follicular Activation and Stem Cell Therapy as a Novel Treatment Strategies in Diminished Ovarian Reserve and Primary Ovarian Insufficiency

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