The Role of microRNAs in Ovarian Granulosa Cells in Health and Disease

Tu, Jiajie; Cheung, Hoi‐Hung; Chan, Casey K.; Chan, Wai‐Yee

doi:10.3389/fendo.2019.00174

Cited by 101 publications

(62 citation statements)

References 103 publications

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“…As expected, fertility issues could be triggered by defects in folliculogenesis. The normal growth of granulosa cells including proliferation and apoptosis seems to be dysregulated by the interaction of miRNA with the TGF-β signaling pathway ( Chan et al, 2010 ; Zhang Q. et al, 2013 ; Nie et al, 2015 ; Tu et al, 2019 ). Interestingly, it has been reported that Smads, the signal transducers of TGF-β/GDF, could promote a specific set of miRNAs by assisting the cleavage reaction by Drosha.…”

Section: Resultsmentioning

confidence: 99%

Reporting on the Role of miRNAs and Affected Pathways on the Molecular Backbone of Ovarian Insufficiency: A Systematic Review and Critical Analysis Mapping of Future Research

Rapani

Nikiforaki

Karagkouni

et al. 2021

Front. Cell Dev. Biol.

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Ovarian insufficiency is identified as a perplexing entity in the long list of pathologies impairing fertility dynamics. The three distinct classifications of ovarian insufficiency are poor ovarian response, premature ovarian insufficiency/failure, and advanced maternal age, sharing the common denominator of deteriorated ovarian reserve. Despite efforts to define clear lines among the three, the vast heterogeneity and overlap of clinical characteristics renders their diagnosis and management challenging. Lack of a consensus has prompted an empirically based management coupled by uncertainty from the clinicians’ perspective. Profiling of patients in the era of precision medicine seems to be the way forward, while the necessity for a novel approach is underlined. Implicating miRNAs in the quest for patient profiling is promising in light of their fundamental role in cellular and gene expression regulation. To this end, the current study sets out to explore and compare the three pathophysiologies—from a molecular point of view—in order to enable profiling of patients in the context of in vitro fertilization treatment and enrich the data required to practice individualized medicine. Following a systematic investigation of literature, data referring to miRNAs were collected for each patient category based on five included studies. miRNA–target pairs were retrieved from the DIANA-TarBase repository and microT-CDS. Gene and miRNA annotations were derived from Ensembl and miRbase. A subsequent gene-set enrichment analysis of miRNA targets was performed for each category separately. A literature review on the most crucial of the detected pathways was performed to reveal their relevance to fertility deterioration. Results supported that all three pathophysiologies share a common ground regarding the affected pathways, naturally attributed to the common denominator of ovarian insufficiency. As evidenced, miRNAs could be employed to explore the fine lines and diverse nature of pathophysiology since they constitute invaluable biomarkers. Interestingly, it is the differentiation through miRNAs and not through the molecular affected pathways that corresponds to the three distinctive categories. Alarming discrepancies among publications were revealed, pertaining to employment of empirical and arbitrary criteria in categorizing the patients. Following bioinformatic analysis, the final step of the current study consisted of a critical analysis of the molecular data sourced, providing a clear and unique insight into the physiological mechanisms involved. It is our intention to contribute to mapping future research dedicated to ovarian insufficiency and to help researchers navigate the overwhelming information published in molecular studies.

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Section: Resultsmentioning

confidence: 99%

Reporting on the Role of miRNAs and Affected Pathways on the Molecular Backbone of Ovarian Insufficiency: A Systematic Review and Critical Analysis Mapping of Future Research

Rapani

Nikiforaki

Karagkouni

et al. 2021

Front. Cell Dev. Biol.

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“…The growth and proliferation of GCs play critical roles in the biological processes of recruitment, selection and maturation of follicles. Several studies demonstrated that the proliferation and apoptosis of GCs were involved in folliculogenesis (Ortega et al, 2012; Tu, Cheung, Chan, & Chan, 2019). FHL2 belongs to the LIM domain‐only proteins and contains four and a half LIM domains (Dahan et al, 2017; McLoughlin, Ehler, Carlile, Licht, & Schafer, 2002).…”

Section: Discussionmentioning

confidence: 99%

Expression, location and biological effects of four and a half LIM domain protein 2 (FHL2) on granulosa cells in ovine

Zhang

Zhao

Chen

et al. 2020

Reprod Domestic Animals

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Previous studies have shown that four and a half LIM domain protein 2 (FHL2) plays an essential role in the regulation of follicular development in mammals. Although the FHL2 genes of human and mouse have been well characterized, the expression and location of FHL2 in ovary and the biological functions of FHL2 on granulosa cells (GCs) of ovine are still not clear. In this study, full‐length complementary DNA (cDNA) of FHL2 from ovine follicular GCs was amplified by real‐time PCR (RT‐PCR). The expression and location of FHL2 in ovary and GCs of ovine were studied by immunohistochemistry and immunofluorescence, and the biological effects of FHL2 on the cell proliferation, cell apoptosis, cell cycles and expression level of related genes of ovine GCs were also explored by overexpression or knockdown of FHL2. The results indicated that FHL2 was expressed in ovine follicular GCs and the sequence of the FHL2 cDNA was consistent with that predicted in GenBank, which did not cause an amino acid change. According to the results, FHL2 was expressed in ovine ovary and mainly located in the cytoplasm and nucleus of GCs. In addition, overexpression of FHL2 significantly reduced the cell viability, promoted the cell apoptosis and decreased the percentage of G0/G1 and S phase cells. RT‐PCR showed that overexpression of FHL2 significantly increased the mRNA expression level of Bax and decreased the expression of Bcl‐2 and the Bcl‐2/Bax mRNA ratio compared with the control group. Besides, the knockdown of FHL2 gene in ovine GCs significantly improved the cell viability, suppressed the cell apoptosis, decreased the mRNA expression level of Caspase‐3 gene, increased the Bcl‐2/Bax mRNA ratio and increased the percentage of S and G2/M phase cells. Our results suggest that FHL2 may play an important role in the biological functions of GCs in ovine.

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“…oocyte-cumulus cell interaction, GC function and luteinization by targeting specific molecules and modulating various signaling pathways, such as TGFB-, FSH-, hormone-and apoptosis-related pathways [16,17]. Single nucleotide polymorphisms (SNPs) in miRNAs, including pri-miRNA (primary miRNA transcripts), pre-miRNA (precursor miRNA) and mature miRNA are associated with the abundance of mature miRNA and may contribute to phenotypic variation in animals [13].…”

Section: A C C E P T E D a R T I C L Ementioning

confidence: 99%

miR-458b-5p regulates ovarian granulosa cells proliferation through Wnt/β‐catenin signaling pathway by targeting catenin beta-1

et al. 2021

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Objective: Ovarian follicular development, which dependent on the proliferation and differentiation of granulosa cells (GCs), is a complex biological process in which miRNA play an important role. Our previous study showed that miR-458b-5p is associated with ovarian follicular development in chicken. The detailed function and molecular mechanism of miR-458b-5p in GCs is unclear. Methods: The luciferase reporter assay was used to verify the targeting relationship between miR-458b-5p and catenin beta-1 (CTNNB1), which is an important transcriptional regulatory factor of the Wnt/β-Catenin pathway. The Cell Counting Kit-8 (CCK-8) assay, flow cytometry with propidium iodide (PI) and Annexin V-fluorescein isothiocyanate (FITC) labeling were applied to explore the effect of miR-458b-5p on proliferation, cell cycle and apoptosis of chicken GCs. Quantitative real-time PCR (qRT-PCR) and Western blot were used to detect the mRNA and protein expression levels. Results: We demonstrated that the expression of miR-458b-5p and CTNNB1 showed the opposite relationship in GCs and theca cells (TCs) of hierarchical follicles. The luciferase reporter assay confirmed that CTNNB1 is the direct target of miR-458b-5p. Using CCK-8 assay and flow cytometry with PI and Annexin V-FITC labeling, we observed that transfection with the miR-458b-5p mimics significantly reduced proliferation and have no effects on apoptosis of chicken GCs. In addition, miR-458b-5p decreased the mRNA and protein expression of CD44 molecule (CD44) and matrix metallopeptidase 7 (MMP7), which are the downstream effector of A c c e p t e d A r t i c l e CTNNB1 in Wnt/β-Catenin pathway and play functional roles in cell proliferation. Conclusion: Taken together, the data indicate that miR-458b-5p regulates ovarian GCs proliferation through Wnt/β-catenin signaling pathway by targeting CTNNB1, suggesting that miR-458b-5p and its target gene CTNNB1 may potentially play a role in chicken ovarian follicular development.

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The Role of microRNAs in Ovarian Granulosa Cells in Health and Disease

Cited by 101 publications

References 103 publications

Reporting on the Role of miRNAs and Affected Pathways on the Molecular Backbone of Ovarian Insufficiency: A Systematic Review and Critical Analysis Mapping of Future Research

Reporting on the Role of miRNAs and Affected Pathways on the Molecular Backbone of Ovarian Insufficiency: A Systematic Review and Critical Analysis Mapping of Future Research

Expression, location and biological effects of four and a half LIM domain protein 2 (FHL2) on granulosa cells in ovine

miR-458b-5p regulates ovarian granulosa cells proliferation through Wnt/β‐catenin signaling pathway by targeting catenin beta-1

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