TGF‐β/SMAD4 signaling pathway activates the HAS2–HA system to regulate granulosa cell state

Li, Xinyu; Du, Xiaohong; Wang, Yao; Pan, Zengxiang; Li, Qifa

doi:10.1002/jcp.29134

Cited by 18 publications

(6 citation statements)

References 43 publications

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“…Furthermore, SMAD4 generally functions as a transcription factor, directly acting on the key genes including the miRNAs of important events in the female reproductive cycle [ 46 ]. For example, the key genes HAS2 , for inducing ovulation [ 47 ], and ALK3 , for maintaining embryo implantation [ 48 ], are all transcriptional targets of SMAD4. Recently, several miRNAs involved in critical events in the female reproductive cycle, such as miR-29c, for influencing the follicular development fate [ 12 ], have also been shown to be directly regulated by the transcription factor SMAD4.…”

Section: Discussionmentioning

confidence: 99%

A Mutation in Endogenous saRNA miR-23a Influences Granulosa Cells Response to Oxidative Stress

Wang

Zeng

et al. 2022

Antioxidants

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Phenotypes are the result of the interaction between the gene and the environment, so the response of individuals with different genotypes to an environment is variable. Here, we reported that a mutation in miR-23a influences granulosa cells (GCs) response to oxidative stress, a common mechanism of environmental factors affecting female reproduction. We showed that nuclear miR-23a is a pro-apoptotic miRNA in porcine GCs through the activation of the transcription and function of NORHA, a long non-coding RNA (lncRNA) induces GC apoptosis and responses to oxidative stress. Mechanistically, miR-23a acts as an endogenous small activating RNA (saRNA) to alter histone modifications of the NORHA promoter through the direct binding to its core promoter. A C > T mutation was identified at −398 nt of the miR-23a core promoter, which created a novel binding site for the transcription factor SMAD4 and recruited the transcription repressor SMAD4 to inhibit miR-23a transcription and function in GCs. Notably, g.−398C > T mutation in the miR-23a promoter reduced GCs response to oxidative stress. In addition, g.−398C > T mutation was significantly associated with sow fertility traits. In short, our findings preliminarily revealed the genetic basis of individual differences in the response to oxidative stress from the perspective of a single mutation and identified miR-23a as a candidate gene for the environmental adaptation to oxidative stress.

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Section: Discussionmentioning

confidence: 99%

A Mutation in Endogenous saRNA miR-23a Influences Granulosa Cells Response to Oxidative Stress

Wang

Zeng

et al. 2022

Antioxidants

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“…Estradiol can stimulate HAS2 mRNA expression when combined with insulin-like growth factor-1, insulin, and follicle-stimulating hormone ( Chavoshinejad et al ., 2016 ). The TGF-β/Smad4 signaling pathway can activate the HAS2-HA system ( Li et al ., 2020 ). In the mammalian ovary, epigenetic factor microRNA-574 directly inhibits HAS2 expression and subsequently improves oocyte maturation ( Pan et al ., 2018 ).…”

Section: Discussionmentioning

confidence: 99%

High Levels of Hyaluronic Acid Synthase-2 Mediate NRF2-Driven Chemoresistance in Breast Cancer Cells

Choi

Ryoo

Sim

et al. 2022

Biomol Ther (Seoul)

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Hyaluronic acid (HA), a ligand of CD44, accumulates in some types of tumors and is responsible for tumor progression. The nuclear factor erythroid 2-like 2 (NRF2) regulates cytoprotective genes and drug transporters, which promotes therapy resistance in tumors. Previously, we showed that high levels of CD44 are associated with NRF2 activation in cancer stem like-cells. Herein, we demonstrate that HA production was increased in doxorubicin-resistant breast cancer MCF7 cells (MCF7-DR) via the upregulation of HA synthase-2 (HAS2). HA incubation increased NRF2, aldo-keto reductase 1C1 (AKR1C1), and multidrug resistance gene 1 (MDR1) levels. Silencing of HAS2 or CD44 suppressed NRF2 signaling in MCF7-DR, which was accompanied by increased doxorubicin sensitivity. The treatment with a HAS2 inhibitor, 4-methylumbelliferone (4-MU), decreased NRF2, AKR1C1, and MDR1 levels in MCF7-DR. Subsequently, 4-MU treatment inhibited sphere formation and doxorubicin resistance in MCF7-DR. The Cancer Genome Atlas (TCGA) data analysis across 32 types of tumors indicates the amplification of HAS2 gene is a common genetic alteration and is negatively correlated with the overall survival rate. In addition, high HAS2 mRNA levels are associated with increased NRF2 signaling and poor clinical outcome in breast cancer patients. Collectively, these indicate that HAS2 elevation contributes to chemoresistance and sphere formation capacity of drug-resistant MCF7 cells by activating CD44/ NRF2 signaling, suggesting a potential benefit of HAS2 inhibition.

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“…SMAD4 is the most studied miRNA target gene among those in the ovarian BMP/Smad signaling pathway. miR-224 (Yao et al, 2010), miR-144 (Zhou et al, 2017, and miR-26b (Li et al, 2019) can regulate ovarian function by targeting SMAD4. In this study, we showed that miR-1306 direct targets BMPR1B gene in the ovine granulosa cells.…”

Section: Discussionmentioning

confidence: 99%

miR-1306 induces cell apoptosis by targeting BMPR1B gene in the ovine granulosa cells

et al. 2022

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Bone morphogenetic protein receptor type-1B (BMPR1B) is one of the major gene for sheep prolificacy. However, few studies investigated its regulatory region. In this study, we reported that miR-1306 is a direct inhibitor of BMPR1B gene in the ovine granulosa cells (ovine GCs). We detected a miRNA response element of miR-1306 in the 3’ untranslated region of the ovine BMPR1B gene. Luciferase assay showed that the ovine BMPR1B gene is a direct target of miR-1306. qPCR and western blotting revealed that miR-1306 reduces the expression of BMPR1B mRNA and protein in the ovine granulosa cells. Furthermore, miR-1306 promoted cell apoptosis by suppressing BMPR1B expression in the ovine granulosa cells. Overall, our results suggest that miR-1306 is an epigenetic regulator of BMPR1B, and may serve as a potential target to improve the fecundity of sheep.

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TGF‐β/SMAD4 signaling pathway activates the HAS2–HA system to regulate granulosa cell state

Cited by 18 publications

References 43 publications

A Mutation in Endogenous saRNA miR-23a Influences Granulosa Cells Response to Oxidative Stress

A Mutation in Endogenous saRNA miR-23a Influences Granulosa Cells Response to Oxidative Stress

High Levels of Hyaluronic Acid Synthase-2 Mediate NRF2-Driven Chemoresistance in Breast Cancer Cells

miR-1306 induces cell apoptosis by targeting BMPR1B gene in the ovine granulosa cells

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