STAT3 signaling stimulates miR-21 expression in bovine cumulus cells during in vitro oocyte maturation

Tscherner, Allison; Brown, Andrea; Stalker, Leanne; Kao, Jennifer; Dufort, Isabelle; Sirard, Marc‐André; LaMarre, Jonathan

doi:10.1038/s41598-018-29874-w

Cited by 37 publications

(27 citation statements)

References 92 publications

(104 reference statements)

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“…Activation of p-STAT3 was found to be involved in meiotic spindle assembly and chromosome segregation in mouse oocytes ( 23 ), and STAT3 activation was able to stimulate the progression of meiosis ( 24 ). In vitro maturation of COCs supplemented with STAT3 inhibitor stattic was found to block cumulus expansion ( 25 ). Based on these findings, we speculated that the inhibition of EGFR and MAPK1/3 in the ovary had been negated by the upregulation of STAT3, thus no effects of lapatinib treatment were noted on ovarian reserve or fertility potential in vivo ( Fig.…”

Section: Discussionmentioning

confidence: 99%

Lapatinib‑induced inhibition of ovarian function is counteracted by the STAT3 pathway both in vivo and in vitro

Liao

Xue

et al. 2020

Oncol Rep

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The present study was designed to ascertain whether lapatinib, a tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR), affects ovarian reserve and fertility potential in a mouse model. Female C57BL/6 mice were treated with either vehicle or lapatinib (100 or 200 mg/kg/day orally) for 4 weeks, after which body weight, vaginal smears, follicle numbers, serum anti-Müllerian hormone (AMH) levels and mating outcomes were analyzed to assess the ovarian reserve and reproductive function. Slices from the ovaries of 4-week-old mice were cultured with lapatinib (0, 5 or 10 µM) for 24 and 48 h, and protein expression levels were assessed to validate the changes in signaling pathways. The results indicated that mice treated with 200 mg/kg lapatinib showed a slight decrease in body weight compared to those treated with vehicle or 100 mg/kg lapatinib. There was no statistical difference in estrous cyclicity among the three groups. No significant difference was observed in follicle numbers, AMH levels, histological morphologies of the ovaries or mating outcomes in the three groups of mice. Western blotting and immunohistochemical staining of the EGF receptor and its main downstream signaling pathways showed decreased phosphorylation of EGFR and mitogen-activated protein kinase (MAPK)3/1 and increased phosphorylation of signal transducers and activators of transcription (STAT)3 in the lapatinib-treated groups compared to the control group. Our study suggests that lapatinib has little effect on ovarian reserve and reproductive function in a mouse model. This lack of effect of lapatinib on ovarian function may be due to the activation of the STAT3 signaling pathway that counteracts the inhibitory effects of lapatinib on EGF receptors.

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Section: Discussionmentioning

confidence: 99%

Lapatinib‑induced inhibition of ovarian function is counteracted by the STAT3 pathway both in vivo and in vitro

Liao

Xue

et al. 2020

Oncol Rep

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“…Results revealed that COCs treated with LIF showed higher expression of miR-21 in both cumulus cells and oocytes when compared to immature oocytes. Increased expression of miR-21 has previously been described in COCs after 24 h in culture under serum free conditions, without supplements or in culture supplemented with LIF alone 12 and miR-21 is recognized as a highly abundant miRNA in cumulus cells 9,38 that is present throughout folliculogenesis 38 . In www.nature.com/scientificreports/ addition, miR-21 is implicated in apoptosis, cell cycle arrest, tumor suppression and chromosome alignment 36 .…”

Section: Discussionmentioning

confidence: 89%

“…Recent studies have shown that miRNA levels change during oocyte maturation and ovarian follicular development implying a regulatory role 9,10 . miRNAs including miR-21 11,12 , miR-155 9,13 and miR-34c are expressed or consistently change their expression patterns from the GV oocyte to the 2-cell embryo stage 14 . miR-146a is a potent regulator of the immune response and inflammation 15 .…”

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confidence: 99%

In vitro maturation in the presence of Leukemia Inhibitory Factor modulates gene and miRNA expression in bovine oocytes and embryos

Vendrell-Flotats

García-Martínez

Martínez-Rodero

et al. 2020

Sci Rep

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Members of the interleukin-6 (IL-6) family of cytokines are important for reproductive function that are mediated through changes in gene and miRNA expression. Herein, we characterized the expression of miR-21, miR-155, miR-34c and miR-146a in bovine oocytes and cumulus cells during in vitro maturation (IVM) with leukemia inhibitory factor (LIF), IL-6 and IL-11 or unsupplemented controls. LIF-exposed COCs showed higher expression of miR-21 and miR-155 in oocytes, whereas miR-146a expression was increased in oocytes matured with IL-6 and IL-11. In cumulus cells, miR-155 expression was elevated by all treatments while only LIF increased miR-21 expression. Based on these results, we next examined how LIF exposure during IVM affected oocyte competence, through IVF and the expression of specific genes in GV- and MII-oocytes, in 2- and 8-cell embryos, and in Day 8-blastocysts. LIF supplementation did not affect cleavage rate, blastocyst yield or several other developmental parameters, but did increase hatching rate. LIF suppressed DPPA3, ZAR1 and NPM2 expression in 2 cell- and/or 8-cell embryos. LIF increased the expression of KAT2A and HSPA1A in MII-oocytes, and that of HDAC1, KAT2A and HSP90AA1 and the BAX:BCL2L1 ratio in 2-cell embryos. In contrast, HDAC1, KAT2A and HSP90AA1 expression and BAX:BCL2L1 ratio was lower in 8-cell embryos derived from LIF oocytes. IVM with LIF also increased the expression of DNMT3A, HSPA1A and HSP90AA1 in blastocysts. In conclusion, supplementation with LIF during IVM was consistently associated with changes in the relative abundance of transcripts in mature bovine oocytes and in specific embryo developmental stages.

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“…Details regarding the mechanism through which STAT3 reduced miR-30a-5p expression are warranted; nonetheless, this study showed that the downregulation of miR-30a-5p played a role in anti-apoptosis. STAT3 has been reported to both induce and repress microRNA expression [ 21 , 22 , 23 , 24 ]. One of the possible mechanisms might be the interaction of STAT3 with G9a and the epigenetic suppression of gene expression through methylation of H3K9, which thereby downregulate the expression levels of miR-200c and miR-145 [ 12 , 13 ].…”

Section: Discussionmentioning

confidence: 99%

STAT3 Mediated miR-30a-5p Inhibition Enhances Proliferation and Inhibits Apoptosis in Colorectal Cancer Cells

Cheng

Yang

Chen

et al. 2020

IJMS

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Signal transducer and activator of transcription 3 (STAT3), a transcriptional factor involved in tumorigenesis and cancer stemness formation, contributes to drug resistance in cancer therapies. STAT3 not only mediates gene transcription but also participates in microRNA suppression. This study identified a STAT3-downstream micro RNA (miRNA) involved in drug resistance against regorafenib in colorectal cancer stem-like tumorspheres. Small RNAseq was used to investigate differential microRNAs in colorectal cancer cell-derived tumorspheres and in a STAT3-knockdown strain. The miRNA-mediated genes were identified by comparing RNAseq data with gene targets predicted using TargetScan. Assays for detecting cell viability and apoptosis were used to validate findings. The formation of colorectal cancer stem-like tumorspheres was inhibited by BBI608, a STAT3 inhibitor, but not by regorafenib. Additional investigations for microRNA expression demonstrated an increase in 10 miRNAs and a decrease in 13 miRNAs in HT29-derived tumorspheres. A comparison of small RNAseq results between tumorspheres and HT29shSTAT3 cells revealed the presence of four STAT3-mediated miRNAs in HT29-derived tumorspheres: hsa-miR-215-5p, hsa-miR-4521, and hsa-miR-215-3p were upregulated, whereas miR-30a-5p was downregulated. Furthermore, hsa-miR-4521 was associated with poor overall survival probability, and miR-30a-5p was associated with better overall survival probability in patients with rectum cancer. Comparisons of RNAseq findings between HCT116- and HT29-derived tumorspheres revealed that HSPA5 were mediated by the STAT3-miR-30a-5p axis, which is overexpressed in colorectal tumorspheres associating to anti-apoptosis. In addition, the transfection of miR-30a-5p and inhibition of HSPA5 by HA15 significantly reduced cell viability and increased apoptosis in HT29 cells. In conclusion, a STAT3-miR-30a-5p-HSPA5 axis was observed against regorafenib-mediated apoptosis in colorectal cancer tumorspheres. The expression of miR-30a-5p was repressed by STAT3; in addition, HSPA5 was identified as the target gene of miR-30a-5p and contributed to both tumorsphere formation and anti-apoptosis.

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STAT3 signaling stimulates miR-21 expression in bovine cumulus cells during in vitro oocyte maturation

Cited by 37 publications

References 92 publications

Lapatinib‑induced inhibition of ovarian function is counteracted by the STAT3 pathway both in vivo and in vitro

Lapatinib‑induced inhibition of ovarian function is counteracted by the STAT3 pathway both in vivo and in vitro

In vitro maturation in the presence of Leukemia Inhibitory Factor modulates gene and miRNA expression in bovine oocytes and embryos

STAT3 Mediated miR-30a-5p Inhibition Enhances Proliferation and Inhibits Apoptosis in Colorectal Cancer Cells

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