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MicroRNA-10a promotes granulosa cells tumor development via PTEN-AKT/Wnt regulatory axis.

ABSTRACT: We have previously reported that microRNA-10 family could disturb normal development of granulosa cells (GC) during follicle formation. In the current study, the effect of miR-10a on granulosa cell tumor (GCT), a subtype of ovarian cancer, was examined. Strong miR-10a signal was detected in tissues from malignant GCT patients. Forced expression of miR-10a significantly promoted cell proliferation, migration, invasion, ovarian hormone production, and repressed anticancer drug-induced apoptosis in vitro. The oncogenic role of miR-10a was further validated in an orthotopic GCT model in vivo. In addition, by using CRISPR-Cas9 system, the aggressive phenotype was repressed in miR-10a knockout cancer GC. By using a heterotopic mice model, the oncogenic role of miR-10a was confirmed in vivo. RNA-seq, FISH, western blot, luciferase reporter assay were used to identified PTEN, a well-known anti-GCT gene, as direct functional target of miR-10a in cancer GC; Akt and Wnt were also found as two associated oncogenic pathways of miR-10a in cancer GC. Taken together, our results demonstrate that the miR-10a could promote GCT development via synergistically regulating PTEN, Akt, and Wnt pathways.

SUBMITTER: Tu J

PROVIDER: S-EPMC6197200 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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MicroRNA-10a promotes granulosa cells tumor development via PTEN-AKT/Wnt regulatory axis.

Tu Jiajie J Cheung Hoi-Hung HH Lu Gang G Chen Zijiang Z Chan Wai-Yee WY

Cell death & disease 20181022 11

We have previously reported that microRNA-10 family could disturb normal development of granulosa cells (GC) during follicle formation. In the current study, the effect of miR-10a on granulosa cell tumor (GCT), a subtype of ovarian cancer, was examined. Strong miR-10a signal was detected in tissues from malignant GCT patients. Forced expression of miR-10a significantly promoted cell proliferation, migration, invasion, ovarian hormone production, and repressed anticancer drug-induced apoptosis in ...[more]

PMID: 30348959

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Project description:The forkhead box (FOX), FOXO1 and FOXO3, transcription factors regulate multiple functions in mammalian cells. Selective inactivation of the Foxo1 and Foxo3 genes in murine ovarian granulosa cells severely impairs follicular development and apoptosis causing infertility, and as shown here, granulosa cell tumor (GCT) formation. Coordinate depletion of the tumor suppressor Pten gene in the Foxo1/3 strain enhanced the penetrance and onset of GCT formation. Immunostaining and Western blot analyses confirmed FOXO1 and phosphatase and tensin homolog (PTEN) depletion, maintenance of globin transcription factor (GATA) 4 and nuclear localization of FOXL2 and phosphorylated small mothers against decapentaplegic (SMAD) 2/3 in the tumor cells, recapitulating results we observed in human adult GCTs. Microarray and quantitative PCR analyses of mouse GCTs further confirmed expression of specific genes (Foxl2, Gata4, and Wnt4) controlling granulosa cell fate specification and proliferation, whereas others (Emx2, Nr0b1, Rspo1, and Wt1) were suppressed. Key genes (Amh, Bmp2, and Fshr) controlling follicle growth, apoptosis, and differentiation were also suppressed. Inhbb and Grem1 were selectively elevated, whereas reduction of Inha provided additional evidence that activin signaling and small mothers against decapentaplegic (SMAD) 2/3 phosphorylation impact GCT formation. Unexpectedly, markers of Sertoli/epithelial cells (SRY [sex determining region Y]-box 9/keratin 8) and alternatively activated macrophages (chitinase 3-like 3) were elevated in discrete subpopulations within the mouse GCTs, indicating that Foxo1/3/Pten depletion not only leads to GCTs but also to altered granulosa cell fate decisions and immune responses. Thus, analyses of the Foxo1/3/Pten mouse GCTs and human adult GCTs provide strong evidence that impaired functions of the FOXO1/3/PTEN pathways lead to dramatic changes in the molecular program within granulosa cells, chronic activin signaling in the presence of FOXL2 and GATA4, and tumor formation.

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MicroRNA-10a promotes granulosa cells tumor development via PTEN-AKT/Wnt regulatory axis.

Publications

MicroRNA-10a promotes granulosa cells tumor development via PTEN-AKT/Wnt regulatory axis.

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