Dataset Information

ETV2/ER71 regulates the generation of FLK1+ cells from mouse embryonic stem cells through miR-126-MAPK signaling.

ABSTRACT: Previous studies including ours have demonstrated a critical function of the transcription factor ETV2 (ets variant 2; also known as ER71) in determining the fate of cardiovascular lineage development. However, the underlying mechanisms of ETV2 function remain largely unknown. In this study, we demonstrated the novel function of the miR (micro RNA)-126-MAPK (mitogen-activated protein kinase) pathway in ETV2-mediated FLK1 (fetal liver kinase 1; also known as VEGFR2)+ cell generation from the mouse embryonic stem cells (mESCs). By performing a series of experiments including miRNA sequencing and ChIP (chromatin immunoprecipitation)-PCR, we found that miR-126 is directly induced by ETV2. Further, we identified that miR-126 can positively regulate the generation of FLK1+ cells by activating the MAPK pathway through targeting SPRED1 (sprouty-related EVH1 domain containing 1). Further, we showed evidence that JUN/FOS activate the enhancer region of FLK1 through AP1 (activator protein 1) binding sequences. Our findings provide insight into the novel molecular mechanisms of ETV2 function in regulating cardiovascular lineage development from mESCs.

SUBMITTER: Kim JY

PROVIDER: S-EPMC6862833 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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ETV2/ER71 regulates the generation of FLK1<sup>+</sup> cells from mouse embryonic stem cells through miR-126-MAPK signaling.

Kim Ju Young JY Lee Dong Hun DH Kim Joo Kyung JK Choi Hong Seo HS Dwivedi Bhakti B Rupji Manali M Kowalski Jeanne J Green Stefan J SJ Song Heesang H Park Won Jong WJ Chang Ji Young JY Kim Tae Min TM Park Changwon C

Stem cell research & therapy 20191119 1

Previous studies including ours have demonstrated a critical function of the transcription factor ETV2 (ets variant 2; also known as ER71) in determining the fate of cardiovascular lineage development. However, the underlying mechanisms of ETV2 function remain largely unknown. In this study, we demonstrated the novel function of the miR (micro RNA)-126-MAPK (mitogen-activated protein kinase) pathway in ETV2-mediated FLK1 (fetal liver kinase 1; also known as VEGFR2)<sup>+</sup> cell generation fr ...[more]

PMID: 31744543

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Project description:Emerging data support the rationale of combined therapies in advanced melanoma. Specifically, the combined use of drugs with different mechanisms of action can reduce the probability of selecting resistant clones. To identify agents active against melanoma cells, we screened a library of 349 anti-cancer compounds, currently in clinical use or trials, and selected PIK-75, an inhibitor of the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathway, as the 'top active' drug. PIK-75 was then used alone or in combination with vemurafenib, the first BRAF inhibitor approved for patients with melanoma harboring BRAF mutations. We identified a combined dose of PIK-75 and vemurafenib that inhibited both the PI3K/AKT and mitogen-activated protein kinase pathways, thereby overcoming any compensatory activation. In view of the important tumor suppressor function induced by restoring expression of microRNA (miR)-126 in metastatic melanoma cells, we examined whether miR-126 has a synergistic role when included in a triple combination alongside PIK-75 and vemurafenib. We found that enforced expression of miR-126 (which alone can reduce tumorigenicity) significantly increased PIK-75 activity when used as either a single agent or in combination with vemurafenib. Interestingly, PIK-75 proved to be effective against early passage cell lines derived from patients' biopsies and on melanoma cell lines resistant to either vemurafenib or dabrafenib, thus suggesting that it potentially has the capability to overcome drug resistance. Finally, the synergistic role played by miR-126 in combination with vemurafenib and/or PIK-75 was demonstrated in vivo in mouse xenograft models, in which tumor growth inhibition was associated with increased apoptosis. These results not only show the efficacy of PIK-75 and vemurafenib co-treatment but also indicate that restoration of miR-126 expression in advanced melanoma can enhance their antitumor activity, which may possibly allow dose reduction to decrease adverse events without reducing the therapeutic benefits.

Dataset Information

ETV2/ER71 regulates the generation of FLK1+ cells from mouse embryonic stem cells through miR-126-MAPK signaling.

Publications

ETV2/ER71 regulates the generation of FLK1<sup>+</sup> cells from mouse embryonic stem cells through miR-126-MAPK signaling.

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