FOXO1 regulates developmental lymphangiogenesis by upregulating CXCR4 in the mouse-tail dermis

Niimi, Kenta; Kohara, Misaki; Sedoh, Eriko; Fukumoto, Moe; Shibata, Satoshi; Sawano, Toshinori; Tashiro, Fumi; Miyazaki, Satsuki; Kubota, Yoshiaki; Miyazaki, Jun; Inagaki, Shinobu; Furuyama, Tatsuo

doi:10.1242/dev.181545

“…A recent study reported that viral ectopic expression of FOXO1 in ductal pancreatic adenocarcinoma cells upregulates LINC01197 (LETR1), resulting in the inhibition of cell proliferation 85 . Interestingly, FOXO1 has previously been shown to promote LEC migration and to participate in the regulation of lymphatic development 86,87 . Moreover, in our sequencing data, FOXO1 was significantly more highly expressed in LECs than BECs.…”

Section: Discussionmentioning

confidence: 99%

LETR1 is a lymphatic endothelial-specific lncRNA governing cell proliferation and migration through KLF4 and SEMA3C

Ducoli

¹

,

Agrawal

²

,

Sibler

³

et al. 2021

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Recent studies have revealed the importance of long noncoding RNAs (lncRNAs) as tissue-specific regulators of gene expression. There is ample evidence that distinct types of vasculature undergo tight transcriptional control to preserve their structure, identity, and functions. We determine a comprehensive map of lineage-specific lncRNAs in human dermal lymphatic and blood vascular endothelial cells (LECs and BECs), combining RNA-Seq and CAGE-Seq. Subsequent antisense oligonucleotide-knockdown transcriptomic profiling of two LEC- and two BEC-specific lncRNAs identifies LETR1 as a critical gatekeeper of the global LEC transcriptome. Deep RNA-DNA, RNA-protein interaction studies, and phenotype rescue analyses reveal that LETR1 is a nuclear trans-acting lncRNA modulating, via key epigenetic factors, the expression of essential target genes, including KLF4 and SEMA3C, governing the growth and migratory ability of LECs. Together, our study provides several lines of evidence supporting the intriguing concept that every cell type expresses precise lncRNA signatures to control lineage-specific regulatory programs.

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“…In addition, FoxO protein is inactivated by major carcinogenic signals such as phosphatidylinositol-3 kinase pathway and MAP kinase . FoxOs regulate the expression of many genes to control many cell functions, such as cell growth (Niimi et al, 2019), survival (Hassell, 2019), metabolism and antioxidant status (Zečić & Braeckman, 2020). However, recent studies have shown new and unknown functions of FoxO in cancer treatment and promotion, which shows that FOXO factor, has complex roles in the disease.…”

Section: Discussionmentioning

confidence: 99%

Diagnostic model of combined ceRNA and DNA methylation related genes in esophageal carcinoma

Guan

¹

,

Yao

²

,

Bao

³

et al. 2020

PeerJ

8

1

0

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Esophageal cancer is a common malignant tumor in the world, and the aim of this study was to screen key genes related to the development of esophageal cancer using a variety of bioinformatics analysis tools and analyze their biological functions. The data of esophageal squamous cell carcinoma from the Gene Expression Omnibus (GEO) were selected as the research object, processed and analyzed to screen differentially expressed microRNAs (miRNAs) and differential methylation genes. The competing endogenous RNAs (ceRNAs) interaction network of differentially expressed genes was constructed by bioinformatics tools DAVID, String, and Cytoscape. Biofunctional enrichment analysis was performed using Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG). The expression of the screened genes and the survival of the patients were verified. By analyzing GSE59973 and GSE114110, we found three down-regulated and nine up-regulated miRNAs. The gene expression matrix of GSE120356 was calculated by Pearson correlation coefficient, and the 11696 pairs of ceRNA relation were determined. In the ceRNA network, 643 lncRNAs and 147 mRNAs showed methylation difference. Functional enrichment analysis showed that these differentially expressed genes were mainly concentrated in the FoxO signaling pathway and were involved in the corresponding cascade of calcineurin. By analyzing the clinical data in The Cancer Genome Atlas (TCGA) database, it was found that four lncRNAs had an important impact on the survival and prognosis of esophageal carcinoma patients. QRT-PCR was also conducted to identify the expression of the key lncRNAs (RNF217-AS1, HCP5, ZFPM2-AS1 and HCG22) in ESCC samples. The selected key genes can provide theoretical guidance for further research on the molecular mechanism of esophageal carcinoma and the screening of molecular markers.

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“…Interestingly, FOXO1 has previously been shown to promote LEC migration and to participate in the regulation of lymphatic development 76,77 . Moreover, in our sequencing data, FOXO1 was significantly more highly expressed in LECs than BECs.…”

Section: Discussionmentioning

confidence: 99%

LETR1 is a lymphatic endothelial-specific lncRNA that governs cell proliferation and migration through KLF4 and SEMA3C

Ducoli

¹

,

Agrawal

²

,

Sibler

³

et al. 2020

Preprint

View full text Add to dashboard Cite

Recent studies have revealed the importance of long noncoding RNAs (lncRNAs) as tissue-specific regulators of gene expression. There is ample evidence that distinct types of vasculature undergo tight transcriptional control to preserve their structure, identity, and functions. We determined, for the first time, the global lineage-specific lncRNAome of human dermal blood and lymphatic endothelial cells (BECs and LECs), combining RNA-Seq and CAGE-Seq. A subsequent genome-wide antisense oligonucleotide-knockdown screen of a robust set of BEC-and LEC-specific lncRNAs identified LESR2 as a critical gatekeeper of the global LEC transcriptome. Deep RNA-DNA, RNA-protein, and phenotype rescue analyses revealed that LESR2 acts as a nuclear trans-acting lncRNA modulating, via key epigenetic factors, the expression of essential target genes, including KLF4 and SEMA3C, governing the growth and migratory ability of LECs. Together, our study provides new evidence supporting the intriguing concept that every cell type expresses precise lncRNA signatures to control lineage-specific regulatory programs.The blood and lymphatic vascular systems are essential for the efficient transport of oxygen, nutrients, signaling molecules, and leukocytes to and from peripheral tissues, the removal of waste products, and the preservation of fluid homeostasis. Increased activation or impaired function of these vascular networks represent a hallmark of many pathological conditions, including cancer progression, chronic inflammatory diseases, and diseases leading to blindness 1-3 .During development, the blood vascular system arises from endothelial cell progenitors that differentiate from mesodermal cells, mostly through the expression of the transcription factor (TF) ETV2. Activation of the VEGFA/VEGFR2 signaling and expression of blood vascular endothelial cell (BEC) markers, such as NRP1 and EphrinB2, further differentiate these precursor cells into BECs, which then form the hierarchical network of blood vessels 4 . In contrast, lymphatic vasculogenesis starts after the establishment of the blood circulatory system. Thereafter, a distinct subpopulation of endothelial cells lining the cardinal vein starts differentiating by expressing the TF PROX1, the master regulator of lymphatic endothelial cell (LEC) identity, via the TFs SOX18 and COUPTFII. Once exiting the veins, LECs starts expressing other lymphatic-specific markers, such as podoplanin, VEGFR3, and NRP2, and they migrate, in a VEGFC-dependent manner, to form the primary lymph sacs from which the lymphatic vascular system further develops following sprouting, branching, proliferation, and remodeling processes 5 . However, a nonvenous origin of LECs has also been described in the skin, mesenteries, and heart 6-8 . In adulthood, while the blood and lymphatic vasculature are generally quiescent, they can be readily activated in pathological conditions such as wound healing, inflammation, and cancer by disturbance of the natural balance of pro-and anti-(lymph)angiogenic factors 1,9 . Therefor...

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FOXO1 regulates developmental lymphangiogenesis by upregulating CXCR4 in the mouse-tail dermis

Cited by 25 publications

References 74 publications

LETR1 is a lymphatic endothelial-specific lncRNA governing cell proliferation and migration through KLF4 and SEMA3C

LETR1 is a lymphatic endothelial-specific lncRNA governing cell proliferation and migration through KLF4 and SEMA3C

Diagnostic model of combined ceRNA and DNA methylation related genes in esophageal carcinoma

LETR1 is a lymphatic endothelial-specific lncRNA that governs cell proliferation and migration through KLF4 and SEMA3C

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