H19 lnc
            <scp>RNA</scp>
            alters stromal cell growth via
            <scp>IGF</scp>
            signaling in the endometrium of women with endometriosis

Ghazal, Sanaz; McKinnon, Brett; Zhou, Jichun; Mueller, Martin; Men, Yu; Yang, Lihua; Mueller, Michael D.; Flannery, Clare; Huang, Yingqun; Taylor, Hugh S.

doi:10.15252/emmm.201505245

Cited by 165 publications

(140 citation statements)

References 36 publications

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“…Thus, in the presence of iLet7, we would expect that the effects of H19 knockdown on EVT would be attenuated, as iLet7 would neutralize let-7 released from H19 sequestration. The ability of iLet7 to relieve inhibition of other let-7 targets has been previously documented [15–17]. …”

Section: Resultsmentioning

confidence: 99%

“…In the cytoplasm, H19 acts as a molecular sponge for microRNA let-7 thereby reducing its bioavailability and preventing it from repressing target gene expression at the posttranscriptional level [14]. Through this action, H19 plays a role in regulation of muscle cell differentiation [14], glucose metabolism [15], tumor metastasis [16], and endometrial development [17]. …”

Section: Introductionmentioning

confidence: 99%

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H19 long noncoding RNA alters trophoblast cell migration and invasion by regulating TβR3 in placentae with fetal growth restriction

Zuckerwise

et al. 2016

Oncotarget

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Fetal growth restriction (FGR) is a well-recognized risk factor for perinatal mortality and morbidity, as well as neurodevelopmental impairment and adulthood onset disorders. Here we report that the H19 long noncoding RNA (lncRNA) is significantly decreased in placentae from pregnancies with FGR. Downregulation of H19 leads to reduced migration and invasion of extravillous trophoblast (EVT) cells in vitro. This is consistent with reduced trophoblast invasion that has been observed in FGR. Genome-scale transcriptome profiling of EVT cells reveals significantly decreased expression of the type III TGF-β receptor (TβR3) following H19 knockdown. Decreased TβR3 expression is also seen in FGR placentae. TβR3 repression decreases EVT cell migration and invasion, owing to impaired TGF-β signaling through a non-canonical TGF-β signaling pathway. Further, we identify TβR3 as a novel regulatory target of microRNA let-7. We propose that dysregulation of this newly identified H19/TβR3-mediated regulatory pathway may contribute to the molecular mechanism of FGR. Our findings are the first to show a lncRNA-based mechanism of FGR, holding promise for the development of novel predictive, diagnostic, and therapeutic modalities for FGR.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

H19 long noncoding RNA alters trophoblast cell migration and invasion by regulating TβR3 in placentae with fetal growth restriction

Zuckerwise

et al. 2016

Oncotarget

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“…H19 RNA consists of the micro RNA675 (miR675) in its first exon which regulates cell proliferation by suppressing retinoblastoma (RB) gene expression [16]. As well, the exons 2-5 fragment of H19 limits the bioavailability of Let-7 microRNA, leading to increased cell proliferation [17,18]. Based on the important role that H19 plays in regulating proliferation of normal and malignant ERα + breast cells, we hypothesize that H19 plays an equally important role in maintaining the ETR in therapy refractory tumours.…”

Section: Introductionmentioning

confidence: 99%

Long Non-Coding RNA H19 Acts as an Estrogen Receptor Modulator that is Required for Endocrine Therapy Resistance in ER+ Breast Cancer Cells

Basak

Chatterjee

Bhat

et al. 2018

Cell Physiol Biochem

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Background/Aims: Blocking estrogen signaling with endocrine therapies (Tamoxifen or Fulverstrant) is an effective treatment for Estrogen Receptor-α positive (ER⁺) breast cancer tumours. Unfortunately, development of endocrine therapy resistance (ETR) is a frequent event resulting in disease relapse and decreased overall patient survival. The long noncoding RNA, H19, was previously shown to play a significant role in estrogen-induced proliferation of both normal and malignant ER⁺ breast epithelial cells. We hypothesized that H19 expression is also important for the proliferation and survival of ETR cells. Methods: Here we utilized established ETR cell models; the Tamoxifen (Tam)-resistant LCC2 and the Fulvestrant and Tam cross-resistant LCC9 cells. Gain and loss of H19 function were achieved through lentiviral transduction as well as pharmacological inhibitors of the Notch and c-Met receptor signaling pathways. The effects of altered H19 expression on cell viability and ETR were assessed using three-dimensional (3D) organoid cultures and 2D co-cultures with low passage tumour-associated fbroblasts (TAFs). Results: Here we report that treating ETR cells with Tam or Fulvestrant increases H19 expression and that it’s decreased expression overcomes resistance to Tam and Fulvestrant in these cells. Interestingly, H19 expression is regulated by Notch and HGF signaling in the ETR cells and pharmacological inhibitors of Notch and c-MET signaling together significantly reverse resistance to Tam and Fulvestrant in an H19-dependent manner in these cells. Lastly, we demonstrate that H19 regulates ERα expression at the transcript and protein levels in the ETR cells and that H19 protects ERα against Fulvestrant-mediated downregulation of ERα protein. We also observed that blocking Notch and the c-MET receptor signaling also overcomes Fulvestrant and Tam resistance in 3D organoid cultures by decreasing ERα and H19 expression in the ETR cells. Conclusion: In endocrine therapy resistant breast cancer cells Fulvestrant is ineffective in decreasing ERα levels. Our data suggest that in the ETR cells, H19 expression acts as an ER modulator and that its levels and subsequently ERα levels can be substantially decreased by blocking Notch and c-MET receptor signaling. Consequently, treating ETR cells with these pharmacological inhibitors helps overcome resistance to Fulvestrant and Tamoxifen.

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“…3 Recently, functional lncRNAs are recognized as critical players of gene regulation in multiple biological processes such as cell growth, development, angiogenesis and inflammation. [4][5][6][7] LncRNAs are also associated with many human diseases such as cancers, Alzheimer disease and cardiovascular diseases. 3,[8][9][10] The functional characterization of lncRNAs is however much more difficult than expected due to their poor conservation and complex mechanisms.…”

Section: Introductionmentioning

confidence: 99%

Long non-coding RNA ANRIL regulates inflammatory responses as a novel component of NF-κB pathway

et al. 2015

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Antisense Noncoding RNA in the INK4 Locus (ANRIL) is the prime candidate gene at Chr9p21, the welldefined genetic risk locus associated with multiple human diseases including coronary artery disease (CAD), while little is known regarding its role in the pathological processes. Endothelial dysfunction triggers atherosclerotic processes that are causatively linked to CAD. To evaluate the function of ANRIL in human endothelial cells (ECs), we examined ANRIL expression under pathological stimuli and found ANRIL was markedly induced by pro-inflammatory factors. Loss-of-function and chromatin immunoprecipitation approaches revealed that NF-kB mediates TNF-a induced ANRIL expression. RNA sequencing revealed that ANRIL silencing dysregulated expression of inflammatory genes including IL6 and IL8 under TNF-a treatment. We explored the regulatory mechanism of ANRIL on IL6/8 and found that Yin Yang 1 (YY1), an ANRIL binding transcriptional factor revealed by RNA immunoprecipitation, was required for IL6/8 expression under TNF-a treatment. YY1 was enriched at promoter loci of IL6/8 and ANRIL silencing impaired the enrichment, indicating a cooperation between ANRIL and YY1 in the regulation of inflammatory genes. For the first time, we establish the connection between ANRIL and NF-kB pathway and show that ANRIL regulates inflammatory responses through binding with YY1. The newly identified TNF-a-NF-kB-ANRIL/YY1-IL6/8 pathway enhances understanding of the etiology of CAD and provides potential therapeutic target for treatment of CAD.

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H19 lnc RNA alters stromal cell growth via IGF signaling in the endometrium of women with endometriosis

Cited by 165 publications

References 36 publications

H19 long noncoding RNA alters trophoblast cell migration and invasion by regulating TβR3 in placentae with fetal growth restriction

H19 long noncoding RNA alters trophoblast cell migration and invasion by regulating TβR3 in placentae with fetal growth restriction

Long Non-Coding RNA H19 Acts as an Estrogen Receptor Modulator that is Required for Endocrine Therapy Resistance in ER+ Breast Cancer Cells

Long non-coding RNA ANRIL regulates inflammatory responses as a novel component of NF-κB pathway

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