Long noncoding RNA H19X is a key mediator of TGF-β–driven fibrosis

Pachera, Elena; Assassi, Shervin; Salazar, Gloria A.; Stellato, Mara; Renoux, Florian; Wunderlin, Adam Sebastian; Błyszczuk, Przemysław; Lafyatis, Robert; Kurreeman, Fina; Vries‐Bouwstra, Jeska de; Messemaker, Tobias; Feghali‐Bostwick, Carol; Rogler, Gerhard; Haaften, Wouter T. van; Dijkstra, Gerard; Oakley, Fiona; Calcagni, Maurizio; Schniering, Janine; Maurer, Britta; Distler, Jörg H W; Kania, Gabriela; Frank-Bertoncelj, Mojca; Distler, Oliver

doi:10.1172/jci135439

Cited by 62 publications

(48 citation statements)

References 56 publications

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“…22 The RNA-seq-derived lincRNA MIR503HG is located at chromosome X, and harbors a coding sequence of miR-503 that is embedded in the first intron. 5,23 MiR-503 is overexpressed in various types of diabetes, especially in complications related to diabetes. MiR-503 was involved in the protective effect of Phase II enzyme inducer (CPDT) in diabetic cardiomyopathy via Nrf2/ARE signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

“…MIR503HG, also known as H19X is an intergenic lncRNA and its gene locus encodes two microRNAs (miR-503, miR-424). And miR-503 is embedded in the first intron; 5 therefore miR-503 is an intronic microRNA. In hepatocellular carcinoma (HCC) cell lines, the expression levels of miR-335 were significantly correlated with those of its protein-coding host gene, MEST , supporting the notion that the intronic miR-335 was co-expressed with its host gene under the control of host gene promoter.…”

Section: Introductionmentioning

confidence: 99%

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<p>LncRNA MIR503HG Promotes High-Glucose-Induced Proximal Tubular Cell Apoptosis by Targeting miR-503-5p/Bcl-2 Pathway</p>

Cao¹,

Fan²

2020

DMSO

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Aim: More than half of microRNAs are located in genes. LncRNAs are host genes of intronic microRNAs that regulate intracellular splicing to form pre-miRNAs that are processed to mature miRNAs. MicroRNAs work as partners or antagonists of their host lncRNAs by fine-tuning their target genes. However, whether lncRNA-MIR503HG (miR-503 host gene) is co-transcribed with miR-503 and affects miR-503 splicing, thereby affecting its target gene Bcl-2 expression and cell mitochondrial apoptotic pathway in diabetic nephropathy (DN) is currently unknown. Methods: Human proximal tubular (HK-2) cells cultured in high glucose were transfected with lncRNA MIR503HG overexpression/inhibition plasmid and miR-503 mimics/inhibitor. Real-time quantitative PCR was used to measure the expression levels of lncRNA MIR503HG, pre-miR-503, miR-503 and Bcl-2. Western blot was used to measure the protein expressions of Bcl-2, Bax, Cytc and cleaved-caspase 9/3. Annexin V/PI flow cytometry was used to measure apoptosis. Results: Host lncRNA MIR503HG was co-transcribed with miR-503. MIR503HG regulated the expression of miR-503 by affecting miR-503 splicing synthesis. In the presence of high glucose, the expression levels of lncRNA MIR503HG and miR-503 were up-regulated in HK-2 cells cultured in high glucose. Bcl-2 expression was inhibited and levels of apoptosisrelated proteins Cytc and Bax were increased in HK-2 cells cultured in high glucose, all of which promoted the caspase cascade reaction, leading to increased caspase-9 and caspase-3 shear fragments inducing apoptosis of the mitochondrial pathway. Inhibition of MIR503HG led to a reduction in miR-503 expression, up-regulated its target gene Bcl-2, inhibited the expression levels of Bax and other apoptosis-related proteins and attenuated HK-2 cell apoptosis induced by high glucose. Co-transfection of miRNA-503 partially offset the effect of MIR503HG-siRNA. Conclusion: MIR503HG indirectly regulates Bcl-2 by promoting the co-transcription of miRNA-503 to participate high-glucose-induced proximal tubular cell apoptosis, providing a new target for diabetic nephropathy treatment.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

<p>LncRNA MIR503HG Promotes High-Glucose-Induced Proximal Tubular Cell Apoptosis by Targeting miR-503-5p/Bcl-2 Pathway</p>

Cao¹,

Fan²

2020

DMSO

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“…lncRNAs are being extensively studied owing to their vast potential as drug targets for immunological diseases, cardiovascular diseases, and cancers (Atianand & Fitzgerald, 2016). Since H19X is a placenta-specific lncRNA that plays critical roles in trophoblasts, it could be a viable target for placenta-related disease (Pachera et al , 2020; Yu et al , 2018). Elucidating the mechanism underlying the actions of H19X and PIWIL1 could pave the way for the development of treatments for placenta-related disease in the near future.…”

Section: Discussionmentioning

confidence: 99%

LncRNA H19X is required for placenta development and angiogenesis through regulating a noncoding RNA regulatory network

Cao

Zou

et al. 2020

Preprint

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H19X is a lncRNA specifically expressed in the placenta, whose expression is induced by hypoxia. H19X overexpression promoted trophoblast proliferation and invasion, while its knockdown or knockout inhibited trophoblast proliferation and invasion. Mechanistically, we demonstrated that reciprocal regulation exists with miR-424/miR-503 in the control of genes related to placental development and angiogenesis, including VEGF and VEGFR2. H19X inhibited ubiquitination of PIWIL1, thereby maintaining its stability and homeostatic expression of piRNAs. PIWIL1 overexpression rescued the defects of cell behavior caused by H19X KO. H19X deletion led to compromised HIF-1A/HIF-2A expression, which was correlated with the dysregulation of downstream genes under hypoxic conditions. CRISPR/Cas-9 knockout of H19X in animals led to defective placenta differentiation and compromised embryo development under hypoxic conditions. Western blotting showed reduced expression levels of PIWIL1 as well as angiogenesis marker genes, including VEGF and VEGFR2, in H19X KO mice. Thus, this study provides evidence of an unexpected link among lncRNA, miRNA, PIWIL1-related piRNA, and angiogenesis in placentation, the dysregulation of which leads to poor placental development and embryo loss under hypoxic conditions.

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“…X inactivate-specific transcript (XIST) could facilitate EMT induced by TGF-β through miR-367/141-ZEB2 axis in NSCLC [ 82 ]. Furthermore, studies of Pachera et al showed lncRNA H19X, which was served as a critical regulator of TGF-β–driven tissue fibrosis, could be induced by TGF-β in a time- and dose-dependent manners in fibroblasts [ 83 ]. Similarly, in HCC TGF-β and lncRNAs could be able to influence each other through diverse mechanisms, which have been reported in HCC initiation and progression.…”

Section: The Interaction Of Tgf-β and Lncrnas In Hcc: How They Influementioning

confidence: 99%

Modulation of the TGF-β signaling pathway by long noncoding RNA in hepatocellular carcinoma

et al. 2020

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Hepatocellular carcinoma (HCC) is a type of liver cancer with poor prognosis. There have been demonstrated to exist many possible mechanisms in HCC tumorigenesis, and recent investigations have provided some promising therapy targets. However, further mechanisms remain to be researched to improve the therapeutic strategy and diagnosis of HCC. Transforming growth factor-β (TGF-β) is a pleiotropic cytokine which plays critical roles in networks of different cellular processes, and TGF-β signaling has been found to participate in tumor initiation and development of HCC in recent years. Moreover, among the molecules and signaling pathways, researchers paid more attention to lncRNAs (long non-coding RNAs), but the connection between lncRNAs and TGF-βremain poorly understood. In this review, we conclude the malignant procedure which lncRNAs and TGF-β involved in, and summarize the mechanisms of lncRNAs and TGF-βin HCC initiation and development. Furthermore, the interaction between lncRNA and TGF-β are paid more attention, and the potential therapy targets are mentioned.

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Long noncoding RNA H19X is a key mediator of TGF-β–driven fibrosis

Abstract: Chimique Belge (UCB) in the area of potential treatments for scleroderma and its complications. In addition, OD has a patent on mir-29 for the treatment of systemic sclerosis issued (US8247389, EP2331143).

Cited by 62 publications

References 56 publications

<p>LncRNA MIR503HG Promotes High-Glucose-Induced Proximal Tubular Cell Apoptosis by Targeting miR-503-5p/Bcl-2 Pathway</p>

<p>LncRNA MIR503HG Promotes High-Glucose-Induced Proximal Tubular Cell Apoptosis by Targeting miR-503-5p/Bcl-2 Pathway</p>

LncRNA H19X is required for placenta development and angiogenesis through regulating a noncoding RNA regulatory network

Modulation of the TGF-β signaling pathway by long noncoding RNA in hepatocellular carcinoma

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