<i>H19</i> Long Noncoding RNA Regulates Intestinal Epithelial Barrier Function via MicroRNA 675 by Interacting with RNA-Binding Protein HuR

Zou, Tongtong; Jaladanki, Suraj; Liu, Lan; Xiao, Lan; Chung, Hee Kyoung; Wang, Junyao; Xu, Yan; Gorospe, Myriam; Wang, Jianying

doi:10.1128/mcb.01030-15

Cited by 121 publications

(120 citation statements)

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“…To determine the in vivo function of HuRmediated Cdc42 expression in the intestinal epithelium, we used IE-HuR Ϫ/Ϫ mice that we recently generated. As reported previously (19,29), HuR levels in the small intestinal ( Fig. 4A, left) and colonic mucosa (data not shown) were undetectable in IE-HuR Ϫ/Ϫ mice but were at wild-type levels in stomach mucosa, lung, liver, and pancreas.…”

Section: Resultssupporting

confidence: 87%

“…Our previous studies (21,32,33) reveal that HuR stabilizes stim1 mRNA, encoding the Ca 2ϩ sensor protein STIM1 (activator of Ca 2ϩ influx in IECs), and also stimulates translation of the transcription factor MYC, two proteins that critically stimulate IEC migration and proliferation and enhance gut mucosal repair after injury (4,48,49). In support of our current findings, targeted deletion of HuR in IECs decreases the regenerative potential of crypt progenitors in mice exposed to irradiation (29) and represses the recovery of the intestinal barrier function after I/R stress (19). However, the exact roles of RhoB and RhoC in inhibition of intestinal epithelial restitution after injury resulting from HuR deletion remain unclear.…”

Section: Discussionsupporting

confidence: 86%

“…An increasing body of evidence indicates that homeostasis of the gut epithelium is controlled by RBPs and ncRNAs acting in concert to regulate gene expression synergistically or antagonistically (8). For example, the RBP HuR directly binds to the lncRNA H19 and prevents miRNA 675 (miR-675) processing from H19, thus rescuing expression of tight junctions and gut barrier function in cells overexpressing H19 (19). In contrast, HuR and lncRNA SPRY4-IT1 increase TJ expression at the posttranscriptional level and promote the gut barrier function synergistically by enhancing the association of SPRY4-IT1 with the TJ mRNAs (20).…”

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confidence: 99%

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HuR Enhances Early Restitution of the Intestinal Epithelium by Increasing Cdc42 Translation

Liu

Zhuang

Xiao

et al. 2017

Molecular and Cellular Biology

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The mammalian intestinal mucosa exhibits a spectrum of responses after acute injury and repairs itself rapidly to restore the epithelial integrity. The RNAbinding protein HuR regulates the stability and translation of target mRNAs and is involved in many aspects of gut epithelium homeostasis, but its exact role in the regulation of mucosal repair after injury remains unknown. We show here that HuR is essential for early intestinal epithelial restitution by increasing the expression of cell division control protein 42 (Cdc42) at the posttranscriptional level. HuR bound to the Cdc42 mRNA via its 3= untranslated region, and this association specifically enhanced Cdc42 translation without an effect on the Cdc42 mRNA level. Intestinal epithelium-specific HuR knockout not only decreased Cdc42 levels in mucosal tissues, but it also inhibited repair of damaged mucosa induced by mesenteric ischemia/reperfusion in the small intestine and by dextran sulfate sodium in the colon. Furthermore, Cdc42 silencing prevented HuR-mediated stimulation of cell migration over the wounded area by altering the subcellular distribution of F-actin. These results indicate that HuR promotes early intestinal mucosal repair after injury by increasing Cdc42 translation and demonstrate the importance of HuR deficiency in the pathogenesis of delayed mucosal healing in certain pathological conditions.

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Section: Resultssupporting

confidence: 87%

Section: Discussionsupporting

confidence: 86%

mentioning

confidence: 99%

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HuR Enhances Early Restitution of the Intestinal Epithelium by Increasing Cdc42 Translation

Liu

Zhuang

Xiao

et al. 2017

Molecular and Cellular Biology

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“…LncRNA H19 is encoded by a paternally imprinted gene, H19, whose oncogenic functions have been investigated in the context of pancreatic ductal adenocarcinoma, hepatocarcinoma, bladder cancer, glioma and gastric cancer [21-25]. Recent data and studies of miR-675-5p derived from lncRNA H19 indicate that the lncRNA H19/miR-675-5p axis plays a pro-oncologic role by regulating the expression of several target genes [26-30]. …”

Section: Introductionmentioning

confidence: 99%

Huaier Extract Inhibits Breast Cancer Progression Through a LncRNA-H19/MiR-675-5p Pathway

Wang

Chen

et al. 2017

Cell Physiol Biochem

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Background/Aims: Increasing evidence indicates that Huaier extract has promising therapeutic effects against cancer. However, the mechanisms that underlie its anti-tumor effects remain unclear. In recent years, various studies have shown that long noncoding RNAs (lncRNAs) play a critical role in the regulation of cancer development and progression. Here, we explored the role of lncRNAs in Huaier-induced tumor suppression. Methods: Microarray profiling was performed to identify the candidate lncRNAs affected by Huaier extract. Quantitative realtime PCR (qPCR) was used to evaluate the transfection efficiency and the influence of Huaier extract on H19 expression. The effect of Huaier extract on the cell viability was examined by MTT. Moreover, the rates of apoptotic cells were detected using flow-cytometric analysis. Western blot analysis was applied to show the protein levels of CBL. Results: Microarray data derived from Huaier-treated breast cancer cells identified H19 as a potential target. Huaier extract reduced the expression of H19. The over-expression of H19 inhibited the cytotoxic effects of Huaier extract; in contrast, reduced H19 expression enhanced the function of Huaier extract. MiR-675-5p was identified as a mature product of H19. Moreover, Huaier extract reduced the miR-675-5p expression. Upregulating miR-675-5p reversed the inhibitory effects of Huaier extract, whereas downregulating miR-675-5p sensitized breast cancer cells to the effect of Huaier extract. In addition, Huaier extract increased the expression of CBL protein, a direct target of miR-675-5p. Conclusion: Collectively, the data demonstrate that Huaier extract reduces viability and induces apoptosis in breast cancer cells via H19-miR-675-5p-CBL axis regulation.

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“…For example, CUGBP1 interacts with miR-222 to inhibit translation of the Cdk4 mRNA synergistically (18), but it competes with HuR to regulate translation of the tight junction occludin and transcription factor MYC antagonistically (25,26). The exact mechanism by which CUGBP1 enhances the association of miR-195 with Igf2r mRNA is unclear at present, but it has been reported that miRNA binding sites are commonly present near RBP binding sites (38,39), suggesting that in some cases RBP and miRNA actions could be enhanced or could compete via their physical interactions with given mRNAs. However, RBPs and coregulatory miRNAs can also bind at locations that are up to several hundreds or thousands of bases apart in some targets (16,40,41).…”

Section: Discussionmentioning

confidence: 99%

Cooperative Repression of Insulin-Like Growth Factor Type 2 Receptor Translation by MicroRNA 195 and RNA-Binding Protein CUGBP1

Zhang

Xiao

et al. 2017

Molecular and Cellular Biology

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Insulin-like growth factor type 2 (IGF2) receptor (IGF2R) recognizes mannose 6-phosphate-containing molecules and IGF2 and plays an important role in many pathophysiological processes, including gut mucosal adaptation. However, the mechanisms that control cellular IGF2R abundance are poorly known. MicroRNAs (miRNAs) and RNA-binding proteins (RBPs) critically regulate gene expression programs in mammalian cells by modulating the stability and translation of target mRNAs. Here we report that miRNA 195 (miR-195) and RBP CUG-binding protein 1 (CUGBP1) jointly regulate IGF2R expression at the posttranscriptional level in intestinal epithelial cells. Both miR-195 and CUGBP1 interacted with the 3= untranslated region (3=-UTR) of Igf2r mRNA, and the association of CUGBP1 with Igf2r mRNA enhanced miR-195 binding to Igf2r mRNA. Ectopically expressed CUGBP1 and miR-195 repressed IGF2R translation cooperatively without altering the stability of Igf2r mRNA. Importantly, the miR-195-and CUGBP1-repressed levels of cellular IGF2R led to a disruption in the structure of the trans-Golgi network. These findings indicate that IGF2R expression is controlled posttranscriptionally by two factors that associate with Igf2r mRNA and suggest that miR-195 and CUGBP1 dampen IGF signaling by inhibiting IGF2R translation.KEYWORDS insulin superfamily, posttranscriptional regulation, trans-Golgi network, intestinal epithelial cells, RNA-binding proteins, noncoding RNAs M ucosal regeneration/adaptation is an essential process in gut homeostasis and tightly regulated by numerous factors, including insulin-like growth factor type 1 (IGF1) and IGF2 (1, 2). Two structurally distinct types of receptors, the IGF1 receptor (IGF1R) and IGF2R, specifically interact with IGF1 and IGF2 as ligands and regulate diverse biological functions such as cell proliferation, differentiation, and apoptosis (3, 4). Like the insulin receptor, IGF1R is a heterotetrameric transmembrane receptor tyrosine kinase, and its activation results in autophosphorylation of tyrosine residues in the intracellular ␤-subunits, thus initiating the phosphatidylinositol 3-kinase (PI3) kinase/AKT and/or mitogen-activated protein (MAP) kinase signaling cascade (5). In contrast, IGF2R is a single-transmembrane-domain protein and binds IGF2 with greater affinity than IGF1, although it does not accept insulin as a ligand (4, 6). IGF2R also recognizes, via distinct sites, mannose-6-phosphate (M6P)-containing molecules and can therefore associate with other growth factors and cytokines (4). The majority of IGF2R is localized in the trans-Golgi network (TGN) and endosomal compartments and, to a lesser extent, on the cell surface (6). A subpopulation of the IGF2R on the plasma membrane regulates IGF2 internalization and various M6P-containing ligands for their

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H19 Long Noncoding RNA Regulates Intestinal Epithelial Barrier Function via MicroRNA 675 by Interacting with RNA-Binding Protein HuR

Cited by 121 publications

References 65 publications

HuR Enhances Early Restitution of the Intestinal Epithelium by Increasing Cdc42 Translation

HuR Enhances Early Restitution of the Intestinal Epithelium by Increasing Cdc42 Translation

Huaier Extract Inhibits Breast Cancer Progression Through a LncRNA-H19/MiR-675-5p Pathway

Cooperative Repression of Insulin-Like Growth Factor Type 2 Receptor Translation by MicroRNA 195 and RNA-Binding Protein CUGBP1

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