Expression of CD44 3′-untranslated region regulates endogenous microRNA functions in tumorigenesis and angiogenesis

Jeyapalan, Zina; Deng, Zhaoqun; Shatseva, Tatiana; Fang, Ling; He, Chengyan; Yang, Burton B.

doi:10.1093/nar/gkq1003

Cited by 181 publications

(168 citation statements)

References 38 publications

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“…We have previously demonstrated that expression of the CD44 39 UTR inhibited tumor growth and angiogenesis, which upregulated CD44 and CDC42 expression by binding to the miRNAs miR-216a, miR-330 and miR-608 (Jeyapalan et al, 2011). We hypothesize that the CD44 39 UTR can also regulate the expression of many other proteins because a 39 UTR has the capacity to bind many miRNAs, which can affect other mRNAs downstream.…”

Section: Discussionmentioning

confidence: 97%

“…In addition, miRNAs can be degraded through binding with the 39 UTR, which will protect target mRNAs from translational inhibition. Previously, we demonstrated that a noncoding transcript, CD44 39 UTR, was able to antagonize miRNAs involved in cell cycle regulation, which resulted in an increase in CDC42, a cell cycle regulator, to result in decreased tumorigenesis in the breast cancer cell line MT1 (Jeyapalan et al, 2011). Additionally, the CD44 39 UTR was found to increase endothelial cell activities and angiogenesis in vivo.…”

Section: Introductionmentioning

confidence: 95%

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The non-coding 3' UTR of CD44 induces metastasis by regulating extracellular matrix functions

Rutnam

Yang

2012

Journal of Cell Science

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SummaryThe importance of non-coding RNA transcripts in regulating microRNA (miRNA) functions, especially the 39-untranslated region (39 UTR), has been revealed in recent years. Genes encoding the extracellular matrix normally produce large mRNA transcripts including the 39 UTR. How these large transcripts affect miRNA functions and how miRNAs modulate extracellular matrix protein expression are largely unknown. Here, we demonstrate that the overexpression of the CD44 39 UTR results in enhanced cell motility, invasion and cell adhesion in human breast carcinoma cell line MDA-MB-231. Furthermore, we found that expression of the CD44 39 UTR enhances metastasis in vivo. We hypothesize that increased expression of the CD44 39 UTR affects miRNA binding and modulates synthesis of the extracellular matrix. Computational analysis indicated that miRNAs that interact with the CD44 39 UTR also have binding sites in other matrix-encoding mRNA 39 UTRs, including collagen type 1a1 (Col1a1) repressed by miR-328 and fibronectin type 1 (FN1) repressed by miR-512-3p, miR-491 and miR-671. Protein analysis demonstrated that expression of CD44, Col1a1 and FN1 were synergistically upregulated in vitro and in vivo upon transfection of the CD44 39 UTR. The non-coding 39 UTR of CD44 interacts with multiple miRNAs that target extracellular matrix properties and thus can be used to antagonize miRNA activities.

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Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 95%

The non-coding 3' UTR of CD44 induces metastasis by regulating extracellular matrix functions

Rutnam

Yang

2012

Journal of Cell Science

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“…For instances, the 3′ UTR of CD44 can be combined by miR-216a, miR-330 and miR-608 to affect the expression of CDC42, thereby regulating the proliferation, apoptosis and angiogenesis phenotype of human breast cancer cell line MT-1 [53]. These studies suggest that miRNAs might also have functional relationships in vascular remodeling.…”

Section: Mirnas In Vascular Injury and Remodeling-related Diseasementioning

confidence: 97%

miRNAs and lncRNAs in vascular injury and remodeling

Song

Shan

Chen

et al. 2014

Sci. China Life Sci.

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Vascular injury, remodeling, as well as angiogenesis, are the leading causes of coronary or cerebrovascular disease. The blood vessel functional imbalance trends to induce atherosclerosis, hypertension, and pulmonary arterial hypertension. As several genes have been identified to be dynamically regulated during vascular injury and remodeling, it is becoming widely accepted that several types of non-coding RNA, such as microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), are involved in regulating the endothelial cell and vascular smooth muscle cell (VSMC) behaviors. Here, we review the progress of the extant studies on mechanistic, clinical and diagnostic implications of miRNAs and lncRNAs in vascular injury and remodeling, as well as angiogenesis, emphasizing the important roles of miRNAs and lncRNAs in vascular diseases. Furthermore, we introduce the interaction between miRNAs and lncRNAs, and highlight the mechanism through which lncRNAs are regulating the miRNA function. We envisage that continuous in-depth research of non-coding RNAs in vascular disease will have significant implications for the treatment of coronary or cerebrovascular diseases. Vascular network is an intricate series of vessels that act as conduits for blood flow. Their injury and remodeling contribute to atherosclerosis, restenosis after angioplasty, hypertension, and other diseases. Molecular mechanisms that underlie vascular injury and remodeling have been intensively studied during the last two decades [13]. As reported, a number of genes have been shown to regulate vascular remodeling and angiogenesis [47]. As it is increasingly acknowledged that several types of non-coding RNAs are also involved in these processes, they have become a new focus of scientific research [8].According to the recent discoveries in the field of RNA, nearly 60% of transcripts seem to lack protein-coding capacity, termed non-coding RNAs [9]. Bioinformatics observations suggest that non-coding RNAs tend to exist in greater numbers in more sophisticated organisms [10]. Functional studies reveal that non-coding RNAs have essential functions in regulating epigenetic processes, and emerge as important regulators of life activities [11]. Among non-coding RNAs, miRNAs and lncRNAs are particularly interesting and are thus intensively investigated. Here, we provide an overview of the extant research findings pertaining to miRNAs and lncRNAs in vascular functional maintenance, injury, remodeling, and angiogenesis. Moreover, we highlight their implications for the treatment of atherosclerosis, hypertension and other vascular-related disease.

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“…Most miRNAs bind and target the 39-untranslated region (39UTR) of mRNAs with imperfect complementarity and function as translational repressors. Conversely, it has been demonstrated that the 39UTR and other non-coding RNAs can regulate miRNA functions (Jeyapalan et al, 2011;Lee et al, 2009;Lee et al, 2011). This newly discovered class of regulatory molecules has been demonstrated to exert diverse biological functions in regulating cell activities such as cell proliferation Viticchiè et al, 2011;Yu et al, 2012), cell differentiation (Goljanek-Whysall et al, 2012;Guo et al, 2012;Kahai et al, 2009), apoptosis , morphogenesis (Wang et al, 2008a), invasion Luo et al, 2012), tissue growth (Shan et al, 2009), tumor formation (Nohata et al, 2012;Volinia et al, 2006), angiogenesis Smits et al, 2010;Zou et al, 2012), and metastasis (Huang et al, 2008;Ma et al, 2007;Rutnam and Yang, 2012a).…”

Section: Introductionmentioning

confidence: 99%

Mature MiR-17-5p and passenger miR-17-3p induce hepatocellular carcinoma by targeting PTEN, GalNT7, and vimentin in different signal pathways

Shan

Fang

Shatseva

et al. 2013

Journal of Cell Science

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160

141

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SummaryTo study the physiological role of a single microRNA (miRNA), we generated transgenic mice expressing the miRNA precursor miR-17 and found that the mature miR-17-5p and the passenger strand miR-17-3p were abundantly expressed. We showed that mature miR-17-5p and passenger strand miR-17-3p could synergistically induce the development of hepatocellular carcinoma. The mature miR-17-5p exerted this function by repressing the expression of PTEN. In contrast, the passenger strand miR-17-3p repressed expression of vimentin, an intermediate filament with the ability to modulate metabolism, and GalNT7, an enzyme that regulates metabolism of liver toxin galactosamine. Hepatocellular carcinoma cells, HepG2, transfected with miR-17 formed larger tumors with more blood vessels and less tumor cell death than mock-treated cells. Expression of miR-17 precursor modulated HepG2 proliferation, migration, survival, morphogenesis and colony formation and inhibited endothelial tube formation. Silencing of PTEN, vimentin or GalNT7 with their respective siRNAs enhanced proliferation and migration. Re-expressing these molecules reversed their roles in proliferation, migration and tumorigenesis. Further experiments indicated that these three molecules do not interact with each other, but appear to function in different signaling pathways. Our results demonstrated that a mature miRNA can function synergistically with its passenger strand leading to the same phenotype but by regulating different targets located in different signaling pathways. We anticipate that our assay will serve as a helpful model for studying miRNA regulation.

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Expression of CD44 3′-untranslated region regulates endogenous microRNA functions in tumorigenesis and angiogenesis

Cited by 181 publications

References 38 publications

The non-coding 3' UTR of CD44 induces metastasis by regulating extracellular matrix functions

The non-coding 3' UTR of CD44 induces metastasis by regulating extracellular matrix functions

miRNAs and lncRNAs in vascular injury and remodeling

Mature MiR-17-5p and passenger miR-17-3p induce hepatocellular carcinoma by targeting PTEN, GalNT7, and vimentin in different signal pathways

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