MicroRNA 339 down‐regulates μ‐opioid receptor at the post‐transcriptional level in response to opioid treatment

Wu, Qiming; Hwang, Cheol Kyu; Zheng, Hui; Wagley, Yadav; Lin, Hsiu-Chin; Kim, Do Kyung; Law, Ping Yee; Loh, Horace H.; Wei, Li‐Na

doi:10.1096/fj.12-213439

Cited by 73 publications

(71 citation statements)

References 63 publications

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“…Expression profiling reports detection of miR-339 in adult hippocampus (Landgraf et al 2007), cervix (Witten et al 2010), placenta (Cummins et al 2006), and in numerous cancers (Kasashima 2004;Landgraf 2007;Stark et al 2010). MiR-339 is reported to regulate ICAM-1 (Ueda et al 2009), BCL6 , and μ-opioid receptor (Wu 2012). Relevant to our interests in KL as an age-related protein, miR-339 is reported to be among only 16 miR upregulated in long-lived humans, showing a 2.37-fold increase in this cohort (ElSharawy et al 2012).…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-339 and microRNA-556 regulate Klotho expression in vitro

Mehi

Maltare

Abraham

et al. 2013

AGE

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Klotho is an anti-aging protein with direct effects on life-span in mice. Klotho functions to regulate pathways classically associated with longevity including insulin/IGF1 and Wnt signaling. Decreased Klotho protein expression is observed throughout the body during the normal aging process. While increased methylation of the Klotho promoter is reported, other epigenetic mechanisms could contribute to age-related downregulation of Klotho expression, including microRNA-mediated regulation. Following in silico identification of potential microRNA binding sites within the Klotho 3′ untranslated region, reporter assays reveal regulation by microRNA-339, microRNA-556, and, to a lesser extent, microRNA-10 and microRNA-199. MicroRNA-339 and microRNA-556 were further found to directly decrease Klotho protein expression indicating that, if upregulated in aging tissue, these microRNA could play a role in agerelated downregulation of Klotho messenger RNA. These microRNAs are differentially regulated in cancer cells compared to normal cells and may imply a role for microRNA-mediated regulation of Klotho in cancer.

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Section: Discussionmentioning

confidence: 99%

MicroRNA-339 and microRNA-556 regulate Klotho expression in vitro

Mehi

Maltare

Abraham

et al. 2013

AGE

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“…There are also other studies showing that DOR agonists can prolong survival of peripheral organs, such as the lungs, heart, liver, and kidney, and that DOR activation is protective against hypoxic/ischemic injury in the heart [22,23]. Since there is a growing body of evidence indicating that miRNAs play several regulatory roles in opioid pharmacology [24,25], and our previous studies demonstrate the involvement of DOR in the regulation of miRNA expression in the brain and kidney [26,27], we wanted to know whether DOR affects miRNA expression in the heart when exposed to prolonged hypoxia.…”

Section: Introductionmentioning

confidence: 99%

δ-Opioid Receptor Activation and MicroRNA Expression in the Rat Heart Under Prolonged Hypoxia

Zhi

Li²,

Shao³

et al. 2016

Cell Physiol Biochem

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Background: Hypoxic/ischemic injury to the heart is a frequently encountered clinical problem with limited therapeutic options. Since microRNAs (miRNAs) are involved in hypoxic/ischemic events, and δ-opioid receptor (DOR) activation is known to protect against hypoxic/ischemic injury, we speculated on the involvement of DOR activation in altering miRNA expression in the heart under hypoxic conditions. The present study aimed to test our hypothesis. Methods: Male Sprague Dawley rats were exposed to hypoxia (9.5-10% O₂) for 1, 5, or 10 days with or without DOR activation. The target miRNAs were selected from TaqMan low-density array (TLDA) data and were further analyzed by quantitative real-time PCR. Results: We found that: 1) hypoxia alters the miRNA expression profiles depending on the hypoxic duration; 2) DOR activation shifts miRNA expression profiles in normoxic conditions and upregulates miR-128a-3p, miR-134-5p, miR-135a, miR-193a-3p, miR-196a, miR-324-3p, and miR-338; and 3) DOR activation modifies hypoxia-induced changes in miRNA expression and increases the levels of miR-128a-3p, miR-134-5p, miR-135a, miR-193a-3p, miR-196a, miR-324-3p, miR-141, miR-200b, and miR-324-3p. For example, miR-196c-5p decreased by 50% while miR-135a-5p increased 2.9 fold after 10 days under hypoxic conditions. Moreover, DOR activation further strengthened the hypoxia-induced increase of the levels of miR-7a-5p. When DOR was activated using UFP-512, the level of miR-107-3p significantly increased 1 day after the administration of UFP-512, but gradually decreased back to normal under normoxia. Conclusion: Hypoxia significantly modifies the miRNA profile in the heart, which can be mimicked or modified by DOR activation. Defining the targeted pathways that regulate the diverse cellular and molecular functions of miRNAs may provide new insights into potential therapies for hypoxic/ischemic injury of the heart.

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“…Mu opioids such as morphine modulate expression of a number of miRNAs (Sanchez-Simon et al, 2010;Zheng et al, 2010;Wu et al, 2008Wu et al, , 2013Dave and Khalili, 2010;He et al, 2010;Wang et al, 2011), and several miRNAs regulate MOR-1 expression (Wu et al, 2008(Wu et al, , 2009He et al, 2010). Dysregulation of miRNAs has been linked to morphine tolerance and addiction Dreyer, 2010;Hwang et al, 2012;Tapocik et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Morphine Regulates Expression ofμ-Opioid Receptor MOR-1A, an Intron-Retention Carboxyl Terminal Splice Variant of theμ-Opioid Receptor (OPRM1) Gene via miR-103/miR-107

et al. 2013

Mol Pharmacol

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The m-opioid receptor (MOR-1) gene OPRM1 undergoes extensive alternative splicing, generating an array of splice variants. Of these variants, MOR-1A, an intron-retention carboxyl terminal splice variant identical to MOR-1 except for the terminal intracellular tail encoded by exon 3b, is quite abundant and conserved from rodent to humans. Increasing evidence indicates that miroRNAs (miRNAs) regulate MOR-1 expression and that m agonists such as morphine modulate miRNA expression. However, little is known about miRNA regulation of the OPRM1 splice variants. Using 39-rapid amplification cDNA end and Northern blot analyses, we identified the complete 39-untranslated region (39-UTR) for both mouse and human MOR-1A and their conserved polyadenylation site, and defined the role the 39-UTR in mRNA stability using a luciferase reporter assay. Computer models predicted a conserved miR-103/107 targeting site in the 39-UTR of both mouse and human MOR-1A. The functional relevance of miR-103/107 in regulating expression of MOR-1A protein through the consensus miR-103/107 binding sites in the 39-UTR was established by using mutagenesis and a miR-107 inhibitor in transfected human embryonic kidney 293 cells and Be (2)C cells that endogenously express human MOR-1A. Chronic morphine treatment significantly upregulated miR-103 and miR-107 levels, leading to downregulation of polyribosome-associated MOR-1A in both Be(2)C cells and the striatum of a morphinetolerant mouse, providing a new perspective on understanding the roles of miRNAs and OPRM1 splice variants in modulating the complex actions of morphine in animals and humans.

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MicroRNA 339 down‐regulates μ‐opioid receptor at the post‐transcriptional level in response to opioid treatment

Cited by 73 publications

References 63 publications

MicroRNA-339 and microRNA-556 regulate Klotho expression in vitro

MicroRNA-339 and microRNA-556 regulate Klotho expression in vitro

δ-Opioid Receptor Activation and MicroRNA Expression in the Rat Heart Under Prolonged Hypoxia

Morphine Regulates Expression ofμ-Opioid Receptor MOR-1A, an Intron-Retention Carboxyl Terminal Splice Variant of theμ-Opioid Receptor (OPRM1) Gene via miR-103/miR-107

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