Functional Analysis of
            <i>PCSK9</i>
            3′UTR Variants and mRNA–miRNA Interactions in Patients with Familial Hypercholesterolemia

Los, Bruna; Borges, Jéssica Bassani; Oliveira, Victor Fernandes de; Freitas, Renata Caroline Costa de; Dagli-Hernandez, Carolina; Bortolin, Raul Hernandes; Gonçalves, Rodrigo Marques; Faludi, André Árpád; Rodrigues, Alice Cristina; Bastos, Gisele Medeiros; Jannes, Cinthia E.; Pereira, Alexandre C.; Hirata, Rosário Dc; Hirata, Mario H.

doi:10.2217/epi-2020-0462

Cited by 9 publications

(8 citation statements)

References 28 publications

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“…′ -UTR and increases PCSK9 expression (93). Conversely, miR-27a upregulates PCSK9 expression, possibly through binding to the upstream of PCSK9 promoter in HepG2 cells (96).…”

Section: Regulation Of Pcsk9 Expressionmentioning

confidence: 98%

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Regulation of PCSK9 Expression and Function: Mechanisms and Therapeutic Implications

Xia

Peng

et al. 2021

Front. Cardiovasc. Med.

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Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes degradation of low-density lipoprotein receptor (LDLR) and plays a central role in regulating plasma levels of LDL cholesterol levels, lipoprotein(a) and triglyceride-rich lipoproteins, increasing the risk of cardiovascular disease. Additionally, PCSK9 promotes degradation of major histocompatibility protein class I and reduces intratumoral infiltration of cytotoxic T cells. Inhibition of PCSK9 increases expression of LDLR, thereby reducing plasma levels of lipoproteins and the risk of cardiovascular disease. PCSK9 inhibition also increases cell surface levels of major histocompatibility protein class I in cancer cells and suppresses tumor growth. Therefore, PCSK9 plays a vital role in the pathogenesis of cardiovascular disease and cancer, the top two causes of morbidity and mortality worldwide. Monoclonal anti-PCSK9 antibody-based therapy is currently the only available treatment that can effectively reduce plasma LDL-C levels and suppress tumor growth. However, high expenses limit their widespread use. PCSK9 promotes lysosomal degradation of its substrates, but the detailed molecular mechanism by which PCSK9 promotes degradation of its substrates is not completely understood, impeding the development of more cost-effective alternative strategies to inhibit PCSK9. Here, we review our current understanding of PCSK9 and focus on the regulation of its expression and functions.

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“…′ -UTR and increases PCSK9 expression (93). Conversely, miR-27a upregulates PCSK9 expression, possibly through binding to the upstream of PCSK9 promoter in HepG2 cells (96).…”

Section: Regulation Of Pcsk9 Expressionmentioning

confidence: 98%

“…′ -UTR in cultured cells, such as Huh7, HepG2 and BON-1 cells (92)(93)(94). A common variant, 1420C>G, decreases the inhibitory effect of miR-1228-3p and miR-143-5p on PCSK9 expression, reducing plasma levels of PCSK9 and LDL cholesterol (95).…”

Section: Regulation Of Pcsk9 Expressionmentioning

confidence: 99%

Regulation of PCSK9 Expression and Function: Mechanisms and Therapeutic Implications

Xia

Peng

et al. 2021

Front. Cardiovasc. Med.

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“…Previous studies have found that microRNAs (miRNAs), as a new class of regulatory factors, play an extremely important role in the growth and development of skeletal muscle. In addition, miRNAs act via targeting the 3 ′ -untranslated region (3 ′ -UTR) of a gene to repress their translation or to degrade mRNA [2,3]. MiRNAs primarily bind to the 3 ′ UTR of target genes through complete or incomplete pairing, exerting inhibition on the target gene at both the mRNA and protein levels.…”

Section: Introductionmentioning

confidence: 99%

miR-423-5p Regulates Skeletal Muscle Growth and Development by Negatively Inhibiting Target Gene SRF

Pang,

Liang,

Huang

et al. 2024

Genes

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The process of muscle growth directly affects the yield and quality of pork food products. Muscle fibers are created during the embryonic stage, grow following birth, and regenerate during adulthood; these are all considered to be phases of muscle development. A multilevel network of transcriptional, post-transcriptional, and pathway levels controls this process. An integrated toolbox of genetics and genomics as well as the use of genomics techniques has been used in the past to attempt to understand the molecular processes behind skeletal muscle growth and development in pigs under divergent selection processes. A class of endogenous noncoding RNAs have a major regulatory function in myogenesis. But the precise function of miRNA-423-5p in muscle development and the related molecular pathways remain largely unknown. Using target prediction software, initially, the potential target genes of miR-423-5p in the Guangxi Bama miniature pig line were identified using various selection criteria for skeletal muscle growth and development. The serum response factor (SRF) was found to be one of the potential target genes, and the two are negatively correlated, suggesting that there may be targeted interactions. In addition to being strongly expressed in swine skeletal muscle, miR-423-5p was also up-regulated during C2C12 cell development. Furthermore, real-time PCR analysis showed that the overexpression of miR-423-5p significantly reduced the expression of myogenin and the myogenic differentiation antigen (p < 0.05). Moreover, the results of the enzyme-linked immunosorbent assay (ELISA) demonstrated that the overexpression of miR-423-5p led to a significant reduction in SRF expression (p < 0.05). Furthermore, miR-423-5p down-regulated the luciferase activities of report vectors carrying the 3′ UTR of porcine SRF, confirming that SRF is a target gene of miR-423-5p. Taken together, miR-423-5p’s involvement in skeletal muscle differentiation may be through the regulation of SRF.

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“…The routine sequencing analysis of FH does not include deep intronic or untranslated regions (UTRs) of LDLR, APOB, or PCSK9 despite the fact that several pathogenic variants have been reported in these regions [16][17][18]. A number of studies on 3 ′ UTR-LDLR and PCSK9 regions have suggested that 3′UTR variants could affect these genes' expression by disrupting microRNA-mRNA binding and causing hypercholesterolemia [19,20].…”

Section: Introductionmentioning

confidence: 99%

“…A number of studies have reported an association between common polymorphisms in the LDLR-3 ′ UTR and PCSK9-3 ′ UTR regions with LDL-c levels [19,20,29], low HDL-c levels [30], and the response to lipid-lowering drugs [31,32]. Dysregulation of miRNA binding by 3 ′ UTR polymorphisms has been proposed as the underlying mechanism of lipid abnormalities.…”

Section: Introductionmentioning

confidence: 99%

Functional Analysis of $3^{'}$ UTR Variants at the LDLR and PCSK9 Genes in Patients with Familial Hypercholesterolemia

Sanguino Otero,

Rodríguez-Jiménez,

Mostaza Prieto

et al. 2024

Human Mutation

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Familial hypercholesterolemia (FH) is an autosomal dominant disease with an estimated prevalence of 1 in 200-250 individuals. Patients with FH are at increased risk of premature coronary artery disease. Early diagnosis and treatment are essential for improving clinical outcomes. In many cases, however, the genetic diagnosis is not confirmed. At present, routine genetic testing does not analyze the 3′UTR regions of LDLR and PCSK9. However, 3′UTR-single nucleotide variants could be of interest because they can modify the target sequence of miRNAs that regulate the expression of these genes. Our study fully characterizes the 3′UTR regions of LDLR and PCSK9 in 409 patients with a suspected diagnosis of FH using next-generation sequencing. In 30 of the 409 patients, we found 21 variants with an allelic frequency of <1%; 14 of them at 3′UTR-LDLR and 8 at 3′UTR-PCSK9. The variants’ pathogenicity was studied in silico; subsequently, a number of the variants were functionally validated using luciferase reporter assays. LDLR:c.∗653G>C showed a 41% decrease in luciferase expression, while PCSK9:c.∗950C>T showed a 41% increase in PCSK9 expression, results that could explain the hypercholesterolemia phenotype. In summary, the genetic analysis of the 3′UTR regions of LDLR and PCSK9 could improve the genetic diagnosis of FH.

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Functional Analysis of PCSK9 3′UTR Variants and mRNA–miRNA Interactions in Patients with Familial Hypercholesterolemia

Cited by 9 publications

References 28 publications

Regulation of PCSK9 Expression and Function: Mechanisms and Therapeutic Implications

Regulation of PCSK9 Expression and Function: Mechanisms and Therapeutic Implications

miR-423-5p Regulates Skeletal Muscle Growth and Development by Negatively Inhibiting Target Gene SRF

Functional Analysis of $3^{'}$ UTR Variants at the LDLR and PCSK9 Genes in Patients with Familial Hypercholesterolemia

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Functional Analysis of PCSK9 3′UTR Variants and mRNA–miRNA Interactions in Patients with Familial Hypercholesterolemia

Cited by 9 publications

References 28 publications

Regulation of PCSK9 Expression and Function: Mechanisms and Therapeutic Implications

Regulation of PCSK9 Expression and Function: Mechanisms and Therapeutic Implications

miR-423-5p Regulates Skeletal Muscle Growth and Development by Negatively Inhibiting Target Gene SRF

Functional Analysis of 3′UTR Variants at the LDLR and PCSK9 Genes in Patients with Familial Hypercholesterolemia

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Functional Analysis of $3^{'}$ UTR Variants at the LDLR and PCSK9 Genes in Patients with Familial Hypercholesterolemia