miR-376a-3p and miR-376b-3p overexpression in Hutchinson-Gilford progeria fibroblasts inhibits cell proliferation and induces premature senescence

Frankel, Diane; Delecourt, Valérie; Novoa-del-Toro, Elva-María; Robin, Jérôme D.; Airault, Coraline; Bartoli, Catherine; Carabalona, Aurelie; Perrin, Sophie; Mazaleyrat, Kilian; Sandre-Giovannoli, Annachiara De; Magdinier, Frédérique; Baudot, Anaı̈s; Lévy, Nicolas; Kaspi, Elise; Roll, Patrice

doi:10.1016/j.isci.2022.103757

Cited by 9 publications

(8 citation statements)

References 56 publications

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“… 40 Furthermore, analysis of miRNA expression profiles in HGPS fibroblasts and control fibroblasts has demonstrated that the accumulation of progerin can result in the overexpression of certain miRNA genes, which may be related to the effect of progerin on epigenetic modification. 41 These findings suggest that the introduction of progerin into tumor cells could potentially impact gene expression through alterations in epigenetic modifications, including dysregulation of microRNAs.…”

Section: Discussionmentioning

confidence: 99%

Progerin Inhibits the Proliferation and Migration of Melanoma Cells by Regulating the Expression of Paxillin

Liu,

Huang,

Luo

et al. 2024

OTT

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Objective Progerin, the underlying cause of Hutchinson-Gilford Progeria Syndrome (HGPS), has been extensively studied for its impact on normal cells and premature aging patients. However, there is a lack of research on its specific effects on tumor cells. Melanoma is one of the most common malignant tumors with high morbidity and mortality. This study aimed to elucidate the potential therapeutic role of progerin in melanoma. Materials and Methods We constructed the melanoma A375 cell line and M14 cell line with stable expression of progerin. The expression of progerin, paxillin, and epithelial-mesenchymal transition (EMT) marker proteins in each cell group was measured using Western blot. The migration, proliferation, and cell cycle of cancer cells were assessed using the transwell assay, wound healing assay, colony formation assay, CCK 8 assay, and flow cytometry. RT-qPCR technology was used to examine the impact of progerin overexpression on microRNA expression. Finally, we transfected paxillin into the progerin overexpression cell group to verify whether progerin regulates the phenotype of tumor cells through paxillin. Results Our study demonstrated that overexpression of progerin leads to decreased expression of paxillin and inhibits cancer cell migration, proliferation, EMT process and cell cycle progression. Additionally, rescue experiments revealed that the migration, proliferation ability, and EMT marker protein expression in progerin overexpressing cancer cells could be partially restored by transfecting a plasmid containing the paxillin gene. Mechanistic investigations further revealed that progerin achieves this inhibition of paxillin expression by upregulating miR-212. Conclusion This study reveals that progerin may inhibit the migration and proliferation of melanoma cells through the miR-212/paxillin axis, which provides a new approach for the future treatment of this disease.

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Section: Discussionmentioning

confidence: 99%

Progerin Inhibits the Proliferation and Migration of Melanoma Cells by Regulating the Expression of Paxillin

Liu,

Huang,

Luo

et al. 2024

OTT

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“…Progerin-mediated functions at the protein level and their relationship with miRNA expression have also been described in recent studies [ 51 , 52 , 53 ]. A structure-based study has revealed that unfarnesylated progerin can form a disulfide bond with an Ig-like domain in the nuclear lamina.…”

Section: Dysfunctional Progerin Expressionmentioning

confidence: 93%

“…The Alphafold2-assisted docking structure showed that disulfide bond formation was promoted by a weak interaction between the groove of the Ig-like domain and the unfarnesylated C-terminal tail region of progerin, providing molecular insights into the abnormal interactions caused by progerin [ 51 ]. The evaluation of miRNA expression profiles in HGPS and normal fibroblasts revealed an enriched set of overexpressed miRNAs belonging to the 14q32.2–14q32.3 miRNA cluster and showed that inducing their overexpression in normal fibroblasts reduced cell proliferation and increased senescence, whereas inhibiting them in HGPS fibroblasts alleviated proliferation defects and senescence and reduced progerin accumulation [ 52 ]. Progerin overexpression induced notable changes in miRNA expression and confirmed that has-miR-59 (miR-59) was markedly upregulated in cells from patients with HGPS and in multiple tissues of an HGPS mouse model ( Lmna G609G/G609G ) [ 53 ].…”

Section: Dysfunctional Progerin Expressionmentioning

confidence: 99%

Progerin, an Aberrant Spliced Form of Lamin A, Is a Potential Therapeutic Target for HGPS

Kim,

Chung,

Woo

et al. 2023

Cells

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Hutchinson–Gilford progeria syndrome (HGPS) is an extremely rare genetic disorder caused by the mutant protein progerin, which is expressed by the abnormal splicing of the LMNA gene. HGPS affects systemic levels, with the exception of cognition or brain development, in children, showing that cellular aging can occur in the short term. Studying progeria could be useful in unraveling the causes of human aging (as well as fatal age-related disorders). Elucidating the clear cause of HGPS or the development of a therapeutic medicine could improve the quality of life and extend the survival of patients. This review aimed to (i) briefly describe how progerin was discovered as the causative agent of HGPS, (ii) elucidate the puzzling observation of the absence of primary neurological disease in HGPS, (iii) present several studies showing the deleterious effects of progerin and the beneficial effects of its inhibition, and (iv) summarize research to develop a therapy for HGPS and introduce clinical trials for its treatment.

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“…In an interesting study by Frankel et al the expression profiles of miRNAs in HGPS and control fibroblasts were performed. An enrichment of overexpressed miRNAs from the 14q32.2-14q32.3 miRNA cluster was found [62]. Using 3D FISH, the authors showed that the overexpression of these miRNAs was associated with chromatin remodeling at this specific locus in HGPS fibroblasts [62].…”

Section: Micro-rna-inhibitorsmentioning

confidence: 98%

“…An enrichment of overexpressed miRNAs from the 14q32.2-14q32.3 miRNA cluster was found [62]. Using 3D FISH, the authors showed that the overexpression of these miRNAs was associated with chromatin remodeling at this specific locus in HGPS fibroblasts [62]. The researchers focus on miR-376b-3p and miR-376a-3p, both of which are overexpressed in HGPS fibroblasts [62].…”

Section: Micro-rna-inhibitorsmentioning

confidence: 99%

Current Pathophysiological and Therapeutic Options for Children with Hutchinson Gilford Syndrome

Bittmann

2024

Asian J. Pediatr. Res.

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Hutchinson-Gilford-Progeria syndrome (HGPS) cannot, to date, be treated causally. Therapy for affected children focus on alleviating the symptoms, treating secondary diseases and preventing complications such as strokes or heart attacks. Various medications and physiotherapeutic methods are primarily available for this extremely rare pediatric genetic disease. Lonafarnib, a farnesyltransferase inhibitor, has been used for the treatment of progeria in children since 2022, which can extend the life of children with HGPS up to 4 years. Farnesyltransferase inhibitors are able to block an enzyme that is involved in progerin processing. Progerin is the altered protein that occurs in HGPS due to the spelling mistake in the lamin A gene and accumulates within the cell nucleus envelope. As a result, the envelope is weakened and the cell nucleus becomes deformed. The spectrum of therapies includes progerin-targeting strategies on one hand and on therapies to alleviate the tremendous effects by progerin. Research focus on different new targets in the management of HGPS-like the farnesyltransferase inhibitor lonafarnib, Acetyltransferase NAT10-inhibitors, KAT 6a/b and -7 inhibitors, paclitaxel, small molecule ICMT-inhibitors, exportin CRM-1 Inhibitors, progerin-lamin A binding inhibitors (Progerinin), Ghrelin, micro-RNA inhibitors, doxycycline and the regulation of rapamycin complex 1 (mTORC1). This manuscript analyses these new therapeutic targets and pathophysiological aspects in a review manuscript.

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miR-376a-3p and miR-376b-3p overexpression in Hutchinson-Gilford progeria fibroblasts inhibits cell proliferation and induces premature senescence

Cited by 9 publications

References 56 publications

Progerin Inhibits the Proliferation and Migration of Melanoma Cells by Regulating the Expression of Paxillin

Progerin Inhibits the Proliferation and Migration of Melanoma Cells by Regulating the Expression of Paxillin

Progerin, an Aberrant Spliced Form of Lamin A, Is a Potential Therapeutic Target for HGPS

Current Pathophysiological and Therapeutic Options for Children with Hutchinson Gilford Syndrome

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