Micro<scp>RNA</scp>‐23b‐3p regulates human keratinocyte differentiation through repression of <scp>TGIF</scp>1 and activation of the <scp>TGF</scp>‐ß–<scp>SMAD</scp>2 signalling pathway

Barbollat-Boutrand, Laetitia; Joly‐Tonetti, Nicolas; Santos, Morgan Dos; Metral, Élodie; Boher, Aurélie; Masse, Ingrid; Berthier‐Vergnes, Odile; Bertolino, Philippe; Damour, O.; Lamartine, Jérôme

doi:10.1111/exd.13119

Cited by 25 publications

(22 citation statements)

References 48 publications

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“…Our data shows that differentiation in keratinocytes at large increases miR-181a expression, suggesting a role for miR-181a in a common pathway of differentiation, and that removing miR-181a is critical for the transition of keratinocytes into SCC. A similar weight has been reported in keratinocytes for miR-203 and miR-24 [ 41 – 43 ], underlining the impact of miRNAs in differentiation [ 44 – 46 ]. We thus believe that miR-181a is an important mediator of differentiation in keratinocytes.…”

Section: Discussionsupporting

confidence: 73%

miR-181a decelerates proliferation in cutaneous squamous cell carcinoma by targeting the proto-oncogene KRAS

et al. 2017

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Cutaneous squamous cell carcinoma (SCC) is the second most common human skin cancer with a rapidly increasing incidence among the Caucasian population. Among the many regulators, responsible for cancer progression and growth, microRNAs (miRNA) are generally accepted as key players by now. In our current study we found that microRNA-181a (miR-181a) shows low abundance in SCC compared to normal epidermal skin. In vitro, miRNA downregulation in normal primary keratinocytes induced increased proliferation, while in vivo miR-181a downregulation in HaCaT normal keratinocytes showed tumor-like growth increase up to 50%. Inversely, upregulation of these miRNAs in cancer cells lead to reduced cellular proliferation and induction of apoptosis in vitro. An in vivo therapeutic model with induced miR-181a expression in SCC13 cancer cells reduced tumor formation in mice by 80%. Modulation of miR-181a levels showed an inverse correlation with the proto-oncogene KRAS both on mRNA and protein level by direct interaction. Knockdown of KRAS mimicked the anti-proliferative effects of miR-181a overexpression in patient-derived SCC cells and abolished the enhanced viability of HaCaT cells following miR-181a knockdown. Furthermore, phospho-ERK levels correlated with KRAS levels, suggesting that the observed effects were mediated via the MAPK signaling pathway. miR-181a seemed regulated during keratinocyte differentiation probably in order to amplify the tumor suppressive character of differentiation. Taken together, miR-181a plays a crucial tumor suppressive role in SCC by targeting KRAS and could be a promising candidate for a miRNA based therapy.

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Section: Discussionsupporting

confidence: 73%

miR-181a decelerates proliferation in cutaneous squamous cell carcinoma by targeting the proto-oncogene KRAS

et al. 2017

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“…Most of these sites overlap with the seed sequence of miR766-3p for which 23 binding sites are present (Figure S4). miR23b-3p is an important regulator of keratinocyte differentiation making it likely that circZNF91 exerts its function in differentiation by sponging this miR [ 42 ]. The binding sites for miR23b-3p were not predicted by CircInteractome, but have previously also been found by Guo and colleagues [ 6 ].…”

Section: Resultsmentioning

confidence: 99%

“…circZNF91 contains most of the host gene's 3’ UTR and has 24 and 23 individual binding sites for miR-23b-3p and miR-766-3p, respectively. miR-23b-3p has been directly implicated in differentiation of EpSCs to keratinocytes [ 42 ], whereas miR-766 targets DNMT3B [ 49 ] and is upregulated in cutaneous squamous cell carcinoma [ 50 ].…”

Section: Discussionmentioning

confidence: 99%

Circular RNAs are abundantly expressed and upregulated during human epidermal stem cell differentiation

et al. 2017

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The expression patterns of endogenous circular RNA (circRNA) molecules during epidermal stem cell (EpSC) differentiation have not previously been explored. Here, we show that circRNAs are abundantly expressed in EpSCs and that their expression change dramatically during differentiation in a coordinated manner. Overall, circRNAs are expressed at higher levels in the differentiated cells, and many upregulated circRNAs are derived from developmental genes, including four different circRNAs from DLG1. The observed changes in circRNA expression were largely independent of host gene expression, and circRNAs independently upregulated upon differentiation are more prone to AGO2 binding and have more predicted miRNA binding sites compared to stably expressed circRNAs. In particular, upregulated circRNAs from the HECTD1 and ZNF91 genes have exceptionally high numbers of AGO2 binding sites and predicted miRNA target sites, and circZNF91 contains 24 target sites for miR-23b-3p, which is known to play important roles in keratinocyte differentiation. We also observed that upregulated circRNAs are less likely to be flanked by homologues inverted Alu repeats compared to stably expressed circRNAs. This coincide with DHX9 being upregulated in the differentiated keratinocytes. Finally, none of the circRNAs upregulated upon differentiation were also upregulated upon DNMT3A or DNMT3B knockdown, making it unlikely that epigenetic mechanisms are governing the observed circRNA expression changes. Together, we provide a map of circRNA expression in EpSCs and their differentiated counterparts and shed light on potential function and regulation of differentially expressed circRNAs.

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“…We and others have previously identified key regulators of this balance, and especially transcription factors such as GATA3, RUNX1 and P63 [ 2 – 4 ], some of which are dis-regulated in aged skin [ 5 ]. In the past ten years, non-coding RNAs emerged as additional regulators of epidermal homeostasis, with the identification of numerous long non-coding RNAs [ 6 ] and microRNAs [ 7 , 8 ] involved in the control of epidermal differentiation. MicroRNAs (miRNAs) are short non-coding RNAs involved in almost all cellular processes, including proliferation, differentiation, cell-cell communication and stress response.…”

Section: Introductionmentioning

confidence: 99%

An expression screen for aged-dependent microRNAs identifies miR-30a as a key regulator of aging features in human epidermis

Muther

Jobeili²,

Garion

et al. 2017

Aging

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The mechanisms affecting epidermal homeostasis during aging remain poorly understood. To identify age-related microRNAs, a class of non-coding RNAs known to play a key role in the regulation of epidermal homeostasis, an exhaustive miRNA expression screen was performed in human keratinocytes from young or elderly subjects. Many microRNAs modulated by aging were identified, including miR-30a, in which both strands were overexpressed in aged cells and epidermal tissue. Stable MiR-30a over-expression strongly impaired epidermal differentiation, inducing severe barrier function defects in an organotypic culture model. A significant increase was also observed in the level of apoptotic cells in epidermis over-expressing miR-30a. Several gene targets of miR-30a were identified in keratinocytes, including LOX (encoding lysyl oxidase, a regulator of the proliferation/differentiation balance of keratinocytes), IDH1 (encoding isocitrate dehydrogenase, an enzyme of cellular metabolism) and AVEN (encoding a caspase inhibitor). Direct regulation of LOX, IDH1 and AVEN by miR-30a was confirmed in human keratinocytes. They were, moreover, observed to be repressed in aged skin, suggesting a possible link between miR-30a induction and skin-aging phenotype. This study revealed a new miRNA actor and deciphered new molecular mechanisms to explain certain alterations observed in epidermis during aging and especially those concerning keratinocyte differentiation and apoptosis.

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MicroRNA‐23b‐3p regulates human keratinocyte differentiation through repression of TGIF1 and activation of the TGF‐ß–SMAD2 signalling pathway

Cited by 25 publications

References 48 publications

miR-181a decelerates proliferation in cutaneous squamous cell carcinoma by targeting the proto-oncogene KRAS

miR-181a decelerates proliferation in cutaneous squamous cell carcinoma by targeting the proto-oncogene KRAS

Circular RNAs are abundantly expressed and upregulated during human epidermal stem cell differentiation

An expression screen for aged-dependent microRNAs identifies miR-30a as a key regulator of aging features in human epidermis

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