Identification of miR-141 as a Regulator of Epidermal Homeostasis.

MicroRNAs, small endogenous noncoding RNAs, are involved in the regulation of epidermal homeostasis. Among them, miR-203 was the most described and expressed in human epidermis, promoting keratinocyte (KC) differentiation by repressing genes involved in proliferation. To identify other microRNAs involved in this process, the miRNomes of normal human KCs cultured in monolayer (2-dimensional) or in 3-dimensional reconstructed skin were compared.

Detecting subtle transcriptomic perturbations induced by lncRNAs knock-down in single-cell CRISPRi screening using a new sparse supervised autoencoder neural network.

Single-cell CRISPR-based transcriptome screens are potent genetic tools for concomitantly assessing the expression profiles of cells targeted by a set of guides RNA (gRNA), and inferring target gene functions from the observed perturbations. However, due to various limitations, this approach lacks sensitivity in detecting weak perturbations and is essentially reliable when studying master regulators such as transcription factors. To overcome the challenge of detecting subtle gRNA induced transcriptomic perturbations and classifying the most responsive cells, we developed a new supervised autoencoder neural network method.

Identification and functional validation of SRC and RAPGEF1 as new direct targets of miR-203, involved in regulation of epidermal homeostasis.

The epidermis is mostly composed of keratinocytes and forms a protecting barrier against external aggressions and dehydration. Epidermal homeostasis is maintained by a fine-tuned balance between keratinocyte proliferation and differentiation. In the regulation of this process, the keratinocyte-specific miR-203 microRNA is of the outmost importance as it promotes differentiation, notably by directly targeting and down-regulating mRNA expression of genes involved in keratinocyte proliferation, such as ΔNp63, Skp2 and Msi2.

KRAS and NRAS Translation Is Increased upon MEK Inhibitors-Induced Processing Bodies Dissolution.

Overactivation of the mitogen-activated protein kinase (MAPK) pathway is a critical driver of many human cancers. However, therapies directly targeting this pathway lead to cancer drug resistance. Resistance has been linked to compensatory RAS overexpression, but the mechanisms underlying this response remain unclear.

A role for metformin in the treatment of Dupuytren disease?

Dupuytren disease (DD) is a hand-localized fibrotic disorder characterized by a scar-like, collagen-rich cord. Treatment usually comprises surgical removal of the cord, but is associated with a high relapse rate, in some cases requiring finger amputation. There is currently no consensual medical approach for treating DD.

New technologies for improved relevance in miRNA research.

After a number of years of research in the field of miRNA, the robustness and biological relevance of many published articles is increasingly being questioned. We propose the use of new RNA-seq approaches, genome editing technologies, and updated public databases to improve the quality, reliability, and relevance of published data.

Cutaneous Squamous Cell Carcinoma Development Is Associated with a Temporal Infiltration of ILC1 and NK Cells with Immune Dysfunctions.

NK cells and tissue-resident innate lymphoid cells (ILCs) are innate effectors found in the skin. To investigate their temporal dynamics and specific functions throughout the development of cutaneous squamous cell carcinoma (cSCC), we combined transcriptomic and immunophenotyping analyses in mouse and human cSCCs. We identified an infiltration of NK cells and ILC1s as well as the presence of a few ILC3s.

Correction: The nuclear hypoxia-regulated NLUCAT1 long non-coding RNA contributes to an aggressive phenotype in lung adenocarcinoma through regulation of oxidative stress.

Lung cancer is the leading cause of cancer death worldwide, with poor prognosis and a high rate of recurrence despite early surgical removal. Hypoxic regions within tumors represent sources of aggressiveness and resistance to therapy. Although long non-coding RNAs (lncRNAs) are increasingly recognized as major gene expression regulators, their regulation and function following hypoxic stress are still largely unexplored.

Identification of oncolytic vaccinia restriction factors in canine high-grade mammary tumor cells using single-cell transcriptomics.

Mammary carcinoma, including triple-negative breast carcinomas (TNBC) are tumor-types for which human and canine pathologies are closely related at the molecular level. The efficacy of an oncolytic vaccinia virus (VV) was compared in low-passage primary carcinoma cells from TNBC versus non-TNBC. Non-TNBC cells were 28 fold more sensitive to VV than TNBC cells in which VV replication is impaired.

Tumor-Associated Neutrophils Dampen Adaptive Immunity and Promote Cutaneous Squamous Cell Carcinoma Development.

Cutaneous squamous cell carcinoma (cSCC) development has been linked to immune dysfunctions but the mechanisms are still unclear. Here, we report a progressive infiltration of tumor-associated neutrophils (TANs) in precancerous and established cSCC lesions from chemically induced skin carcinogenesis. Comparative in-depth gene expression analyses identified a predominant protumor gene expression signature of TANs in lesions compared to their respective surrounding skin.

The nuclear hypoxia-regulated NLUCAT1 long non-coding RNA contributes to an aggressive phenotype in lung adenocarcinoma through regulation of oxidative stress.

Lung cancer is the leading cause of cancer death worldwide, with poor prognosis and a high rate of recurrence despite early surgical removal. Hypoxic regions within tumors represent sources of aggressiveness and resistance to therapy. Although long non-coding RNAs (lncRNAs) are increasingly recognized as major gene expression regulators, their regulation and function following hypoxic stress are still largely unexplored.

Tetrafunctional Block Copolymers Promote Lung Gene Transfer in Newborn Piglets.

Tetrafunctional block copolymers are molecules capable of complexing DNA. Although ineffective in vitro, studies in mice have shown that the tetrafunctional block copolymer 704 is a more efficient lung gene transfer agent than the cationic liposome GL67A, previously used in a phase II clinical trial in cystic fibrosis patients. In the present study, we compared the gene transfer capacity of the 704-DNA formulation and a cationic liposome-DNA formulation equivalent to GL67A in a larger-animal model, the newborn piglet.

Impact of MicroRNAs in the Cellular Response to Hypoxia.

In mammalian cells, hypoxia, or inadequate oxygen availability, regulates the expression of a specific set of MicroRNAs (MiRNAs), termed "hypoxamiRs." Over the past 10 years, the appreciation of the importance of hypoxamiRs in regulating the cellular adaptation to hypoxia has grown dramatically. At the cellular level, each hypoxamiR, including the master hypoxamiR MiR-210, can simultaneously regulate expression of multiple target genes in order to fine-tune the adaptive response of cells to hypoxia.

A new long noncoding RNA (lncRNA) is induced in cutaneous squamous cell carcinoma and down-regulates several anticancer and cell differentiation genes in mouse.

Keratinocyte-derived cutaneous squamous cell carcinoma (cSCC) is the most common metastatic skin cancer. Although some of the early events involved in this pathology have been identified, the subsequent steps leading to tumor development are poorly defined. We demonstrate here that the development of mouse tumors induced by the concomitant application of a carcinogen and a tumor promoter (7,12-dimethylbenz[]anthracene (DMBA) and 12--tetradecanoylphorbol-13-acetate (TPA), respectively) is associated with the up-regulation of a previously uncharacterized long noncoding RNA (lncRNA), termed AK144841.

Identification of a novel PPARβ/δ/miR-21-3p axis in UV-induced skin inflammation.

Although excessive exposure to UV is widely recognized as a major factor leading to skin perturbations and cancer, the complex mechanisms underlying inflammatory skin disorders resulting from UV exposure remain incompletely characterized. The nuclear hormone receptor PPARβ/δ is known to control mouse cutaneous repair and UV-induced skin cancer development. Here, we describe a novel PPARβ/δ-dependent molecular cascade involving TGFβ1 and miR-21-3p, which is activated in the epidermis in response to UV exposure.

miR-193b/365a cluster controls progression of epidermal squamous cell carcinoma.

Incidence of cutaneous squamous cell carcinomas (cSCCs) constantly increases in the Caucasian population. Developing preferentially on precancerous lesions such as actinic keratoses due to chronic sunlight exposure, cSCCs result from the malignant transformation of keratinocytes. Although a resection of the primary tumor is usually curative, a subset of aggressive cSCCs shows a high risk of recurrence and metastases.

MicroRNA target identification: lessons from hypoxamiRs.

Significance: MicroRNAs (miRNAs) are small noncoding RNAs that have emerged as key regulators of many physiological and pathological processes, including those relevant to hypoxia such as cancer, neurological dysfunctions, myocardial infarction, and lung diseases.

Recent Advances: During the last 5 years, miRNAs have been shown to play a role in the regulation of the cellular response to hypoxia. The identification of several bona fide targets of these hypoxamiRs has underlined their pleiotropic functions and the complexity of the molecular rules directing miRNA::target transcript pairing.

Tumor suppressor function of miR-483-3p on squamous cell carcinomas due to its pro-apoptotic properties.

The frequent alteration of miRNA expression in many cancers, together with our recent reports showing a robust accumulation of miR-483-3p at the final stage of skin wound healing, and targeting of CDC25A leading to an arrest of keratinocyte proliferation, led us to hypothesize that miR-483-3p could also be endowed with antitumoral properties. We tested that hypothesis by documenting the in vitro and in vivo impacts of miR-483-3p in squamous cell carcinoma (SCC) cells. miR-483-3p sensitized SCC cells to serum deprivation- and drug-induced apoptosis, thus exerting potent tumor suppressor activities.

"Seed-Milarity" confers to hsa-miR-210 and hsa-miR-147b similar functional activity.

Specificity of interaction between a microRNA (miRNA) and its targets crucially depends on the seed region located in its 5'-end. It is often implicitly considered that two miRNAs sharing the same biological activity should display similarity beyond the strict six nucleotide region that forms the seed, in order to form specific complexes with the same mRNA targets. We have found that expression of hsa-miR-147b and hsa-miR-210, though triggered by different stimuli (i.

miR-483-3p controls proliferation in wounded epithelial cells.

The mechanisms that regulate keratinocyte migration and proliferation in wound healing remain largely unraveled, notably regarding possible involvements of microRNAs (miRNAs). Here we disclose up-regulation of miR-483-3p in 2 distinct models of wound healing: scratch-injured cultures of human keratinocytes and wounded skin in mice. miR-483-3p accumulation peaks at the final stage of the wound closure process, consistent with a role in the arrest of "healing" progression.

Antifibroblast antibodies in systemic sclerosis induce fibroblasts to produce profibrotic chemokines, with partial exploitation of toll-like receptor 4.

Objective: Previous studies have revealed the presence of IgG antifibroblast antibodies (AFAs) capable of binding to the surface of fibroblasts in systemic sclerosis (SSc) sera. Since chemokines may directly or indirectly affect the development of fibrosis, this study was undertaken to investigate the production of chemokines induced by AFAs in fibroblasts, and to characterize the signaling pathways and surface molecules involved.

Methods: AFA-positive and AFA-negative IgG were tested on fibroblasts.

HIF1 transcription factor regulates laminin-332 expression and keratinocyte migration.

Epidermal wound repair is a complex process involving the fine orchestrated regulation of crucial cell functions, such as proliferation, adhesion and migration. Using an in vitro model that recapitulates central aspects of epidermal wound healing, we demonstrate that the transcription factor HIF1 is strongly stimulated in keratinocyte cultures submitted to mechanical injury. Signals generated by scratch wounding stabilise the HIF1alpha protein, which requires activation of the PI3K pathway independently of oxygen availability.

Silencing of hSlo potassium channels in human osteosarcoma cells promotes tumorigenesis.

Potassium channels, the most diverse superfamily of ion channels, have recently emerged as regulators of carcinogenesis, thus introducing possible new therapeutic strategies in the fight against cancer. In particular, the large conductance Ca(2+)-activated K(+) channels, often referred to as BK channels, are at the crossroads of several tumor-associated processes such as cell proliferation, survival, secretion and migration. Despite the high BK channel expression in osteosarcoma (OS), their function has not yet been investigated in this malignant bone pathology.

Tissue engineering for full-thickness burns: a dermal substitute from bench to bedside.

Our aim was to obtain a viable and easily available dermal substitute (DS) for the definitive coverage of full-thickness burns. A DS composed of a collagen-glycosaminoglycan-chitosan dermal matrix (DM) colonized with foreskin fibroblasts (FF) is described. FF-colonized DS were compared to the DM seeded with adult dermal fibroblasts (DF).