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Metabolic rewiring in keratinocytes by miR-31-5p identifies therapeutic intervention for psoriasis

ABSTRACT: Besides genetic alterations, the cellular environment also determines disease onset and progression. When different cell types contribute to disease outcome, this imposes environmental challenges as different cell types likely differ in their extracellular dependencies. Hsa-microRNA-31-5p (miR-31), is highly expressed in keratinocytes of psoriatic skin, and we show that expression in keratinocytes is induced by limited glucose availability and enables increased survival under limiting glucose conditions, by increasing glutamine metabolism. In addition, miR-31 expression results in secretion of specific metabolites (aspartate and glutamate) but also secretion of immuno-modulatory factors. We show that this miR-31-induced secretory phenotype is sufficient to induce Th17 cell differentiation, a hallmark of psoriasis. Inhibitors of miR31-induced metabolic rewiring and metabolic crosstalk with immune cells alleviate psoriasis pathology in a mouse model of psoriasis. Together our data illustrate an emerging concept of metabolic interaction across cell compartments that characterizes disease development, which can be employed to design effective treatment options for disease, as shown here for psoriasis.

SUBMITTER: Mr. Maojie Wang

PROVIDER: S-SCDT-10_15252-EMMM_202215674 | biostudies-other |

REPOSITORIES: biostudies-other

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Hsa-miR-31-5p controls a metabolic switch in psoriatic keratinocytes that identifies therapeutic intervention

Project description:Next to genetic alterations, it is being recognized that the cellular environment also acts as a major determinant in onset and progression of disease. In cases where different cell types contribute to the final disease outcome, this imposes environmental challenges as different cell types likely differ in their extracellular dependencies. A number of skin diseases, including psoriasis is characterized by a combination of keratinocyte hyperproliferation and immune cell activation. Activation of immune cells involves increased glucose consumption thereby intrinsicly limiting glucose availability for other cell types. Thus, these type of skin diseases require metabolic adaptations that enable coexistence between hyperproliferative keratinocytes and activated immune cells in a nutrient-limited environment. Hsa-microRNA-31-5p (miR-31) is highly expressed in keratinocytes within the psoriatic skin. Here we show that miR-31 expression in keratinocytes is induced by limited glucose availability and enables increased survival of keratinocytes under limiting glucose conditions, by increasing glutamine metabolism. In addition, miR-31 induced glutamine metabolism results in secretion of specific metabolites (aspartate and glutamate) but also secretion of immuno-modulatory factors. We show that this miR-31-induced secretory phenotype is sufficient to induce Th17 cell differentiation, a hallmark of psoriasis. Inhibition of glutaminase (GLS) using CB-839 impedes miR31-induced metabolic rewiring and secretion of immuno-modulatory factors. Concordantly, pharmacological targeting of GLS alleviated psoriasis pathology in a mouse model of psoriasis. Together our data illustrate an emerging concept of metabolic interaction across cell compartments that characterizes disease development, which can be employed to design effective treatment options for disease, as shown here for psoriasis.

2023-02-06 | PXD029030 | Pride

PETACC-8 miR-31-3p and miR-31-5p Ancillary Study

Project description:This is a prospective-retrospective study to determine if the expression of the miRNA’s miR-31-3p and miR-31-5p are prognostic of patient outcomes or predictive of the benefit from anti-EGFR therapy in stage III Colon Cancer. The present study will utilize FFPE tumor samples collected from patients enrolled in the PETACC-8 study conducted by the Fédération Francophone de Cancérologie Digestive (FFCD). This phase 3 clinical trial prospectively randomized fully resected stage III colon cancer patients to receive adjuvant treatment with either FOLFOX-4 plus cetuximab or FLOFOX-4 alone.

| 2260465 | ecrin-mdr-crc

miR-31-5p Is a Potential Circulating Biomarker and Therapeutic Target for Oral Cancer.

Project description:MicroRNAs have been proposed as novel biomarkers for the diagnosis and treatment of many types of cancer. The levels of five candidate microRNAs (miRNAs) (miR-99a-5p, miR-31-5p, miR-138-5p, miR-21-5p, and miR-375-3p) in sera from oral cancer patients and paired tumor and normal tissues were detected by real-time qPCR. The diagnostic power of these miRNAs was analyzed by receiver operating characteristic (ROC) curves. Patient-derived xenograft (PDX) models of oral cancer were established and utilized to verify the potential therapeutic effect of miR-31-5p. Candidate miRNAs were screened from our previous studies and verified in 11 paired oral cancer and adjacent normal tissues. Only serum miR-31-5p levels were significantly different between oral cancer patients and healthy controls and between pre- and postoperative patients. Based on the logistic regression model, this panel of five miRNAs distinguished oral cancer patients from healthy control, with an area under the ROC curve (AUC) of 0.776 (sensitivity = 76.8% and specificity = 73.6%). Furthermore, a miR-31-5p mimic enhanced the proliferation of normal epithelial cells, and antagomiR-31-5p inhibited the proliferation of oral cancer cells in vitro. In vivo, antagomiR-31-5p significantly inhibited tumor growth in oral cancer PDX models. Our findings suggest that circulating miR-31-5p might act as an independent biomarker for oral cancer diagnosis and could serve as a therapeutic target for oral cancer.

| S-EPMC6495075 | biostudies-literature

How miR-31-5p and miR-33a-5p Regulates SP1/CX43 Expression in Osteoarthritis Disease: Preliminary Insights.

Project description:Osteoarthritis (OA) is a degenerative bone disease that involved micro and macro-environment of joints. To date, there are no radical curative treatments for OA and novel therapies are mandatory. Recent evidence suggests the role of miRNAs in OA progression. In our previous studies, we demonstrated the role of miR-31-5p and miR-33a families in different bone regeneration signaling. Here, we investigated the role of miR-31-5p and miR-33a-5p in OA progression. A different expression of miR-31-5p and miR-33a-5p into osteoblasts and chondrocytes isolated from joint tissues of OA patients classified in based on different Kellgren and Lawrence (KL) grading was highlighted; and through a bioinformatic approach the common miRNAs target Specificity proteins (Sp1) were identified. Sp1 regulates the expression of gap junction protein Connexin43 (Cx43), which in OA drives the modification of i) osteoblasts and chondrocytes genes expression, ii) joint inflammation cytokines releases and iii) cell functions. Concerning this, thanks to gain and loss of function studies, the possible role of Sp1 as a modulator of CX43 expression through miR-31-5p and miR-33a-5p action was also evaluated. Finally, we hypothesize that both miRNAs cooperate to modulate the expression of SP1 in osteoblasts and chondrocytes and interfering, consequently, with CX43 expression, and they might be further investigated as new possible biomarkers for OA.

| S-EPMC7957523 | biostudies-literature

High miR-31-5p expression promotes colon adenocarcinoma progression by targeting TNS1.

Project description:Overexpression of the miR-31-5p contributes to tumorigenesis and metastasis in diverse neoplasms. In this study, we evaluated expression of miR-31-5p in patients with colon adenocarcinoma (COAD). We found that miR-31-5p was overexpressed in four cohorts (GSE30454, GSE41655, GSE18392, GSE108153) of COAD patients. Importantly, a LinkedOmics analysis revealed that high miR-31-5p expression was associated with poor overall survival of COAD patients. At total of 133 putative target genes of miR-31-5p were identified from TargetScan, miRDB, and TargetMiner. After integrating the target genes with 1,556 deregulated genes in COAD, 8 were acquired that may be targeted by miR-31-5p and contribute to COAD progression. Among these, tensin 1 (TNS1) showed the greatest prognostic ability in COAD and was strongly correlated with M2 macrophages, regulatory T cells, and other immune cells. These findings indicate that, in COAD, miR-31-5p is a potential prognostic factor that affects immune infiltration by targeting TNS1.

| S-EPMC7202535 | biostudies-literature

Metabolic Rewiring in Radiation Oncology Toward Improving the Therapeutic Ratio.

Project description:To meet the anabolic demands of the proliferative potential of tumor cells, malignant cells tend to rewire their metabolic pathways. Although different types of malignant cells share this phenomenon, there is a large intracellular variability how these metabolic patterns are altered. Fortunately, differences in metabolic patterns between normal tissue and malignant cells can be exploited to increase the therapeutic ratio. Modulation of cellular metabolism to improve treatment outcome is an emerging field proposing a variety of promising strategies in primary tumor and metastatic lesion treatment. These strategies, capable of either sensitizing or protecting tissues, target either tumor or normal tissue and are often focused on modulating of tissue oxygenation, hypoxia-inducible factor (HIF) stabilization, glucose metabolism, mitochondrial function and the redox balance. Several compounds or therapies are still in under (pre-)clinical development, while others are already used in clinical practice. Here, we describe different strategies from bench to bedside to optimize the therapeutic ratio through modulation of the cellular metabolism. This review gives an overview of the current state on development and the mechanism of action of modulators affecting cellular metabolism with the aim to improve the radiotherapy response on tumors or to protect the normal tissue and therefore contribute to an improved therapeutic ratio.

| S-EPMC8143268 | biostudies-literature

Circ-BPTF promotes bladder cancer progression and recurrence through the miR-31-5p/RAB27A axis.

Project description:Circ-BPTF (hsa_circ_0000799) is a novel circular RNA derived from BPTF exons. Although BPTF is a well-studied predecessor gene, the characteristics and functions of circ-BPTF have not yet been reported. Here, we show that expression of circ-BPTF is increased in bladder cancer (BCa) tissues and cell lines compared with noncancerous tissues and cell lines. Consistently, BCa patients with higher expression levels of circ-BPTF were found to have higher tumor grades and poorer prognosis. Functionally, knockdown of circ-BPTF inhibited tumor progression in vitro and in vivo. Mechanistically, a target microRNA of circ-BPTF was confirmed to be miR-31-5p, and miR-31-5p mimics partially reversed the effect of circ-BPTF. Furthermore, RAB27A was predicted and shown to be a target of miR-31-5p, and circ-BPTF attenuated the anti-oncogenic effect of miR-31-5p and consequently enhanced RAB27A expression. In summary, our findings reveal that circ-BPTF promotes BCa progression through the miR-31-5p/RAB27A axis, suggesting that circ-BPTF may be a potential target for BCa treatment.

| S-EPMC6128440 | biostudies-other

N-Myc-induced metabolic rewiring creates novel therapeutic vulnerabilities in neuroblastoma.

Project description:N-Myc is a transcription factor that is aberrantly expressed in many tumor types and is often correlated with poor patient prognosis. Recently, several lines of evidence pointed to the fact that oncogenic activation of Myc family proteins is concomitant with reprogramming of tumor cells to cope with an enhanced need for metabolites during cell growth. These adaptions are driven by the ability of Myc proteins to act as transcriptional amplifiers in a tissue-of-origin specific manner. Here, we describe the effects of N-Myc overexpression on metabolic reprogramming in neuroblastoma cells. Ectopic expression of N-Myc induced a glycolytic switch that was concomitant with enhanced sensitivity towards 2-deoxyglucose, an inhibitor of glycolysis. Moreover, global metabolic profiling revealed extensive alterations in the cellular metabolome resulting from overexpression of N-Myc. Limited supply with either of the two main carbon sources, glucose or glutamine, resulted in distinct shifts in steady-state metabolite levels and significant changes in glutathione metabolism. Interestingly, interference with glutamine-glutamate conversion preferentially blocked proliferation of N-Myc overexpressing cells, when glutamine levels were reduced. Thus, our study uncovered N-Myc induction and nutrient levels as important metabolic master switches in neuroblastoma cells and identified critical nodes that restrict tumor cell proliferation.

| S-EPMC7188804 | biostudies-literature

Identification of Tumor Suppressive Genes Regulated by <i>miR-31-5p</i> and <i>miR-31-3p</i> in Head and Neck Squamous Cell Carcinoma.

Project description:We identified the microRNA (miRNA) expression signature of head and neck squamous cell carcinoma (HNSCC) tissues by RNA sequencing, in which 168 miRNAs were significantly upregulated, including both strands of the miR-31 duplex (miR-31-5p and miR-31-3p). The aims of this study were to identify networks of tumor suppressor genes regulated by miR-31-5p and miR-31-3p in HNSCC cells. Our functional assays showed that inhibition of miR-31-5p and miR-31-3p attenuated cancer cell malignant phenotypes (cell proliferation, migration, and invasion), suggesting that they had oncogenic potential in HNSCC cells. Our in silico analysis revealed 146 genes regulated by miR-31 in HNSCC cells. Among these targets, the low expression of seven genes (miR-31-5p targets: CACNB2 and IL34; miR-31-3p targets: CGNL1, CNTN3, GAS7, HOPX, and PBX1) was closely associated with poor prognosis in HNSCC. According to multivariate Cox regression analyses, the expression levels of five of those genes (CACNB2: p = 0.0189; IL34: p = 0.0425; CGNL1: p = 0.0014; CNTN3: p = 0.0304; and GAS7: p = 0.0412) were independent prognostic factors in patients with HNSCC. Our miRNA signature and miRNA-based approach will provide new insights into the molecular pathogenesis of HNSCC.

| S-EPMC8227492 | biostudies-literature

Gene expression profiles of U87 cells after transfection with hsa-miR-145-5p and 31-5p

Project description:We analyzed the expression profiles of hsa-miR-145-5p or hsa-miR-31-5p-targeting genes relating to invasion or migration after co-overexpression of hsa-miR-145-5p and 31-5p Gene expression profiles of U87 cells after co-transfection with hsa-miR-145-5p and 31-5p mimics, and U87 cells after transfection miR mimic negative control

2016-06-23 | E-GEOD-83643 | biostudies-arrayexpress

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