|Year : 2021 | Volume
| Issue : 2 | Page : 67-73
Diagnostic value of microRNA-106a-5p in patients with psoriasis and its regulatory role in inflammatory responses
Xiaolin Dr. Miao1, Xinyun Tong2, Jingsang Hu1, Juan Wang3
1 Department of Dermatology and Venereology, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang, China
2 Department of Dermatology and Venereology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
3 Department of Laboratory, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang, China
|Date of Submission||27-Oct-2020|
|Date of Decision||20-Jan-2021|
|Date of Acceptance||24-Jan-2021|
|Date of Web Publication||23-Jun-2021|
Xiaolin Dr. Miao
Department of Dermatology and Venereology, Tongde Hospital of Zhejiang Province, 234 Gucui Road in Xihu District, Hangzhou, Zhejiang 310 012
Source of Support: None, Conflict of Interest: None
Background: Psoriasis is a multifactorial, recurring, and chronic inflammatory skin disease. Objectives: This study was designed to explore the potential role of microRNA-106a-5p (miR-106a-5p) in psoriasis. Methods: The expression levels of miR-106a-5p in the serum of psoriasis patients and healthy individuals were detected by quantitative real-time polymerase chain reaction. The diagnostic value of miR-106a-5p in serum was evaluated by the receiver operating characteristic (ROC) curve. The levels of interleukin-22 (IL-22), IL-17A, and tumor necrosis factor-alpha (TNF-alpha) were determined by enzyme-linked immunosorbent assay. Dual-luciferase reporter assay was used for the target gene verification. Results: The serum expression of miR-106a-5p was found to be upregulated in psoriasis patients. ROC curve showed that miR-106a-5p had high specificity and sensitivity in the diagnosis of psoriasis. The correlation between the serum expression level of miR-106a-5p and Psoriasis Area and Severity Index was positive. The relative expression levels of IL-17A, IL-22, and TNF-alpha in serum of psoriasis patients were significantly upregulated compared with that in healthy controls, and showed a positive association with serum miR-106a-5p levels. Cell experiments demonstrated that upregulation of miR-106a-5p could promote cell proliferation, and the levels of IL-22, IL-17A, and TNF-alpha were upregulated significantly in M5-induced HaCaT cells. Phosphatase and tensin homolog was proved to be the target gene of miR-106a-5p. Conclusion: Considering the novel and vital role in psoriasis progression, miR-106a-5p is expected to be a new potent target for the treatment of psoriasis. MiR-106-5p was expected to use for more immunity diseases research and therapy.
Keywords: Biomarker, microRNA-106a-5p, Psoriasis Area and Severity Index, proliferation, psoriasis
|How to cite this article:|
Miao XD, Tong X, Hu J, Wang J. Diagnostic value of microRNA-106a-5p in patients with psoriasis and its regulatory role in inflammatory responses. Dermatol Sin 2021;39:67-73
|How to cite this URL:|
Miao XD, Tong X, Hu J, Wang J. Diagnostic value of microRNA-106a-5p in patients with psoriasis and its regulatory role in inflammatory responses. Dermatol Sin [serial online] 2021 [cited 2021 Aug 3];39:67-73. Available from: https://www.dermsinica.org/text.asp?2021/39/2/67/319150
| Introduction|| |
Psoriasis, a chronic inflammatory disease of the skin, is characterized by well-demarcated, raised, and scaling skin lesions., The interaction of epidermal cells and cytokines promotes the proliferation of abnormal keratinocytes, angiogenesis, and the development and maturation of psoriasis. Psoriasis is a complex disorder requiring a genetic susceptibility and an environmental trigger. It is commonly used as a model of immune-mediated diseases. The gene expression profile of the affected skin has made people deeply understand the pathogenesis of psoriasis. However, the mechanism leading to psoriasis-specific mRNA expression is unclear.
MicroRNAs (miRNAs), a class of small noncoding RNA molecules, are 18–25 nucleotides in length generally. More and more evidence has confirmed the role of miRNAs in normal biological processes and human disease pathogenesis through posttranscriptional regulation of gene expression. Some miRNAs have been found to have an effect on psoriasis.,, MicroRNA-106a-5p (miR-106a-5p) is a member of miR-17 precursor family. Recently, it has been reported that miR-106a-5p is connected with tumor growth and immune response as well as suppressing tumor necrosis factor (TNF)-α-induced transcription of pro-inflammatory genes., Torri et al. explored the differences in the expression levels of circulating miRNAs among patients with psoriasis and healthy individuals, in which the serum expression of miR-106a-5p was significantly increased. In addition, a recent study has also reported that miR-106a-5p is highly expressed in the lesional skin of psoriasis patients. These findings prompted us to fully investigate the role of miR-106a-5p in psoriasis patients and its effect on inflammatory response.
In our study, we detected the serum level of miR-106a-5p in patients with psoriasis, and further evaluated its association with the clinical severity of psoriasis. Furthermore, the role of miR-106a-5p in inflammatory responses in keratinocytes was investigated. We aimed to provide a basis for finding potential biomarkers for evaluating the onset and severity of psoriasis, and investigating the molecular mechanisms underlying psoriasis.
| Materials and Methods|| |
Sixty-seven patients with psoriasis who had no previous treatment for psoriasis (mean age: 43.33 ± 12.16 years) and 70 healthy controls (mean age: 48.37 ± 14.99 years) were recruited from September 2015 to January 2018 in Tongde Hospital of Zhejiang Province. Patients with cardiovascular and cerebrovascular diseases, autoimmune diseases and other serious systemic diseases, pregnancy, lactation, and so on were excluded. All patients enrolled in our study underwent no systemic treatment including glucocorticoids, immunosuppressive drugs, or phototherapy at least 1 month before the Psoriasis Area and Severity Index (PASI) score evaluation and sample collection period. To evaluate disease type and severity, patients were all examined by a dermatologist. PASI scores of each patient were detected, and individuals with PASI index ranging from 1 to 10 were considered as mild psoriasis, patients with PASI >10 as moderate or severe psoriasis.
Informed consent was obtained from every patient with psoriasis and healthy individuals, and this study was approved by the Ethics Committee of Tongde Hospital of Zhejiang Province (201503).
Human keratinocyte HaCaT cells were purchased from Cell Lines Service (Eppelheim, Germany). The cells were cultured in Dulbecco's modified Eagle's medium (Invitrogen, Carlsbad, CA, USA) supplemented with 10% fetal bovine serum (Sigma-Aldrich, St. Louis, MO, USA), and placed in a humidified atmosphere of 5% CO2 at 37°C. TNF-alpha, IL-17A, IL-22, IL-1alpha, and Oncostatin-M (10 ng/mL, Prospec, East Brunswick, NJ, USA) were included in the mixture of five pro-inflammatory cytokines (M5). HaCaT cells were induced with M5, causing inflammation response and showing kinds of symptoms of psoriasis. The culture medium was changed every day. The cells were disaggregated and subcultured at a confluency of 70%–90%.
HaCaT cells were transfected with miR-106a-5p mimic, miR-106a-5p inhibitor, and its negative control (miR-NC) using the Lipofectamine 2000 reagent (Invitrogen) in accordance with manufacturer protocols. The miR-106a-5p mimic, miR-106a-5p inhibitor, and miR-NC were obtained from GenePharma (Shanghai, China). The quantitative real-time polymerase chain reaction (qRT-PCR) was performed for measuring the transfection efficiency. After 24-h transfection, HaCaT cells were treated with M5 (a cocktail of cytokines) for 24 h to induce psoriatic inflammation-like condition.
Quantitative real-time polymerase chain reaction assay
According to the manufacturer's instructions, total RNA was isolated using TRIzol reagent (Invitrogen, USA). miR-106a-5p was detected by reverse transcription of miRNA using a TaqMan MicroRNA Reverse Transcription Kit (Applied Biosystems, CA, USA), and measured by RT-PCR with the TaqMan MicroRNA Assay kit (Applied Biosystems, CA, USA). U6 small nuclear RNA (U6 snRNA) was quantified as an endogenous reference. Experiments were performed in triplicate and run at least three times.
Enzyme-linked immunosorbent assay
Reference to the instructions of the manufacturer, the serum levels of IL-22, IL-17A, and TNF-alpha were detected by specific enzyme-linked immunosorbent kits (Beyotime Biotechnology, Shanghai, China). The absorbance was determined by an enzyme labeling instrument (SpectraMAX 340, Molecular Devices, Sunnyvale, CA, USA) at 450 nm.
Cell proliferation assay
The Cell Counting Kit-8 (CCK-8) assay was performed to determine the effect of miR-106a-5p on the proliferation of HaCaT cells. Briefly, cells were seeded in 96-well plates at the density of 1× 104 per well. After 24, 48, and 72 h, 20 μL of CCK-8 reagent were added into each well, and then incubated for 2 h at 37°C. After all the treatment, the optical density values of each well were measured by a microplate reader (Bio-Rad, USA) at a wavelength of 450 nm, which could exhibit the proliferation capacity of the cells. The experiment was performed in triplicate.
Dual-luciferase reporter assay
TargetScan (v7.2) bioinformatic software (Whitehead Institute for Biomedical Research in the Massachusetts Institute of Technology) (http://www.targetscan.org/vert_72/) was used to predict target genes of miR-106a-5p. The wide type (Wt) or mutant (Mut) 3'-untranslated region (UTR) of phosphatase and tensin homolog (PTEN) was cloned into the luciferase reporter vector psiCHECK-2 (Promega Corporation) according to the manufacturer's instruction. Briefly, 500 ng of each reporter construct and miR-106a-5p mimic, miR-106a-5p inhibitor, or miR-NC were co-transfected into HaCaT cells plated in a 24-well plate using Lipofectamine 2000 for 48 h at 37°C. Then, relative luciferase activity was detected with a microplate reader (Molecular Devices, LLC). Renilla fluorescence activity was identified as the internal reference.
The experimental data were expressed as mean ± standard deviation. Statistical analysis of all data was used the SPSS 24.0 (SPSS Inc., Chicago, IL, USA) and GraphPad Prism 7.04 software (GraphPad, San Diego, CA, USA). The statistical differences between groups were compared by Student's t-test and one-way ANOVA. Pearson's correlation coefficient was applied for the correlation analysis. P < 0.05 was considered as a statistically significant criterion. Each experiment runs at least three times.
| Results|| |
Increased serum levels of microRNA-106a-5p in psoriasis patients
The expression level of miR-106a-5p in the serum of healthy controls and psoriasis patients was detected by the method of qRT-PCR. The result demonstrated that the expression level of miR-106a-5p in the serum of psoriasis patients significantly increased compared with the healthy controls [Figure 1], P < 0.001].
|Figure 1: The expression levels of serum microRNA-106a-5p are related to disease severity of psoriasis. (a) Serum microRNA-106a-5p levels were significantly higher in psoriasis patients than that in healthy controls. ***P < 0.001, compared with healthy controls. (b) The correlation between the serum expression level of microRNA-106a-5p and Psoriasis Area and Severity Index was positive.|
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MicroRNA-106a-5p was correlated with the Psoriasis Area and Severity Index in psoriasis patients
The correlation analyses between the serum expression level of miR-106a-5p and psoriasis activity were performed. Psoriasis activity was evaluated by the PASI score, and we found a significantly positive association between PASI scores with the serum expression level of miR-106a-5p [Figure 1]b; Pearson's r = 0.6187; P < 0.001].
Diagnostic potential of serum microRNA-106a-5p levels in psoriasis patients
To assess the diagnostic potential of serum miR-106a-5p levels in psoriasis patients, the receiver operating characteristic (ROC) curve was established. [Figure 2] shows that miR-106a-5p could discriminate the psoriasis patients from the healthy individuals. The area under the curve (AUC) for miR-106a-5p was 0.901 with a sensitivity of 74.6% and specificity of 91.7% at the cutoff value of 1.195.
|Figure 2: Receiver operating characteristic curve was performed to assess the diagnostic value of serum microRNA-106a-5p in psoriasis patients and healthy controls.|
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Association of microRNA-106a-5p with inflammatory factors
First, we detected the protein expression levels of IL-22, IL-17A, and TNF-alpha. As shown in [Figure 3], the protein levels of IL-17A [Figure 3]a, IL-22 [Figure 3]b, and TNF-alpha [Figure 3]c in psoriasis group were significantly increased compared with that in control group (P < 0.001).
|Figure 3: The relation between the serum expression level of microRNA-106a-5p and inflammation factor (interleukin-17A, interleukin-22, and tumor necrosis factor-alpha) was analyzed. (a-c) The relative expression levels of interleukin-17A, interleukin-22, and tumor necrosis factor-alpha in psoriasis patients were all significantly upregulated compared with that in healthy controls (P < 0.001). ***P < 0.001, compared with control group.(d-f) Correlation between the expression level of microRNA-106a-5p and serum interleukin-17A, interleukin-22, and tumor necrosis factor-alpha levels.|
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In addition, the correlations between the serum expression level of miR-106a-5p and inflammatory factors (IL-22, IL-17A, and TNF-alpha) were analyzed. We found that serum levels of miR-106a-5p were positively correlated with the protein levels of IL-17A [Figure 3]d; Pearson's r = 0.7017; P < 0.001], IL-22 [Figure 3]e; Pearson's r = 0.6740; P < 0.001], and TNF-alpha [Figure 3]f; Pearson's r = 0.7721; P < 0.001].
MicroRNA-106a-5p regulated HaCaT cells proliferation and inflammatory response in vitro
To explore the effects of miR-106a-5p in psoriasis, we transfected HaCaT cells with a miR-106a-5p mimic to upregulate miR-106a-5p [P < 0.05; [Figure 4]a]. The CCK-8 assay was used to detect the effect of miR-106a-5p on the proliferation of M5-induced HaCaT cells. Further analysis demonstrated that miR-106a-5p mimic can significantly increase the proliferation of M5-stimulated HaCaT cells, while miR-106a-5p inhibitor can significantly inhibit the proliferation of cells [P < 0.001, [Figure 4]b]. These data suggested that miR-106a-5p regulated M5-induced keratinocyte proliferation.
|Figure 4: Effects of microRNA-106a-5p on proliferation of HaCaT cells. (a) Changes in microRNA-106a-5p levels in cells after transfection with microRNA-106a-5p mimic and inhibitors were detected by quantitative real-time polymerase chain reaction. **P < 0.01, compared with control group. ##P < 0.01, #P < 0.05, compared with M5 group. (b) Cell proliferation was detected by CCK-8 assay. microRNA-106a-5p mimic significantly promoted cell proliferation, while microRNA-106a-5p inhibitors significantly inhibited cell proliferation. (c) The inflammatory cytokine levels in HaCaT cells were determined by enzyme-linked immunosorbent assay. ***P < 0.001, compared with control group. ###P < 0.001, compared with M5 group.|
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To further study the effect of miR-106a-5p on the expression of inflammation factor in M5-induced HaCaT cells, we detected the protein expression levels of IL-22, IL-17A, and TNF-alpha in cells. After transfecting by miR-106a-5p mimic, the levels of IL-22, IL-17A, and TNF-alpha were upregulated significantly in M5-induced HaCaT cells [Figure 4]c, P < 0.001]. Moreover, miR-106a-5p downregulation had the opposite effect [Figure 4]c, P < 0.001].
Phosphatase and tensin homolog is the target gene of microRNA-106a-5p in HaCaT cells
Bioinformatic analysis showed that miR-106a-5p contains binding sites for PTEN [Figure 5]a. Furthermore, the luciferase reporter assay results revealed that overexpression of miR-106a-5p mimic significantly reduced the luciferase activity in cells transfected with wild type 3'-UTR of PTEN, whereas the luciferase activity was increased by miR-381 inhibitor downregulation [P < 0.001, [Figure 5]b]. However, the luciferase activity of cells transfected with mutant 3'-UTR of PTEN was not influenced by miR-106a-5p expression level.
|Figure 5: Phosphatase and tensin homolog is the target gene of microRNA-106a-5p in HaCaT cells. (a) Bioinformatic analyses showed that microRNA-106a-5p contains binding sites for phosphatase and tensin homolog. (b) Overexpression of microRNA-106a-5p mimic significantly reduced the luciferase activity in cells transfected with wild type 3'-untranslated region of phosphatase and tensin homolog, whereas the luciferase activity was increased by miR-381 inhibitor downregulation. However, the luciferase activity of cells transfected with mutant 3'-untranslated region of phosphatase and tensin homolog was not influenced by microRNA-106a-5p expression level. ***P < 0.001, compared with control group.|
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| Discussion|| |
Psoriasis, an immune-mediated chronic inflammatory skin disease, is featured with epidermal hyperplasia, angiogenesis, and inflammatory cell infiltration., It is a key psoriasis treatment to inhibit these cellar events. Evidences indicated that numerous internal and external factors might participate in psoriasis pathogenesis, including the immune system, environmental factors, keratinocytes, and susceptibility genes. Owing to the complexity of the cause of psoriasis, its pathogenesis has not yet been fully understood.
Increasing evidence has shown that abnormally expressed miRNA takes effects on psoriasis progression, such as miR-146a, miR-125b, and miR-135b. These dysregulated miRNAs play an important role in diagnosis and treatment and have attracted increasing attention for their therapeutic potential in diseases. For instance, in psoriasis patients, the level of miR-205-5p was downregulated, and played its roles by targeting Ang-2, VEGFA, and BAMBI, and deactivating the Wnt/β-catenin and MAPK signaling pathways, which provided a potential therapeutic target for clinical treatment of psoriasis. Work by Wang et al. established that miR-223 was overexpressed in psoriatic lesions and in IL-22-stimulated HaCaT cells, and increased proliferation and inhibited apoptosis of IL-22-stimulated keratinocytes via the PTEN/Akt pathway. Another study demonstrated that miR-876-5p was downregulated in psoriatic tissue and blood of patients and would be expected to be biomarker and potential therapeutic targets for the treatment of psoriasis. In this study, the serum expression level of miR-106a-5p in psoriasis patients was higher than that in healthy controls. Consistently, in a study about human T-cells and autoimmunity, miR-106a-5p is reported to be elevated in the serum of psoriasis patients, and miR-106a-5p is suggested to be enriched in Th1/Th17-derived extracellular vesicles. In inflammatory bowel disease (IBD), miR-106a-5p is also suggested to be actually upregulated after T-cell activation. As Delić et al. reported, a high level of miR-106a-5p is also detected in the lesional skin of psoriasis patients. miRNAs can be expressed by all cell types and tissues, and in response to physiological stimuli and pathological processes, and the same miRNA may be derived from a variety of cell sources, such as endothelial cells, monocytes and macrophages, vascular smooth cells, and platelets, and eventually are secreted into blood. The in vitro experiments demonstrated that miR-106a-5p was also overexpressed in M5-treated keratinocytes. Accordingly, we hypothesized that serum miR-106a-5p in psoriasis patients may derive from the T-cells, keratinocytes, as well as other cell types. However, because of the representativeness of psoriatic lesions and the acceptance willingness of patients, the human psoriatic lesions cannot be collected in the present study. Therefore, it is of great significance and should be taken into consideration in future studies. Moreover, only the levels of miR-106a-5p in the serum of patients before treatment were detected in the present study; its level after successful treatment is also interesting and significant, which should be studied in future studies., These results motivated us to study the role of miR-106a-5p in psoriasis further.
miR-106a-5p was reported to be dysregulated in various diseases, such as prostate cancer, atherosclerosis, and cervical cancer. The clinical value of miR-106a-5p in diseases attracted researcher attention. As reported by Zhang et al., miR-106a-5p level was downregulated in osteoarthritis samples and IL-1b-treated chondrocytes; miR-106a-5p overexpression led to proliferation promotion and apoptosis inhibition in chondrocytes treated by IL-1 β. Another study in HPV-16-associated cervical cancer reported that miR-106a-5p played an important role in regulatory mechanism of cervical squamous cell carcinoma and could be a potential therapeutic target in HPV-associated cervical cancer. Considering the dysregulation of miR-106a-5p in the serum of psoriasis patients, we further explored whether serum miR-106a-5p could differentiate between the psoriasis patients and the healthy. The area under the ROC curve (AUC) of miR-106a-5p on the diagnosis of psoriasis was 0.901 with a sensitivity of 74.60% and specificity of 91.7% at the cutoff value of 1.195, indicating that miR-106a-5p has ability to distinguish the psoriasis patients from healthy controls. We further studied the correlation between miR-106a-5p and PASI score, and a significant positive association was detected. These results demonstrated that serum miR-106a-5p might be a potential diagnostic biomarker for psoriasis.
In this study, it was found that the protein levels of IL-17A, IL-22, and TNF-alpha were significantly increased in serum. The result demonstrated that inflammation plays an important role in psoriasis. We further explored the correlations between the serum expression level of miR-106a-5p and inflammation cytokines. Results indicated that serum levels of miR-106a-5p were positively correlated with the protein levels of IL-22, IL-17A, and TNF-alpha. Therefore, it came to the conclusion that upregulated miR-106a-5p might promote the occurrence and development of psoriasis through promoting inflammatory response. Consistently, overexpression of miR-106a-5p is also reported in the serum of IBD patients; knockdown of miR-106a-5p attenuates inflammation in murine IBD models, which supported our present results. In addition to melanoma, no research is reported between miR-106a-5p expression and other skin diseases. However, the current study collected healthy individuals as a control group; the expression pattern of miR-106a-5p in other inflammatory dermatoses is also interesting and needs to be studied further in future studies. Moreover, the clinical value of miR-106a-5p to differentiate psoriasis from other inflammatory skin diseases is also of great significance.
HaCaT cells are immortalized cells, which are commonly used in the studies relevant to psoriasis. IL-17A and IL-22 are the two key Th17-related cytokines, and the expression of IL-17A and IL-22 has been reported to be elevated in human psoriatic lesional biopsies. The release of inflammatory cytokines contributes to the pathogenesis of psoriasis by inducing keratinocyte proliferation and pro-inflammatory cytokine production and secretion. In the current study, HaCaT cells were induced with M5 to establish an in vitro psoriasis model and to investigate the role of miR-106a-5p in psoriasis. Consistent with the previous evidence, a high level of IL-17A and IL-22 was detected in M5-treated keratinocytes. The expression level of miR-106a-5p was also apparently increased in M5-treated HaCaT cells, which was consistent with the results observed in the serum of psoriasis patients. The gain and loss function study results indicated that downregulation of miR-106a-5p inhibited the inflammatory cytokine release, and inhibited keratinocyte proliferation. These results suggested that miR-106a-5p might be a potential treatment target in psoriasis. PTEN, a major tumor suppressor, exerts lipid and protein phosphatase activities. It has been reported to be a mediator of the PI3K/Akt pathway, and regulates various cell behaviors. Notably, PTEN has been reported to be a direct target gene of miR-106a-5p in several human diseases.,, In our study, PTEN was proved to be a direct gene of miR-106a-5p, and PTEN showed low expression in psoriasis cell models. Consistently, PTEN is also reported to be significantly downregulated in psoriatic lesions as well as IL-22-treated HaCaT cells., PTEN knockdown promoted the keratinocyte proliferation. PTEN is the upstream regulator of PI3K/Akt pathway; the downregulation of PTEN expressions may play a role in the overactivation of the PI3K/Akt pathway in psoriatic lesions and correlate with the hyperproliferation of psoriatic keratinocytes. These findings prompted us to speculate that miR-106a-5p might be involved in the psoriasis pathogenesis through targeting PTEN and regulating the PI3K/Akt pathway.
| Conclusion|| |
Our work demonstrates that miR-106a-5p had a high expression in psoriasis patients and can distinguish psoriasis patients from healthy controls. miR-106a-5p might be involved in the disease progression and regulating inflammatory response through targeting PTEN and regulating the PI3K/Akt pathway. Our results provide new insight of miR-106a-5p and may contribute to the development of target for psoriasis treatment.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]