Startseite MicroRNAs as regulatory elements in psoriasis
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MicroRNAs as regulatory elements in psoriasis

  • Yuan Liu und Quanzhong Liu EMAIL logo
Veröffentlicht/Copyright: 12. August 2016
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Open Medicine
Aus der Zeitschrift Open Medicine Band 11 Heft 1

Abstract

Psoriasis is a chronic, autoimmune, and complex genetic disorder that affects 23% of the European population. The symptoms of Psoriatic skin are inflammation, raised and scaly lesions. microRNA, which is short, nonprotein-coding, regulatory RNAs, plays critical roles in psoriasis. microRNA participates in nearly all biological processes, such as cell differentiation, development and metabolism. Recent researches reveal that multitudinous novel microRNAs have been identified in skin. Some of these substantial novel microRNAs play as a class of posttranscriptional gene regulator in skin disease, such as psoriasis. In order to insight into microRNAs biological functions and verify microRNAs biomarker, we review diverse references about characterization, profiling and subtype of microRNAs. Here we will share our opinions about how and which microRNAs are as regulatory in psoriasis.

Keywords: microRNAs; Psoriasis

1 Introduction

Human skin is the outermost bodily barrier; it protects inner organs from stress and hazards [1, 2]. Human skin tends to rapidly repair when injured, although that involves a complex healing process. These functions of skin are maintained by a system of regulatory mechanisms that involves various mediators [3, 4]. Some reports indicate that epigenetic regulatory mechanisms are contributing factors [5].

Skin diseases, including skin cancer and psoriasis, exert more and more severe influence on public health, for example psoriasis, a common skin disease. It characterized by a chronic, autoimmune, and complex genetic disorder. Psoriasis undergoes three different processes of cellular alteration in skin: abnormal differentiation of keratinocyte, hyperproliferation of keratinocyte, and infiltration of immune into the dermis and epidermis [6]. Some common molecular components, genetic alterations of genes that participate in inflammatory pathways, and environmental risks can contribute to the pathogenesis of psoriasis [7,8].

Recent research reveals that microRNAs have an important influence on psoriasis. MicroRNAs (microRNAs) are single-stranded, noncoding, short RNA molecules; they act as regulators of gene expression and play critical roles in nearly all biological processes. One example is the differentiation, development, and metabolism of the human body cell [9,10], which is influenced complementary mRNAs by binding to a target. As recent reports have indicated, expression of distinct microRNAs is upregulated in psoriatic skin compared with healthy skin, and that this process is related to regulation of keratinocyte proliferation and/or differentiation or suppression of T-cell apoptosis in psoriasis [11]. A plethora of microRNAs have been reported to be related to regulation in psoriasis, and different microRNAs can play a vital role at different stages of the disease. For example, miR-31 can modulate inflammatory mediator production and leucocyte infiltration to skin, and thus be present in psoriatic keratinocytes and contribute to psoriatic inflammation [11]. miR-203 is upregulated during keratinocyte differentiation of psoriatic skin by regulating the expression of TNF-a, IL-8, IL-24. Whereas miR-21 can be suppressed during apoptosis, miR-146a is upregulated in Th1 cells from T cells [12]. Thus, an appropriate combination of microRNAs could act as a regulator of psoriasis and thereby could potentially provide biomarker, therapy and diagnostic information.

2 MicroRNAs in skin

MicroRNAs are typically defined as the most abundant small RNAs on pre-microRNA hairpins. More and more diverse variants of microRNAs have been discovered, including canonical and noncanonical microRNAs [13-15], microRNA-like–RNA, [16] and microRNA isoforms [17]. The Drosha and Dicer pathways are the essential differences between canonical and noncanonical. For example, previously discovered noncanonical microRNAs, mirtrons that arise from disbranched intron lariats, serve as substrates for Dicer cleavage [18, 19]. Another less abundant variant of small RNAs, isoforms or isomiRs, that exiss in nearly all sepsis, also act as regular microRNAs [20, 21]. This small RNA regulates the same mRNA target as their companion microRNAs and accompany them to their exclusive target genes [22]. This phenomenon indicates that microRNA-mediated gene expression regulators have robustness and plasticity, and that they have abundant functions complementary to canonical microRNAs [23].

During skin development and cell differentiation, microRNAs play an important role in regulating different signaling pathways by interacting with their target mRNAs. Their regulated targets has been implicated in the pathogenesis of psoriasis [24, 25]. This evidence suggests that microRNA can be participate in early skin development and affect the psoriasis process. When knocking out either Dicer or Dgcr8, severe defects in murine embryonic skin development have emerged, which produce rough skin, body weight loss, defects in hair follicle downgrowth, and abnormal apoptosis [26]. Hyperproliferation that topically appears as a feature of psoriasis has been observed in the Dicer knocked-out epidermis, showing the close relationship between microRNA and epidermal proliferation [27]. Several microRNAs with functions in skin morphogenesis and homeostasis have been studied (Table 1). For example, miR-21 is up-regulated in diseased skin, as well as in psoriasis and squamous cell skin cancer [28]. The miR-199 family is highly expressed in hair follicles, which indicates a potential regulatory function in hair morphogenesis [29]. miR-203 is also upregulated when keratinocytes differentiate, inducing expression of TNF-a, IL-8, IL-24 and suppressing cytokine signaling 3 [30]. In addition, many studies have recognized that several other microRNAs are related to skin development and homeostasis (Table 1). For instance, the miR-200 family and miR-205 have been shown to target ZEB1 and ZEB2 and are highly expressed in normal skin. Downregulation of miR-200 and miR-205 will induce upregulation of ZEB1 and ZEB2 via epithelial-to-mesenchymal transition [31].

Table 1

microRNAs involved in skin development

microRNAFunction
miR-203Inhibit cell proliferation by repressing p63; as the regulation in transition from basal to suprabasal layer in epidermis [30]
miR-34a/cMaintain cell cycle progression and expression of cyclin D1 and Cdk4 via repression by p63 in epidermal cells [32]
mir-125bContribute to self-renew and early lineage commitment of skin stem cell [33]
miR-200/miR-205Maintains proliferation of progenitor cells and epithelial-mesenchymal transition to restrict basal layer [31]

3 microRNAs in psoriatic skin

Psoriasis, which appears as white silvery scales, is a common skin disease with characteristics of a chronic, autoimmune, and complex genetic disorder. Many factors, both genetic and environmental, can contribute to its emergence. Humans with psoriasis may suffer from hyperproliferation, aberrant differentiation of keratinocytes, loss of the superficial granular layer, and thickening of the cornified envelope. Research over last few years suggests that epigenetic regulatory mechanisms may enable skin regeneration and execution of gene expression in skin. This theory may be applicable to processes of skin repair, regulation of keratinocyte proliferation, differentiation, and migration, along with dermal regeneration and neoangiogenesis [5]. The grainyhead-like 3 (Grhl3/Get1) transcription factor is one of the regulators in epidermal genes that control the expression of specific microRNAs [27]. As one of the most widely studied microRNAs, miR-21 is abundantly expressed in skin [34]. Some records have indicated that it is upregulated in pathological conditions such as psoriasis [35]. When miR-21 is upregulated, the differentiation and hyperplasia are impaired and Grhl3 tends to be down regulated [5]. microRNA-31, one of the most dynamic microRNAs, exists in the skin of psoriatic patients and of mouse models. Transcription of miR-31 will be triggered by activated NF-κB and then promotes the keratinocyte hyperproliferation in psoriasis. When the miR-31 seed sequence is blocked by antagomirs and its effects are tested on an imiquimod (IMQ)-induced psoriasis mouse model, we found that there was a pronounced decrease in acanthosis and dermal cellular infiltration [11]. Furthermore, the majority of the collected data suggest that more and more novel human microRNAs have been detected. For example, miR-4623 acts on TNFRSF1B that is reported existing in psoriatic arthritis [36]. As another intronic, miR-944 is encoded in KPT15, which acts as a downregulator in psoriatic skin [37]. miR-944 contributes to maintaining stemness in skin by located in an intron of p63 [38]. A very special microRNA, miR-203-AS, is identified as a distinct microRNA on the DNA strand at the locus antisense to miR-203 [39]. Another example is miR-103, it also encodes on both antisense and sense strands. As for noncanonical microRNAs and microRNA-like RNAs in psoriatic skin, has-miR-1983 as a t-RNA-derived microRNA expresses in psoriatic and normal human skin [40].

A systematic analysis has revealed that microRNA isoforms originate from diverse tissues and across species [41,42]. For example, 5’-isomiRs (Table 2). miR-142 and miR-233 with high 5’-heterogeneities in human psoriatic lesions is expressed in dendritic cells and neutrophils, respectively [43-45].

Table 2

Some of microRNAs that express aberrantly in human psoriatic skin

microRNADescriptionFold Change (PP/NN)
miR-31triggered by activated NF-kB to promotes keratinocyte hyperproliferation in psoriasis [11,23]42.9
miR-21Upregulated in pathological induced impaire in differentiation and hyperplasia and down regulation of Grhl3 [35,23]4.0
miR-1983tRNA-derived human homolog of murine miR-1983 [40]4.9
miR-203-ASAntisense to miR-203 [39]2.7
miR-142Highly expressed in dendritic cell and play vital roel in hematopoietic development [41]2.5
miR-203As the regulation in development of epidermis from basal to suprabasal layer [30, 23]1.6
miR-205Primarily in the basal layer expressed in normal skin and regulates the transcriptional[42]1.6

Fold change is a value of microRNA expression in psoriatic skin (PP) divided by that in normal skin (NN).

4 Summary and future

Although the study of microRNAs in mammalian skin, such as in psoriatic skin, is an early stage, the research has already provided new insights into a novel layer of gene regulation. In the present article, some microRNAs, along with their targets, have been discussed; this provide us increased knowledge of psoriasis mechanisms. Taking miR-203 as an example, it has an essential role in early skin development and a critical role in psoriasis (shown in Table 2). This knowledge gives us hope that we will eventually find an excellent candidate for treatment of psoriasis.

Although the science is incomplete, new threads for future research have emerged. To reveal the etiology of autoimmune skin disorders, psoriasis included, a high-quality and rapid analysis system should be put in place to find the complex genetic networks; this will require a comprehensive profile of the transcriptome. Finding these complex genetic networks bring along another challenge: to integrate the information of genotypic variations. These genotypic variations hold a potential to explore causal genetic variations and then to lead to a connection with disease phenotypes. Furthermore, detailed genetic knowledge of the mechanism behind psoriasis development will be beneficial to developing animal models for research.

No matter how great the challenge, we are optimistic regarding the future of this field and are willing to make efforts to contribute to it. We believe that there is a possible cure for skin-related disease in deeper understanding of small RNA- and microRNA-based therapies.

Quanzhong Liu, Tel: 86-022-60363131; Fax:86-022-60363131

Acknowledgements

This study was supported by Tianjin Medical University General Hospital Youth Incubation Foundation (ZYYFY2014018)

Conflict of interest statement

  1. Authors state no conflict of interest.

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Received: 2016-1-13
Accepted: 2016-3-12
Published Online: 2016-8-12
Published in Print: 2016-1-1

© 2016 Yuan Liu, Quanzhong Liu

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License.

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  136. Prenatal diagnosis, 3-D virtual rendering and lung sparing surgery by ligasure device in a baby with “CCAM and intralobar pulmonary sequestration”
  137. Special Issue on Italian Society for the Study of Vascular Anomalies
  138. Serum levels of inhibin B in adolescents after varicocelelectomy: A long term follow up
  139. Special Issue on Italian Society for the Study of Vascular Anomalies
  140. Our experience in the treatment of Malignant Fibrous Hystiocytoma of the larynx: clinical diagnosis, therapeutic approach and review of literature
  141. Special Issue on Italian Society for the Study of Vascular Anomalies
  142. Delayed recurrent nerve paralysis following post-traumatic aortic pseudoaneurysm
  143. Special Issue on Italian Society for the Study of Vascular Anomalies
  144. Integrated therapeutic approach to giant solitary fibrous tumor of the pleura: report of a case and review of the literature
  145. Special Issue on Italian Society for the Study of Vascular Anomalies
  146. Celiac axis compression syndrome: laparoscopic approach in a strange case of chronic abdominal pain in 71 years old man
  147. Special Issue on Italian Society for the Study of Vascular Anomalies
  148. A rare case of persistent hypoglossal artery associated with contralateral proximal subclavian stenosis
  149. Focus on Medico-Legal and Ethical Topics in Surgery in Italy
  150. Contralateral risk reducing mastectomy in Non-BRCA-Mutated patients
  151. Focus on Medico-Legal and Ethical Topics in Surgery in Italy
  152. Professional dental and oral surgery liability in Italy: a comparative analysis of the insurance products offered to health workers
  153. Focus on Medico-Legal and Ethical Topics in Surgery in Italy
  154. Informed consent in robotic surgery: quality of information and patient perception
  155. Focus on Medico-Legal and Ethical Topics in Surgery in Italy
  156. Malfunctions of robotic system in surgery: role and responsibility of surgeon in legal point of view
  157. Focus on Medico-Legal and Ethical Topics in Surgery in Italy
  158. Medicolegal implications of surgical errors and complications in neck surgery: A review based on the Italian current legislation
  159. Focus on Medico-Legal and Ethical Topics in Surgery in Italy
  160. Iatrogenic splenic injury: review of the literature and medico-legal issues
  161. Focus on Medico-Legal and Ethical Topics in Surgery in Italy
  162. Donation of the body for scientific purposes in Italy: ethical and medico-legal considerations
  163. Focus on Medico-Legal and Ethical Topics in Surgery in Italy
  164. Cosmetic surgery: medicolegal considerations
  165. Focus on Medico-Legal and Ethical Topics in Surgery in Italy
  166. Voluntary termination of pregnancy (medical or surgical abortion): forensic medicine issues
  167. Review Article
  168. Role of Laparoscopic Splenectomy in Elderly Immune Thrombocytopenia
  169. Review Article
  170. Endoscopic diagnosis and treatment of neuroendocrine tumors of the digestive system
  171. Review Article
  172. Efficacy and safety of splenectomy in adult autoimmune hemolytic anemia
  173. Research Article
  174. Relationship between gastroesophageal reflux disease and Ph nose and salivary: proposal of a simple method outpatient in patients adults
  175. Case Report
  176. Idiopathic pleural panniculitis with recurrent pleural effusion not associated with Weber-Christian disease
  177. Research Article
  178. Morbid Obesity: treatment with Bioenterics Intragastric Balloon (BIB), psychological and nursing care: our experience
  179. Research Article
  180. Learning curve for endorectal ultrasound in young and elderly: lights and shades
  181. Case Report
  182. Uncommon primary hydatid cyst occupying the adrenal gland space, treated with laparoscopic surgical approach in an old patient
  183. Research Article
  184. Distraction techniques for face and smile aesthetic preventing ageing decay
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  186. Preoperative high-intensity training in frail old patients undergoing pulmonary resection for NSCLC
  187. Review Article
  188. Descending necrotizing mediastinitis in the elderly patients
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  190. Prophylactic GSV surgery in elderly candidates for hip or knee arthroplasty
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  192. Diagnostic yield and safety of C-TBNA in elderly patients with lung cancer
  193. Research Article
  194. The learning curve of laparoscopic holecystectomy in general surgery resident training: old age of the patient may be a risk factor?
  195. Research Article
  196. Self-gripping mesh versus fibrin glue fixation in laparoscopic inguinal hernia repair: a randomized prospective clinical trial in young and elderly patients
  197. Research Article
  198. Anal sphincter dysfunction in multiple sclerosis: an observation manometric study
https://doi.org/10.1515/med-2016-0063
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microRNAs; Psoriasis
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  127. Special Issue on Italian Society for the Study of Vascular Anomalies
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  129. Special Issue on Italian Society for the Study of Vascular Anomalies
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  131. Special Issue on Italian Society for the Study of Vascular Anomalies
  132. Role of FDG-PET scan in staging of pulmonary epithelioid hemangioendothelioma
  133. Special Issue on Italian Society for the Study of Vascular Anomalies
  134. Sternal reconstruction by extracellular matrix: a rare case of phaces syndrome
  135. Special Issue on Italian Society for the Study of Vascular Anomalies
  136. Prenatal diagnosis, 3-D virtual rendering and lung sparing surgery by ligasure device in a baby with “CCAM and intralobar pulmonary sequestration”
  137. Special Issue on Italian Society for the Study of Vascular Anomalies
  138. Serum levels of inhibin B in adolescents after varicocelelectomy: A long term follow up
  139. Special Issue on Italian Society for the Study of Vascular Anomalies
  140. Our experience in the treatment of Malignant Fibrous Hystiocytoma of the larynx: clinical diagnosis, therapeutic approach and review of literature
  141. Special Issue on Italian Society for the Study of Vascular Anomalies
  142. Delayed recurrent nerve paralysis following post-traumatic aortic pseudoaneurysm
  143. Special Issue on Italian Society for the Study of Vascular Anomalies
  144. Integrated therapeutic approach to giant solitary fibrous tumor of the pleura: report of a case and review of the literature
  145. Special Issue on Italian Society for the Study of Vascular Anomalies
  146. Celiac axis compression syndrome: laparoscopic approach in a strange case of chronic abdominal pain in 71 years old man
  147. Special Issue on Italian Society for the Study of Vascular Anomalies
  148. A rare case of persistent hypoglossal artery associated with contralateral proximal subclavian stenosis
  149. Focus on Medico-Legal and Ethical Topics in Surgery in Italy
  150. Contralateral risk reducing mastectomy in Non-BRCA-Mutated patients
  151. Focus on Medico-Legal and Ethical Topics in Surgery in Italy
  152. Professional dental and oral surgery liability in Italy: a comparative analysis of the insurance products offered to health workers
  153. Focus on Medico-Legal and Ethical Topics in Surgery in Italy
  154. Informed consent in robotic surgery: quality of information and patient perception
  155. Focus on Medico-Legal and Ethical Topics in Surgery in Italy
  156. Malfunctions of robotic system in surgery: role and responsibility of surgeon in legal point of view
  157. Focus on Medico-Legal and Ethical Topics in Surgery in Italy
  158. Medicolegal implications of surgical errors and complications in neck surgery: A review based on the Italian current legislation
  159. Focus on Medico-Legal and Ethical Topics in Surgery in Italy
  160. Iatrogenic splenic injury: review of the literature and medico-legal issues
  161. Focus on Medico-Legal and Ethical Topics in Surgery in Italy
  162. Donation of the body for scientific purposes in Italy: ethical and medico-legal considerations
  163. Focus on Medico-Legal and Ethical Topics in Surgery in Italy
  164. Cosmetic surgery: medicolegal considerations
  165. Focus on Medico-Legal and Ethical Topics in Surgery in Italy
  166. Voluntary termination of pregnancy (medical or surgical abortion): forensic medicine issues
  167. Review Article
  168. Role of Laparoscopic Splenectomy in Elderly Immune Thrombocytopenia
  169. Review Article
  170. Endoscopic diagnosis and treatment of neuroendocrine tumors of the digestive system
  171. Review Article
  172. Efficacy and safety of splenectomy in adult autoimmune hemolytic anemia
  173. Research Article
  174. Relationship between gastroesophageal reflux disease and Ph nose and salivary: proposal of a simple method outpatient in patients adults
  175. Case Report
  176. Idiopathic pleural panniculitis with recurrent pleural effusion not associated with Weber-Christian disease
  177. Research Article
  178. Morbid Obesity: treatment with Bioenterics Intragastric Balloon (BIB), psychological and nursing care: our experience
  179. Research Article
  180. Learning curve for endorectal ultrasound in young and elderly: lights and shades
  181. Case Report
  182. Uncommon primary hydatid cyst occupying the adrenal gland space, treated with laparoscopic surgical approach in an old patient
  183. Research Article
  184. Distraction techniques for face and smile aesthetic preventing ageing decay
  185. Research Article
  186. Preoperative high-intensity training in frail old patients undergoing pulmonary resection for NSCLC
  187. Review Article
  188. Descending necrotizing mediastinitis in the elderly patients
  189. Research Article
  190. Prophylactic GSV surgery in elderly candidates for hip or knee arthroplasty
  191. Research Article
  192. Diagnostic yield and safety of C-TBNA in elderly patients with lung cancer
  193. Research Article
  194. The learning curve of laparoscopic holecystectomy in general surgery resident training: old age of the patient may be a risk factor?
  195. Research Article
  196. Self-gripping mesh versus fibrin glue fixation in laparoscopic inguinal hernia repair: a randomized prospective clinical trial in young and elderly patients
  197. Research Article
  198. Anal sphincter dysfunction in multiple sclerosis: an observation manometric study
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