Keloid Development Research Articles

Decoy Wnt receptor (sLRP6E1E2)-expressing adenovirus induces anti-fibrotic effect via inhibition of Wnt and TGF-\u03b2 signaling

Aberrant activation of the canonical Wingless type (Wnt) signaling pathway plays a key role in the development of hypertrophic scars and keloids, and this aberrant activation of Wnt pathway can be a potential target for the development of novel anti-fibrotic agents. In this study, we evaluated the anti-fibrotic potential of a soluble Wnt decoy receptor (sLRP6E1E2)-expressing non-replicating adenovirus (Ad; dE1-k35/sLRP6E1E2) on human dermal fibroblasts (HDFs), keloid fibroblasts (KFs), and keloid tissue explants. Higher Wnt3a and β-catenin expression was observed in the keloid region compared to the adjacent normal tissues. The activity of β-catenin and mRNA expression of type-I and -III collagen were significantly decreased following treatment with dE1-k35/sLRP6E1E2 in HDFs and KFs. The expression of LRP6, β-catenin, phosphorylated glycogen synthase kinase 3 beta, Smad 2/3 complex, and TGF-β1 were decreased in Wnt3a- or TGF-β1-activated HDFs, following administration of dE1-k35/sLRP6E1E2. Moreover, dE1-k35/sLRP6E1E2 markedly inhibited nuclear translocation of both β-catenin and Smad 2/3 complex. The expression levels of type-I and -III collagen, fibronectin, and elastin were also significantly reduced in keloid tissue explants after treatment with dE1-k35/sLRP6E1E2. These results indicate that Wnt decoy receptor-expressing Ad can degrade extracellular matrix in HDFs, KFs, and primary keloid tissue explants, and thus it may be beneficial for treatment of keloids.

Endothelial dysfunction may promote keloid growth.

Keloid is a cutaneous fibroproliferative disorder. It results from impaired wound healing that generates persistent inflammation and extensive deposition of collagen fibers in the wound/scar. Keloids tend to be worse in hypertensive patients. The present prospective cross-sectional study assessed whether endothelial dysfunction, which occurs in hypertension, associates with keloid formation and progression. This study included randomly selected patients with keloids who were assessed for surgical keloid treatment in 2013-2014. A series of nonkeloid patients admitted to the hospital was also recruited during this period. To measure endothelial function, all patients underwent digital reactive hyperemia peripheral arterial tonometry. Test results were expressed as reactive hyperemia index (RHI) and augmentation index (AI). In total, 57 patients with keloids and 19 nonkeloid controls were recruited. Keloid patients did not differ from the controls in terms of demographic or clinical variables, but had significantly worse RHI and AI values. Moreover, poor RHI and AI values associated with keloid development on binomial logistic regression. The keloid patients were then divided into four groups depending on whether their keloids started at age 0-12, 13-18, 19-29, or ≥30 years. Patients whose keloids arose before and well after puberty tended to have lower RHI than the controls, but these differences did not achieve statistical significance. However, these two groups did have significantly poorer AI values than the controls. Thus, endothelial dysfunction could cause keloid formation and/or aggravation. This indicates that vascular endothelial cells are important for wound healing.

Tumor suppressive role of miR-1224-5p in keloid proliferation, apoptosis and invasion via the TGF-β1/Smad3 signaling pathway

The molecular mechanism of the pathogenesis of keloids is still not known and the clinical management of keloids remains challenging. MiRNA (microRNA) is a novel class of small regulatory RNAs that has emerged as key post-transcriptional regulators of gene expression. MiRNAs participate in diverse biological processes of various skin diseases and function as key regulators in the occurrence and development of tumors. The purpose of this study was to investigate the involvement of miRNAs in keloid pathogenesis. We performed miRNA microarray analysis to compare miRNA expression between keloid and normal skin samples. We found that 46 miRNAs were upregulated and 28 miRNAs were downregulated in keloid compared with normal skin samples. We focused on miR-1224-5p, which has been reported to function in cancers, although the expression and mechanism of miR-1224-5p in keloids remain to be explored. Overexpression of miR-1224-5p led to inhibition of keloid fibroblast proliferation, promotion of apoptosis and decrease of migration and invasion. Our results suggest that downregulation of miR-1224-5p may be one of the mechanisms involved in the occurrence and development of keloids.

Identification of ASAH1 as a susceptibility gene for familial keloids.

Keloids result from abnormal proliferative scar formation with scar tissue expanding beyond the margin of the original wound and are mostly found in individuals of sub-Saharan African descent. The etiology of keloids has not been resolved but previous studies suggest that keloids are a genetically heterogeneous disorder. Although possible candidate genes have been suggested by genome-wide association studies using common variants, by upregulation in keloids or their involvement in syndromes that include keloid formation, rare coding variants that contribute to susceptibility in non-syndromic keloid formation have not been previously identified. Through analysis of whole-genome data we mapped a locus to chromosome 8p23.3-p21.3 with a statistically significant maximum multipoint LOD score of 4.48. This finding was followed up using exome sequencing and led to the identification of a c.1202T>C (p.(Leu401Pro)) variant in the N-acylsphingosine amidohydrolase (ASAH1) gene that co-segregates with the keloid phenotype in a large Yoruba family. ASAH1 is an acid ceramidase known to be involved in tumor formation by controlling the ratio of ceramide and sphingosine. ASAH1 is also involved in cell proliferation and inflammation, and may affect the development of keloids via multiple mechanisms. Functional studies need to clarify the role of the ASAH1 variant in wound healing.

Патофізіологічні механізми розвитку колоїдних рубців у дітей (огляд літератури)

The article contains the modern views revision of the basic pathophysiologic mechanisms of the keloid scars development, the analysis of the peculiarities of the keloid scars development in children. The systematization of the basic theories of keloid scar formation and the analysis of the latest scientific data on the hereditary and acquired factors is presented.

Bilateral breast keloids in an elderly woman associated with bilateral breast cancers and high concentration of serum tumor growth factor‐β

We report a case of bilateral annular breast keloids in a 72-year-old woman who had been suffering from bilateral breast cancers. Histopathologically, the keloids showed unique distribution of α-SMA+, CD34- myofibroblasts and α-SMA-, CD34+ fibroblasts depending on the region. High serum levels of tumor growth factor-β were detected at 6 months after the development of the breast keloids, but not at 10 months. CD163-positive cells were abundantly detected in the skin of the elevated portion of the keloids. In contrast, these cells were considerably less numerous in the skin of the central healing portion compared with the skin of the elevated expanding portion. One interesting idea based on these results is that high levels of tumor growth factor-β released from CD163-positive cells played a crucial role in the formation of breast keloids through active induction of fibroblast differentiation into myofibroblasts. The present case strongly supports the previously proposed idea that keloids can form as a paraneoplastic phenomenon in breast cancer patients with keloid constitution.

Massive ear keloids: Natural history, evaluation of risk factors and recommendation for preventive measures - A retrospective case series.

Keloid disorder (KD) is an inherited wound healing ailment, frequently seen among Africans /African Americans and Asians. Genetics of this disorder continues to be obscure and poorly understood. Clinical manifestation of KD is quite variable and very diverse, spanning from individuals with one or very few small keloidal lesions, to those with numerous and very large lesions covering large portion of their skin. Ears are common locations for development of keloids. Ear piercing is by far the leading triggering factor for ear keloid formation in genetically predisposed individuals. Although there are numerous publications about ear and earlobe keloids, there is a void in medical literature about massive ear keloids. This paper focuses on the natural history of massive ear keloids and risk factors that lead to formation of these life-changing and debilitating tumors and recommendations for prevention.

Identification of Key Modules and Hub Genes of Keloids with Weighted Gene Coexpression Network Analysis.

Keloid scarring impairs patients' quality of life, and although many therapeutic strategies have been developed, most remain unsatisfactory because of limited understanding of the mechanisms underlying keloid development. A microarray gene expression data set from keloid tissue was acquired from the Gene Expression Omnibus. Differentially expressed genes in fibroblasts and keratinocytes underwent functional annotation and pathway analysis. Weighted gene coexpression network analysis was applied to identify the gene targets of keloid scars within differentially expressed genes. Modules and hub genes for keloids were identified. Enrichment analysis was undertaken to verify the modules' and hub genes' relationship with keloids. Enrichment analysis and pathway analysis showed gene ontology terms and pathways related to keloids. Each cell type generated three modules in weighted gene coexpression network analysis, with one module most related to keloids. Enrichment analysis showed that the modules concerned are enriched with terms related to keloids. Three hub genes were selected for fibroblasts and keratinocytes, and their relationship to keloids was verified. Immunohistochemical staining verified expression change of some hub genes. This is the first study to describe the gene networks underlying keloids. Modules and hub genes generated in the present study are highly related to keloids and may identify novel therapeutic targets for treatment of keloids. Therapeutic, V.

Keloid progression: a stiffness gap hypothesis.

Keloids are fibroproliferative skin disorders characterised clinically by continuous horizontal progression and post-surgical recurrence and histologically by the accumulation of collagen and fibroblast ingredients. Till now, their aetiology remains clear, which may cover genetic, environmental and metabolic factors. Evidence in the involvement of local mechanics (e.g. predilection site and typical shape) and the progress in mechanobiology have incubated our stiffness gap hypotheses in illustrating the chronic but constant development in keloid. We put forward that the enlarged gap between extracellular matrix (ECM) stiffness and cellular stiffness potentiates keloid progression. Matrix stiffness itself provides organisational guidance cues to regulate the mechanosensitive resident cells (e.g. proliferation, migration and apoptosis). During this dynamic process, the ECM stiffness and cell stiffness are not well balanced, and the continuously enlarged stiffness gap between them potentiates keloid progression. The cushion factors, such as prestress for cell stiffness and topology for ECM stiffness, serve as compensations, the decompensation of which aggravates keloid development. It can well explain the typical shape of keloids, their progression in a horizontal but not vertical direction and the post-surgical recurrence, which were evidenced by our clinical cases. Such a stiffness gap hypothesis might be bridged to mechanotherapeutic approaches for keloid progression.

Association of plasminogen activator inhibitor-1 and vitamin D receptor expression with the risk of keloid disease in a Chinese population

Keloid disease (KD) is a benign fibroproliferative scarring condition of unknown etiopathogenesis. Plasminogen activator inhibitor-1 (PAI-1) and vitamin D receptor (VDR) have been shown to play important roles in the progression of tissue fibrosis; therefore, both these genes are potential susceptibility genes for KD. We aimed to determine whether the gene expression levels of PAI-1 and VDR are altered in Chinese KD patients. We measured the expression of PAI and VDR in human peripheral blood lymphocytes in 236 patients with keloid and 219 age- and sex-matched healthy controls by quantitative real-time polymerase chain reaction. We found that PAI-1 expression in peripheral blood lymphocytes was significantly higher in patients with KD than in control individuals (p < 0.0001), while VDR expression was significantly lower in KD patients than in control individuals (p < 0.0001). High levels of PAI-1 and low levels of VDR expression were significantly associated with an increased risk for KD. PAI-1 and VDR might play important roles in keloid development. Gene expression levels of PAI-1 and VDR may, therefore, be used as potential markers for the prediction of keloid development after scarring.

Examination of Epithelial Mesenchymal Transition in Keloid Tissues and Possibility of Keloid Therapy Target.

Background:Keloid is a fibroproliferative skin disorder that is characterized by collagen accumulation and blood vessel proliferation in the reticular layer of the dermis. It is caused by prolonged inflammation after cutaneous injury. Several studies suggested recently that epithelial mesenchymal transition (EMT) is involved in the development of fibrosis. This study assessed whether EMT also participates in keloid development and/or aggravation.Methods:Resected keloid (n = 19) and normal skin (n = 13) samples were subjected to immunohistochemical, immunofluorescent, and Western blot analyses of their expression of epidermal (E-cadherin) and mesenchymal (vimentin) proteins.Results:Immunohistochemical analysis showed that the keloid tissues had more vimentin-positive cells in the epidermis than the normal tissues. When normal primary keratinocytes were cultured with proinflammatory cytokines, the cobblestone-shaped cells changed to a spindle shape and many vimentin-positive cells were detected. When immortalized HaCaT keratinocytes were cocultured in split-well plates with normal or keloid-derived fibroblasts, they also underwent EMT, as indicated by their greater vimentin expression on Western blot analysis compared with HaCaT cells that were cultured alone.Conclusions:EMT was observed in keloid specimens. EMT was induced by inflammatory cytokines and fibroblasts. EMT may be involved in keloid generation and/or aggravation and may have potential as a keloid treatment target.

Massive ear keloids: Natural history, evaluation of risk factors and recommendation for preventive measures – A retrospective case series

Keloid disorder (KD) is an inherited wound healing ailment, frequently seen among Africans /African Americans and Asians. Genetics of this disorder continues to be obscure and poorly understood. Clinical manifestation of KD is quite variable and very diverse, spanning from individuals with one or very few small keloidal lesions, to those with numerous and very large lesions covering large portion of their skin. Ears are common locations for development of keloids. Ear piercing is by far the leading triggering factor for ear keloid formation in genetically predisposed individuals. Although there are numerous publications about ear and earlobe keloids, there is a void in medical literature about massive ear keloids. This paper focuses on the natural history of massive ear keloids and risk factors that lead to formation of these life-changing and debilitating tumors and recommendations for prevention.

Reconstruction after Anterior Chest Wall Keloid Resection Using Internal Mammary Artery Perforator Propeller Flaps.

Background:It is difficult to completely resect huge anterior chest wall keloids and then close the wound directly. We report here our retrospective analysis of our case series of patients with such keloids who underwent reconstruction with internal mammary artery perforator (IMAP) pedicled propeller flaps and then received postoperative high-dose-rate superficial brachytherapy.Methods:All consecutive patients with large/severe keloids on the anterior chest wall who underwent keloid resection followed by reconstruction with IMAP-pedicled propeller flaps and then high-dose-rate superficial brachytherapy in our academic hospital were identified. All cases were followed for >18 months. Donor site position, perforator pedicle, flap size, angle of flap rotation, complications, and recurrence were documented.Results:There were nine men and one woman. The average age was 37.9 years. The average follow-up duration was 28.7 months. The largest flap was 16 × 4 cm. The dominant perforators of the internal mammary artery were located in the sixth (n = 2), seventh (n = 5), eighth (n = 1), and ninth (n = 2) intercostal spaces. Twelve months after surgery, patients reported marked relief from keloid-associated pain and itching, except in two patients who underwent partial keloid resection; their remaining keloids were still troublesome but after conservative therapies, including steroid ointments/plasters, the keloids gradually ameliorated. Eighteen months after surgery, there was no keloid recurrence or new development of keloids on the donor site.Conclusions:IMAP-pedicled propeller flaps transfer skin tension from the anterior chest wall to the abdomen. Our series suggests that this approach combined with radiation therapy can control keloid recurrence.

Neck keloids: evaluation of risk factors and recommendation for keloid staging system.

Importance:Health care providers have long struggled with recurrent and hard to treat keloids. Advancing our understanding of natural history and risk factors for development of large, very large and massive neck keloids can lead to improved treatment outcomes. Clinical staging system for the categorization of keloid lesions, as well as grouping of keloid patients according to the extent of skin involvement is both fundamental for design and delivery of proper plan of care and an absolute necessity for methodical trial design and interpretation of the results thereof. Objective: To review clinical presentation and natural history of neck keloids; to explore risk factors for development of large, very large and massive neck keloids; and to propose a clinical staging system that allows for categorization of keloid lesions by their size and grouping of keloid patients by the extent of their skin involvement. Setting:This is a retrospective analysis of 82 consecutive patients with neck keloids who were seen by the author in his keloid specialty medical practice. Intervention: Non-surgical treatment was offered to all patients. Results: Neck-area keloids were found to have several unique characteristics. All 65 African Americans in this study had keloidal lesions elsewhere on their skin. Very large and massive neck keloids appear to be race-specific and almost exclusively seen among African Americans. Submandibular and submental skin was the most commonly involved area of the neck.Keloid removal surgery was found to be the main risk factor for development of very large and massive neck keloids. Conclusions and relevance: Surgical removal of neck keloids results in wounding of the skin and triggering a pathological wound-healing response that often leads to formation of a much larger keloid. Given the potential for greater harm from surgery, the author proposes non-surgical approach for treatment of all primary neck keloids. Author's attempts to properly categorize keloid lesions and to group the study subjects was hampered by the lack of a previously defined methodology. A clinical staging system is proposed to address the deficiency in grouping of keloid patients according to the size and extent of skin involvement with keloid lesions.

Neck keloids: evaluation of risk factors and recommendation for keloid staging system

Importance: Health care providers have long struggled with recurrent and hard to treat keloids. Advancing our understanding of natural history and risk factors for development of large, very large and massive neck keloids can lead to improved treatment outcomes. Clinical staging system for the categorization of keloid lesions, as well as grouping of keloid patients according to the extent of skin involvement is both fundamental for design and delivery of proper plan of care and an absolute necessity for methodical trial design and interpretation of the results thereof. Objective: To review clinical presentation and natural history of neck keloids; to explore risk factors for development of large, very large and massive neck keloids; and to propose a clinical staging system that allows for categorization of keloid lesions by their size and grouping of keloid patients by the extent of their skin involvement. Setting: This is a retrospective analysis of 68 consecutive patients with neck keloids who were seen by the author in his keloid specialty medical practice. Intervention: Non-surgical treatment was offered to all patients. Results: Neck-area keloids were found to have several unique characteristics. All 53 African Americans in this study had keloidal lesions elsewhere on their skin. Very large and massive neck keloids appear to be race-specific and almost exclusively seen among African Americans. Keloid removal surgery was found to be the main risk factor for development of very large and massive neck keloids. Conclusions and relevance: Surgical removal of neck keloids results in wounding of the skin and triggering a pathological wound-healing response that often leads to formation of a much larger keloid. Given the potential for greater harm from surgery, the author proposes non-surgical approach for treatment of all primary neck keloids. Author’s attempts to properly categorize keloid lesions and to group the study subjects was hampered by the lack of a previously defined methodology. A clinical staging system is proposed to address the deficiency in grouping of keloid patients according to the size and extent of skin involvement with keloid lesions.

112. Potent Antifibrotic Effect on Human Dermal Fibroblasts and Keloid Spheroids by Adenovirus-Mediated Inhibition of Wnt and TGF-β Signaling

Aberrant activation of the canonical Wingless type (Wnt) signaling pathway plays a key role in the development of hypertrophic scars and keloids. This aberrant activation of the canonical Wnt pathway and its potent profibrotic effects suggest that Wnt pathway can be a potential target for the development of novel anti-fibrotic agents. In this study, we evaluated the anti-fibrotic potential of a soluble Wnt decoy receptor (sLRP6E1E2)-expressing non-replicating adenovirus (Ad; dE1-k35/sLRP6E1E2) on human dermal fibroblasts (HDFs) and keloid spheroid. Wnt family member 3a and its effector β-catenin expression in keloid tissues were analyzed by hematoxylin and eosin and immunohistochemical staining. HDFs were transduced with dE1-k35/sLRP6E1E2 or control Ad vector (dEl-k35/LacZ), and then luciferase reporter assay for β-catenin activity was performed. Furthermore, change in type-I and -III collagen mRNA levels in HDFs were measured by quantitative real time PCR. Wnt intracellular signaling and secreted transforming growth factor-β1 (TGF-β1) protein expression were examined by western blot and the enzyme-linked immunosorbent assay, respectively. The effect of sLRP6E1E2 on the nuclear localization of β-catenin and Smad 2/3 complex was evaluated by immunofluorescence staining. Lastly, the expression levels of major extracellular matrix components were investigated by immunohistochemistry in keloid spheroids after transduction with dEl-k35/LacZ or dE1-k35/sLRP6E1E2. Higher Wnt3a and β-catenin expression was observed in the keloid region compared to the adjacent normal tissues. The activity of β-catenin and mRNA expression of type-I and -III collagen were significantly decreased following treatment with dE1-k35/sLRP6E1E2. The expression of LRP6, β-catenin, phosphorylated glycogen synthase kinase 3 beta, Smad 2/3 complex, and TGF-β1 were decreased in Wnt3a- or TGF-β1-activated HDFs, following administration of dE1-k35/sLRP6E1E2. Moreover, dE1-k35/sLRP6E1E2 markedly inhibited nuclear translocation of both β-catenin and Smad 2/3 complex. The expression levels of type-I and -III collagen, fibronectin, and elastin were also significantly reduced in keloid spheroids after treatment with dE1-k35/sLRP6E1E2. These results indicate that Wnt decoy receptor-expressing Ad can degrade extracellular matrix in HDFs and primary keloid spheroids, and thus it could be highly beneficial for treatment of keloids.

Causal network analysis of head and neck keloid tissue identifies potential master regulators.

To generate novel insights and hypotheses in keloid development from potential master regulators. Prospective cohort. Six fresh keloid and six normal skin samples from 12 anonymous donors were used in a prospective cohort study. Genome-wide profiling was done previously on the cohort using the Infinium HumanMethylation450 BeadChip (Illumina, San Diego, CA). The 190 statistically significant CpG islands between keloid and normal tissue mapped to 152 genes (P < .05). The top 10 statistically significant genes (VAMP5, ACTR3C, GALNT3, KCNAB2, LRRC61, SCML4, SYNGR1, TNS1, PLEKHG5, PPP1R13-α, false discovery rate <.015) were uploaded into the Ingenuity Pathway Analysis software's Causal Network Analysis (QIAGEN, Redwood City, CA). To reflect expected gene expression direction in the context of methylation changes, the inverse of the methylation ratio from keloid versus normal tissue was used for the analysis. Causal Network Analysis identified disease-specific master regulator molecules based on downstream differentially expressed keloid-specific genes and expected directionality of expression (hypermethylated vs. hypomethylated). Causal Network Analysis software identified four hierarchical networks that included four master regulators (pyroxamide, tributyrin, PRKG2, and PENK) and 19 intermediate regulators. Causal Network Analysis of differentiated methylated gene data of keloid versus normal skin demonstrated four causal networks with four master regulators. These hierarchical networks suggest potential driver roles for their downstream keloid gene targets in the pathogenesis of the keloid phenotype, likely triggered due to perturbation/injury to normal tissue. NA Laryngoscope, 126:E319-E324, 2016.

Intralesional cryosurgery for the treatment of keloid scars following cochlear implant surgery and removal of cholesteatoma

The development of hypertrophic scars and keloids is a relatively common complication of different otologic procedures involving incision of the skin behind the ear. This case report aims to describe the successful treatment of keloids that developed following ear surgeries that have been performed via a retro-auricular approach (cochlear implantation and the removal of cholesteatoma) by an intralesional cryosurgery method. Two patients who were previously operated for an extensive pediatric cholesteatoma and one patient who underwent a cochlear implant surgery have developed large keloids at the radix helix. The keloids were treated under local anesthesia by the intralesional cryosurgery method. Over a 6-month period, the scars gradually flattened and became paler and the clinical symptoms of itchiness, pain, and tenderness have significantly been reduced. No complications were documented, and there were no recurrences in a follow-up period of 30 months. This case report demonstrates that intralesional cryosurgery provides the surgeon with an effective method to treat keloid scars following the removal of cholesteatoma or cochlear implantation, thus improving the quality of life and body image and enabling the patients to use the implanted device in an adequate and satisfactory way. Level of Evidence: Level V, therapeutic study.

Clinical Analysis of Lobular Keloid after Ear Piercing.

BackgroundLobular keloid appears to be a consequence of hypertrophic inflammation secondary to ear piercings performed under unsterile conditions. We wish to understand the pathogenesis of lobular keloids and report operative outcomes with a literature review.MethodsA retrospective review identified 40 cases of lobular keloids between January, 2005 and December, 2010. Patient records were reviewed for preclinical factors such as presence of inflammation after ear piercing prior to keloid development, surgical management, and histopathologic correlation to recurrence.ResultsThe operation had been performed by surgical core extirpation or simple excision, postoperative lobular compression, and scar ointments. Perivascular infiltration was noted in intra- and extra-keloid tissue in 70% of patients. The postoperative recurrence rate was 10%, and most of the patients satisfied with treatment outcomes.ConclusionHistological perivascular inflammation is a prominent feature of lobular keloids. Proper surgical treatment, adjuvant treatments, and persistent follow-up observation were sufficient in maintaining a relatively low rates of recurrence.

MiR-181a Targets PHLPP2 to Augment AKT Signaling and Regulate Proliferation and Apoptosis in Human Keloid Fibroblasts

Background/Aims: Keloids are fibrous overgrowths induced by cutaneous injury. MicroRNAs (miRNAs) have recently emerged as post-transcriptional gene repressors and participants in a diverse array of pathophysiological processes leading to skin disease. The purpose of the current study was to explore the precise functions of miR-181a in human keloid development and the underlying mechanisms. Methods: A miRNA microarray analysis was performed to compare expression profiles between keloid and normal skin tissues. Quantitative real-time PCR was conducted to estimate miR-181a expression. Cell proliferation was determined using the cell counting kit-8 (CCK-8) and 5-ethynyl-2-deoxyuridine (EdU) assays, and cell cycle and apoptosis were detected with flow cytometry. Direct targets of miR-181a were identified using the luciferase reporter assay. Results: miR-181a was significantly upregulated in human keloid tissues and fibroblasts, compared with their control counterparts. Overexpression of miR-181a enhanced keloid fibroblast DNA synthesis and proliferation and inhibited apoptosis, whereas miR-181a suppression triggered the opposite effects. Moreover, miR-181a suppressed the expression of PH domain leucine-rich repeat protein phosphatase 2 (PHLPP2) through direct interactions with its 3′UTR region and subsequently enhanced AKT activation. Overexpression of PHLPP2 without its 3′UTR attenuated the effects of miR-181a on cell proliferation and apoptosis in keloid fibroblast cells. Furthermore, miR-181a mimics increased normal skin fibroblast proliferation. Conclusions: Our results highlight a novel pathway mediated by miR-181a, which may be effectively used as a therapeutic target for treatment of keloids.