WNT5A drives interleukin-6-dependent epithelial–mesenchymal transition via the JAK/STAT pathway in keloid pathogenesis

Lee, Young In; Shim, Jung Eun; Kim, Jihee; Lee, Won Jai; Kim, Jae Woo; Nam, Kee Hyun

doi:10.1093/burnst/tkac023

Cited by 19 publications

(14 citation statements)

References 59 publications

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“… 167 Moreover, activation of the IL-6-JAK-STAT pathway by WNT5A is known to facilitate epithelial-mesenchymal transition (EMT) in keloid scarring. 160 A more comprehensive understanding of the effects of the JAK-STAT signaling pathway on lineage plasticity will provide a plausible molecular basis for the development of new therapies for malignant diseases. 168 …”

Section: The Jak-stat Pathway Immunoregulation and Lineage Plasticitymentioning

confidence: 99%

“…[156][157][158] Cancer cells amplify this plasticity to cause tumor heterogeneity, metastasis, and therapy resistance. 156,159,160 The histologic transformation of lung cancers harboring epidermal growth factor receptor (EGFR) mutations from adenocarcinoma to aggressive neuroendocrine cancer is a notable example of lineage plasticity in cancer. 161,162 Numerous lines of evidence suggest that JAK-STAT signaling is tightly connected to lineage plasticity and resistance through stem cell self-renewal modulation and multilineage differentiation.…”

Section: Jak Stat and The Jak-stat Pathwaymentioning

confidence: 99%

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Evolving cognition of the JAK-STAT signaling pathway: autoimmune disorders and cancer

Xue

Yao

et al. 2023

Sig Transduct Target Ther

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The Janus kinase (JAK) signal transducer and activator of transcription (JAK-STAT) pathway is an evolutionarily conserved mechanism of transmembrane signal transduction that enables cells to communicate with the exterior environment. Various cytokines, interferons, growth factors, and other specific molecules activate JAK-STAT signaling to drive a series of physiological and pathological processes, including proliferation, metabolism, immune response, inflammation, and malignancy. Dysregulated JAK-STAT signaling and related genetic mutations are strongly associated with immune activation and cancer progression. Insights into the structures and functions of the JAK-STAT pathway have led to the development and approval of diverse drugs for the clinical treatment of diseases. Currently, drugs have been developed to mainly target the JAK-STAT pathway and are commonly divided into three subtypes: cytokine or receptor antibodies, JAK inhibitors, and STAT inhibitors. And novel agents also continue to be developed and tested in preclinical and clinical studies. The effectiveness and safety of each kind of drug also warrant further scientific trials before put into being clinical applications. Here, we review the current understanding of the fundamental composition and function of the JAK-STAT signaling pathway. We also discuss advancements in the understanding of JAK-STAT–related pathogenic mechanisms; targeted JAK-STAT therapies for various diseases, especially immune disorders, and cancers; newly developed JAK inhibitors; and current challenges and directions in the field.

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Section: The Jak-stat Pathway Immunoregulation and Lineage Plasticitymentioning

confidence: 99%

Section: Jak Stat and The Jak-stat Pathwaymentioning

confidence: 99%

Evolving cognition of the JAK-STAT signaling pathway: autoimmune disorders and cancer

Xue

Yao

et al. 2023

Sig Transduct Target Ther

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“…For example, in some instances, Wnt5a acting as a particularly attractive growth factor stimulates tissue regeneration (such as colonic crypt [ 22 ], osteochondral regeneration [ 23 ] and cartilage interface integration [ 23 ]) and wound healing [ 24 ]. While in other cases, the upregulation of Wnt5a has been implicated in aggravating a variety of tissue fibrosis and scar formation, such as cardiac fibrosis under pressure overload [ 25 ], myocardial fibrosis following myocardial infarction [ 26 ], atrial fibrosis [ 25 ], keloid scarring caused by aberrant genetic activation [ 13 ], idiopathic pulmonary fibrosis [ 27 ], renal fibrosis [ 28 ], and liver fibrosis [ 29 ]. However, the specific involvement of Wnt5a in the EMT process of RPE cells and subretinal fibrosis formation in nAMD remains elusive.…”

Section: Introductionmentioning

confidence: 99%

Wnt5a/β-catenin-mediated epithelial-mesenchymal transition: a key driver of subretinal fibrosis in neovascular age-related macular degeneration

Liu,

Du,

Xie

et al. 2024

J Neuroinflammation

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Background Neovascular age-related macular degeneration (nAMD), accounts for up to 90% of AMD-associated vision loss, ultimately resulting in the formation of fibrotic scar in the macular region. The pathogenesis of subretinal fibrosis in nAMD involves the process of epithelial–mesenchymal transition (EMT) occurring in retinal pigment epithelium (RPE). Here, we aim to investigate the underlying mechanisms involved in the Wnt signaling during the EMT of RPE cells and in the pathological process of subretinal fibrosis secondary to nAMD. Methods In vivo, the induction of subretinal fibrosis was performed in male C57BL/6J mice through laser photocoagulation. Either FH535 (a β-catenin inhibitor) or Box5 (a Wnt5a inhibitor) was intravitreally administered on the same day or 14 days following laser induction. The RPE-Bruch's membrane-choriocapillaris complex (RBCC) tissues were collected and subjected to Western blot analysis and immunofluorescence to examine fibrovascular and Wnt-related markers. In vitro, transforming growth factor beta 1 (TGFβ1)-treated ARPE-19 cells were co-incubated with or without FH535, Foxy-5 (a Wnt5a-mimicking peptide), Box5, or Wnt5a shRNA, respectively. The changes in EMT- and Wnt-related signaling molecules, as well as cell functions were assessed using qRT-PCR, nuclear-cytoplasmic fractionation assay, Western blot, immunofluorescence, scratch assay or transwell migration assay. The cell viability of ARPE-19 cells was determined using Cell Counting Kit (CCK)-8. Results The in vivo analysis demonstrated Wnt5a/ROR1, but not Wnt3a, was upregulated in the RBCCs of the laser-induced CNV mice compared to the normal control group. Intravitreal injection of FH535 effectively reduced Wnt5a protein expression. Both FH535 and Box5 effectively attenuated subretinal fibrosis and EMT, as well as the activation of β-catenin in laser-induced CNV mice, as evidenced by the significant reduction in areas positive for fibronectin, alpha-smooth muscle actin (α-SMA), collagen I, and active β-catenin labeling. In vitro, Wnt5a/ROR1, active β-catenin, and some other Wnt signaling molecules were upregulated in the TGFβ1-induced EMT cell model using ARPE-19 cells. Co-treatment with FH535, Box5, or Wnt5a shRNA markedly suppressed the activation of Wnt5a, nuclear translocation of active β-catenin, as well as the EMT in TGFβ1-treated ARPE-19 cells. Conversely, treatment with Foxy-5 independently resulted in the activation of abovementioned molecules and subsequent induction of EMT in ARPE-19 cells. Conclusions Our study reveals a reciprocal activation between Wnt5a and β-catenin to mediate EMT as a pivotal driver of subretinal fibrosis in nAMD. This positive feedback loop provides valuable insights into potential therapeutic strategies to treat subretinal fibrosis in nAMD patients.

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“…[37][38][39][40][41] Abnormalities of keloid keratinocytes have also been described, with aberrant expression of genes involved in migration, adhesion and differentiation, as well as abnormal paracrine interactions with fibroblasts. [42][43][44][45][46] Thus, the transcriptional profile of keloid keratinocytes resembles epithelial-mesenchymal transition (EMT), 42,47 a process that is involved in embryonic development and has been associated with fibrosis in other organs as well as with cancer metastasis. In EMT, epithelial cells acquire characteristics of mesenchymal cells, such as decreased adhesion and increased migration, in addition to expression of mesenchymal markers.…”

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confidence: 99%

A role for vitamin D and the vitamin D receptor in keloid disorder

Hahn

Combs

Powell

et al. 2023

Wound Repair Regeneration

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Keloids are disfiguring fibroproliferative lesions that can occur in susceptible individuals following any skin injury. They are extremely challenging to treat, with relatively low response rates to current therapies and high rates of recurrence after treatment. Although several distinct genetic loci have been associated with keloid formation in different populations, there has been no single causative gene yet identified and the molecular mechanisms guiding keloid development are incompletely understood. Further, although it is well known that keloids are more commonly observed in populations with dark skin pigmentation, the basis for increased keloid risk in skin of colour is not yet known. Because individuals with dark skin pigmentation are at higher risk for vitamin D deficiency, the role of vitamin D in keloid pathology has gained interest in the keloid research community. A limited number of studies have found lower serum vitamin D levels in patients with keloids, and reduced expression of the vitamin D receptor (VDR) in keloid lesions compared with uninjured skin. Vitamin D has documented anti‐inflammatory, anti‐proliferative and pro‐differentiation activities, suggesting it may have a therapeutic role in suppression of keloid fibrosis. Here we review the evidence supporting a role for vitamin D and VDR in keloid pathology.

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WNT5A drives interleukin-6-dependent epithelial–mesenchymal transition via the JAK/STAT pathway in keloid pathogenesis

Cited by 19 publications

References 59 publications

Evolving cognition of the JAK-STAT signaling pathway: autoimmune disorders and cancer

Evolving cognition of the JAK-STAT signaling pathway: autoimmune disorders and cancer

Wnt5a/β-catenin-mediated epithelial-mesenchymal transition: a key driver of subretinal fibrosis in neovascular age-related macular degeneration

A role for vitamin D and the vitamin D receptor in keloid disorder

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