Melanocyte Precursors in the Hair Follicle Bulge of Repigmented Vitiligo Skin Are Controlled by RHO-GTPase, KCTD10, and CTNNB1 Signaling

Goldstein, Nathaniel B.; Steel, Andrea; Barbulescu, Chauncey C.; Koster, Maranke I.; Wright, Michael; Jones, Kenneth L.; Gao, Bifeng; Ward, Brian M.; Woessner, Brian; Trottier, Zachary; Pakieser, Jen; Hu, Junxiao; Lambert, K.; Shellman, Yiqun G.; Fujita, Mayumi; Robinson, William A.; Roop, Dennis R.; Norris, David A.; Birlea, Stanca A.

doi:10.1016/j.jid.2020.07.016

Cited by 11 publications

(11 citation statements)

References 72 publications

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“…These findings were in line with previous studies. In a study about human vitiligo, Goldstein et al demonstrated that knockdown of RhoJ impacted epidermal melanocyte migration, differentiation and cell cycle 41 . Here, we found that RhoJ deficit in HUVEC cells suppressed the migration of GBM cells by transwell assay with the conditioned medium treatment.…”

Section: Discussionmentioning

confidence: 99%

RhoJ facilitates angiogenesis in glioblastoma via JNK/VEGFR2 mediated activation of PAK and ERK signaling pathways

Wang¹,

Zhang²,

Zheng³

et al. 2022

Int. J. Biol. Sci.

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Glioblastoma (GBM) is a highly vascularized malignant tumor that depends on new blood vessel formation. Small molecules targeting the angiogenic process may be an effective anti-GBM therapeutic strategy. We previously demonstrated that RhoJ promoted the progression and invasion of GBM. RhoJ has also been shown to be expressed in endothelial cells and plays an important role in regulating endothelial cell migration and tumor angiogenesis. Therefore, we aimed to evaluate the role and mechanism of actions of RhoJ in GBM angiogenesis. We analyzed the expression of RhoJ in different grade gliomas and investigated its role in GBM angiogenesis in vivo and in vitro. Furtherly, RNA sequencing (RNA-seq), Western blotting and immunofluorescence were performed to identify the molecular mechanism of RhoJ in regulating endothelial cell behavior and GBM angiogenesis. Here, we found that silencing RhoJ resulted in inhibition of HUVEC cell migration and blood vessel formation. Overexpression of RhoJ promoted the expression of CD31, EpCAM and moesin, suggesting RhoJ facilitated angiogenesis and the malignant progression of GBM. RNA-seq data showed that VEGF/TNF signaling pathway positively regulated RhoJ. The expression levels of RhoJ was upregulated with the stimulation of VEGF, and reduced by the treatment of JNK inhibitor SP600125. It was also found that the activity of PAK-BRAF-ERK was down-regulated upon RhoJ and JNK knockdown. In conclusion, these results suggested that RhoJ plays an essential role in regulating GBM angiogenesis through the JNK/VEGFR2-PAK-ERK signaling pathway and there might exist a VEGF-JNK/ERK-VEGF circuitry. Thus, RhoJ may be a candidate therapeutic target for anti-angiogenesis treatment in GBM.

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Section: Discussionmentioning

confidence: 99%

RhoJ facilitates angiogenesis in glioblastoma via JNK/VEGFR2 mediated activation of PAK and ERK signaling pathways

Wang¹,

Zhang²,

Zheng³

et al. 2022

Int. J. Biol. Sci.

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“…Interestingly, a study showed that the β‐catenin expression in TCQA‐treated mouse skin was increased in the hair follicle bulb area 125 . Of note, repigmentation in the hair follicle bulge melanocyte precursors has been driven by CTNNB1 (encoding β‐catenin) 65 . These findings suggest that TCQA may contribute to vitiligo repigmentation by activating β‐catenin in hair follicle bulge McSCs.…”

Section: Agents and Nature Compounds Activating Wnt/β‐catenin Signall...mentioning

confidence: 99%

“…Using genetic mouse models, it was shown that β‐catenin is required for hair follicle McSC differentiation 59 . Recently, combination of laser capture microdissection and subsequent whole transcriptome RNA sequencing identified β‐catenin as the top activated transcription regulator in the melanocyte precursors of narrow‐band (NB) UVB‐treated hair follicle bulge in vitiligo skin 57 and identified CTNNB1 (encoding β‐catenin), the top stem cell gene upregulated in the bulge melanocytes of NBUVB‐treated vitiligo skin, a driver of repigmentation in the bulge melanocyte precursors 65 . These findings reemphasize the role of β‐catenin activation in the differentiation of hair follicle McSCs, driving repigmentation in vitiligo skin.…”

Section: The Role Of Wnt/β‐catenin Pathway In Melanocyte Regenerationmentioning

confidence: 99%

The possible role of Wnt/β‐catenin signalling in vitiligo treatment

Lin

Meng

Lin

2023

Acad Dermatol Venereol

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Vitiligo is a common chronic skin disease which has an adverse impact on patients' life. Its pathogenesis is complex, involving autoimmunity and oxidative stress (OS). Autoimmunity leads to the loss of epidermal melanocytes and the formation of the depigmented patches of the disease. Treatment of vitiligo should control the exaggerated immune response to arrest the progress of active disease, and then promote melanocytes to repigmentation. Wnt/β‐catenin signalling pathway has been of recent interest in vitiligo. Wnt/β‐catenin signalling pathway is downregulated in vitiligo. Upregulation of Wnt/β‐catenin signalling possibly control vitiligo autoimmune response by protecting melanocyte from OS damage, inhibiting CD8+ T cell effector cell differentiation and enhancing Treg. Wnt/β‐catenin signalling plays a critical role in the melanocyte regeneration by driving the differentiation of melanocyte stem cells (McSCs) into melanocytes. Promoting Wnt/β‐catenin signalling can not only arrest the progress of active disease of vitiligo but also promote repigmentation. Some of the main effective therapies for vitiligo are likely to work by activating Wnt/β‐catenin signalling. Agents that can enhance the effect of Wnt/β‐catenin signalling may become potential candidates for the development of new drugs for vitiligo treatment.

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“…Occludin mediates cell adhesion through a unique self-ligand mechanism (see supplementary materials figure S1 ). Interestingly, OCLN was upregulated in melanocyte precursors of vitiligo patients via transcriptome sequencing [ 16 ]. However, it remains unclear whether occludin, a membrane protein, mediates the adhesion of lymphocytes and melanocytes, thereby assisting CD8 + T cells to kill melanocytes.…”

Section: Introductionmentioning

confidence: 99%

Occludin Promotes Adhesion of CD8+ T Cells and Melanocytes in Vitiligo via the HIF-1α Signaling Pathway

Zou

Xiao

Deng

et al. 2022

Oxidative Medicine and Cellular Longevity

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Loss of melanocytes induced by activated CD8+ T cells is the pathological hallmark of vitiligo. Melanocyte-specific CD8+ T cells are recruited to the skin via chemokines, thereby releasing perforin, granzyme, and other cytotoxic substances that destroy the melanocytes. However, the mechanism of CD8+ T cells to adhere to melanocytes is unknown. Previous transcriptome sequencing results published by our group showed that the occluding (OCLN) gene was significantly upregulated in CD8+ T cells from skin lesions of vitiligo. Occludin is a crucial component of the tight junction between cells; in cells without tight junction, occludin mediates the adhesion of two cells in the form of a self-ligand. This study demonstrated that OCLN gene expression was elevated in the CD8+ T cells of vitiligo patients, and occludin mediates the adherence of CD8+ T cells to melanocytes. Besides, pathological changes in vitiligo skin lesions reveal that CD8+ T cells continuously persist in the skin lesions, which is related to the persistence of the disease. In this regard, we found that fibroblasts from vitiligo patients significantly express occludin, which may participate in the continuous retention of CD8+ T cells in the skin lesions. The pathogenesis of vitiligo is closely related to oxidative stress, and our data suggest that overexpression of hypoxia-inducible factor-1α (HIF-1α) increases the expression of occludin. Besides, ChIP-qPCR of CD8+ T cells revealed that HIF-1α directly binds to the OCLN promoter. Thus, occludin upregulation promotes the adhesion of CD8+ T cells and melanocytes via the HIF-1α signaling pathway. Our study results suggested a critical role for OCLN in the occurrence, progression, and maintenance of vitiligo. Therefore, inhibiting the expression of OCLN gene may be a potential targeted treatment strategy.

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Melanocyte Precursors in the Hair Follicle Bulge of Repigmented Vitiligo Skin Are Controlled by RHO-GTPase, KCTD10, and CTNNB1 Signaling

Cited by 11 publications

References 72 publications

RhoJ facilitates angiogenesis in glioblastoma via JNK/VEGFR2 mediated activation of PAK and ERK signaling pathways

RhoJ facilitates angiogenesis in glioblastoma via JNK/VEGFR2 mediated activation of PAK and ERK signaling pathways

The possible role of Wnt/β‐catenin signalling in vitiligo treatment

Occludin Promotes Adhesion of CD8+ T Cells and Melanocytes in Vitiligo via the HIF-1α Signaling Pathway

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