The role of melanocytes in the human choroidal microenvironment and inflammation: Insights from the transcriptome

Cioanca, Adrian V.; Wu, Chieh‐Lin; Natoli, Riccardo; Conway, R Max; McCluskey, Peter; Jager, Martine J.; Sitiwin, E.; Eamegdool, Steven S.; Madigan, Michele C.

doi:10.1111/pcmr.12972

Cited by 14 publications

(4 citation statements)

References 67 publications

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“…Recent studies indicate that ITGA1 is associated with melanoma proliferation via the regulation of miR-3065-5p ( 25 ). In addition, as a mediator of cell-cell and cell-matrix adhesion, ITGA1 was differentially expressed in melanoma samples ( 26 ). In the present study, we found that ITGA1 expression levels in SKCM tissues are correlated with different stages of SKCM and with migration in SKCM.…”

Section: Discussionmentioning

confidence: 99%

Identification of Therapeutic Targets and Prognostic Biomarkers Among Integrin Subunits in the Skin Cutaneous Melanoma Microenvironment

Nurzat

Min

et al. 2021

Front. Oncol.

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The roles of different integrin alpha/beta (ITGA/ITGB) subunits in skin cutaneous melanoma (SKCM) and their underlying mechanisms of action remain unclear. Oncomine, UALCAN, GEPIA, STRING, GeneMANIA, cBioPortal, TIMER, TRRUST, and Webgestalt analysis tools were used. The expression levels of ITGA3, ITGA4, ITGA6, ITGA10, ITGB1, ITGB2, ITGB3, ITGB4, and ITGB7 were significantly increased in SKCM tissues. The expression levels of ITGA1, ITGA4, ITGA5, ITGA8, ITGA9, ITGA10, ITGB1, ITGB2, ITGB3, ITGB5, ITGB6 and ITGB7 were closely associated with SKCM metastasis. The expression levels of ITGA1, ITGA4, ITGB1, ITGB2, ITGB6, and ITGB7 were closely associated with the pathological stage of SKCM. The expression levels of ITGA6 and ITGB7 were closely associated with disease-free survival time in SKCM, and the expression levels of ITGA6, ITGA10, ITGB2, ITGB3, ITGB6, ITGB7, and ITGB8 were markedly associated with overall survival in SKCM. We also found significant correlations between the expression of integrin subunits and the infiltration of six types of immune cells (B cells, CD8+ T cells, CD4+T cells, macrophages, neutrophils, and dendritic cells). Finally, Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed, and protein-protein interaction (PPI) networks were constructed. We have identified abnormally-expressed genes and gene regulatory networks associated with SKCM, improving understanding of the underlying pathogenesis of SKCM.

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Section: Discussionmentioning

confidence: 99%

Identification of Therapeutic Targets and Prognostic Biomarkers Among Integrin Subunits in the Skin Cutaneous Melanoma Microenvironment

Nurzat

Min

et al. 2021

Front. Oncol.

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“…Choroidal melanocytes represent neural crest‐derived melanin‐producing cells, which are located abundantly in the human choroid (Nickla & Wallman, 2010). The functional roles of NCM include light absorption by cytoplasmic melanins, antioxidant protection and were recently shown to modulate inflammatory pathways (Cioanca et al, 2021; Wakamatsu et al, 2008). The UM is originated from melanocytes of the uveal tract, furthermore, more than 90% of cases involving the choroid (Park et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Autophagy and vesicular trafficking in human uveal melanoma: A histopathological study

Taskaeva,

Shatruk,

Bgatova

et al. 2023

Microscopy Res & Technique

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Uveal melanoma is an ocular tumor with a high risk of developing metastases. The endo‐lysosomal system can affect the melanoma progression by accelerating and facilitating invasion or metastasis. This study aims to conduct comparative analysis of normal choroidal melanocytes and uveal melanoma cells ultrastructure with a focus on intracellular transport system, and to examine the patterns of autophagy‐ and vesicular trafficking‐related proteins expression in a case series of uveal melanomas. Transmission electron microscopy was used to assess the ultrastructure of normal choroidal melanocytes and uveal melanoma cells. The expression levels of autophagy‐ and vesicular trafficking‐related proteins in three histological types of uveal melanoma were analyzed by immunofluorescence staining. Electron microscopy results showed that the autophagic vacuoles were more abundant in normal choroidal melanocytes, than in uveal melanoma cells. The normal choroidal melanocytes were characterized by active intracellular vesicular trafficking; however, the proportion of caveolae was higher in uveal melanoma cells. The spindle type of tumor was characterized by a high expression levels of LC3 beta, while Rab7 and Rab11 proteins expression was significantly up‐regulated in the mixed‐type tumor cells. The results indicate that uveal melanoma cells probably have lower basal levels of autophagy and higher receptor‐mediated endocytic trafficking‐associated with caveolae than normal choroidal melanocytes.Research Highlights The autophagic vacuoles are abundant in normal choroidal melanocytes. Uveal melanoma cells are characterized by a high proportion of caveolae. The high expression levels of LC3 beta were revealed in a spindle type of tumor, while Rab7 and Rab11 proteins expression was up‐regulated in the mixed‐type tumor cells.

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“…Recently, human choroidal melanocytes were shown to respond to inflammation by increased expression of inflammatory cytokines and genes associated with cell adhesion and angiogenesis [26]. Impaired melanogenesis may impact ability of the choroid to respond to inflammation, leading to increased inflammation and a thicker choroid.…”

Section: Discussionmentioning

confidence: 99%

Loss of REP1 impacts choroidal melanogenesis in choroideremia

Sarkar

Tracey‐White

Hagag

et al. 2023

Preprint

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Choroideremia (CHM) is a rare X-linked chorioretinal dystrophy affecting the photoreceptors, retinal pigment epithelium (RPE) and choroid, however, the involvement of the choroid in disease progression is not fully understood. CHM is caused by mutations in the CHM gene, encoding the ubiquitously expressed Rab escort protein 1 (REP1). REP1 plays an important role in intracellular trafficking of vesicles, including melanosomes. In this study, we examined ultrastructure of the choroid in chmru848 fish and Chmnull/WT mouse models using transmission electron microscopy. Significant pigmentary disruptions were observed, with a lack of melanosomes in the choroid of chmru848 fish from 4 days post fertilisation (4dpf). Total melanin and expression of melanogenesis genes tyr, tryp1a, mitf, dct and pmel were also reduced from 4dpf. In Chmnull/WT mice, choroidal melanosomes were significantly smaller at 1 month and at 1 year, eumelanin was reduced, and the choroid was thicker. The choroid in CHM patients was also examined using optical coherence tomography (OCT) and OCT-angiography (OCT-A) and the area of preserved choriocapillaris (CC) was found to be smaller than that of overlying photoreceptors, indicating that the choroid is degenerating at a faster rate. Histopathology of an enucleated eye from a 74-year-old CHM male patient revealed isolated areas of RPE but no associated underlying CC. Significant degenerative changes in the choroid of CHM patients and animal models are seen, highlighting the importance of administrative routes involving the choroid, such as suprachoroidal delivery. Pigmentary disruptions in CHM animal models reveal an important role for REP1 in melanogenesis, and drugs that improve melanin production represent a potential novel therapeutic avenue.

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The role of melanocytes in the human choroidal microenvironment and inflammation: Insights from the transcriptome

Cited by 14 publications

References 67 publications

Identification of Therapeutic Targets and Prognostic Biomarkers Among Integrin Subunits in the Skin Cutaneous Melanoma Microenvironment

Identification of Therapeutic Targets and Prognostic Biomarkers Among Integrin Subunits in the Skin Cutaneous Melanoma Microenvironment

Autophagy and vesicular trafficking in human uveal melanoma: A histopathological study

Loss of REP1 impacts choroidal melanogenesis in choroideremia

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