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BACKGROUND: As the most important modifications on the RNA level, N6-methyladenosine (m6A-) and 5-methylcytosine (m5C-) modification could have a direct influence on the RNAs. Long non-coding RNAs (lncRNAs) could also be modified by methylcytosine modification. Compared with mRNAs, the function of lncRNAs could be more potent to some extent in biological processes like tumorigenesis. Until now, rare reports have been done associated with cutaneous melanoma. Herein, we wonder if the m6A- and m5C- modified lncRNAs could influence the immune landscape and prognosis in melanoma, and we also want to find some lncRNAs which could directly affect the malignant behaviors of melanoma. METHODS: Systematically, we explored the expression pattern of m6A- and m5C- modified lncRNAs in melanoma from datasets including UCSC Xena and NCBI GEO, and the prognostic lncRNAs were selected. Then, according to the expression pattern of lncRNAs, melanoma samples from these datasets were divided into several subtypes. Prognostic model, nomogram survival model, drug sensitivity, GO, and KEGG pathway analysis were performed. Furthermore, among several selected lncRNAs, we identified one lncRNA named LINC00893 and investigated its expression pattern and its biological function in melanoma cell lines. RESULTS: We identified 27 m6A- and m5C- related lncRNAs which were significantly associated with survival, and we made a subtype analysis of melanoma samples based on these 27 lncRNAs. Among the two subtypes, we found differences of immune cells infiltration between these two subtypes. Then, LASSO algorithm was used to screen the optimized lncRNAs combination including ZNF252P-AS1, MIAT, FAM13A-AS1, LINC-PINT, LINC00893, AGAP2-AS1, OIP5-AS1, and SEMA6A-AS1. We also found that there was a significant correlation between the different risk groups predicted based on RS model and the actual prognosis. The nomogram survival model based on independent survival prognostic factors was also constructed. Besides, sensitivity to chemotherapeutic agents, GO and KEGG analysis were performed. In different risk groups, a total of 14 drug molecules with different distributions were obtained, which included AZD6482, AZD7762, AZD8055, camptothecin, dasatinib, erlotinib, gefitinib, gemcitabine, GSK269962A, nilotinib, rapamycin, and sorafenib. A total of 55 significantly related biological processes and 17 KEGG signaling pathways were screened. At last, we noticed that LINC00893 had a relatively lower expression in melanoma tissue and cell lines compared with adjacent tissues and epidermal melanocyte, and down-regulation of LINC00893 could promote the malignant behavior of melanoma cells in A875 and MV3. In these two melanoma cell lines, down-regulation of m6A-related molecules like YTHDF3 and METTL3 could promote the expression of LINC00893. CONCLUSION: We made an analysis of m6A- and m5C- related lncRNAs in melanoma samples and a prediction of these lncRNAs' role in prognosis, tumor microenvironment, immune infiltration, and clinicopathological features. We also found that LINC00893, which is potentially regulated by m6A modification, could serve as a tumor-suppressor in melanoma and play an inhibitory role in melanoma metastasis.
Assuntos
Adenosina , Melanoma , RNA Longo não Codificante , Neoplasias Cutâneas , Humanos , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Melanoma/genética , Melanoma/patologia , Melanoma/mortalidade , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/mortalidade , Adenosina/análogos & derivados , Adenosina/metabolismo , Prognóstico , 5-Metilcitosina/análogos & derivados , 5-Metilcitosina/metabolismo , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Melanoma Maligno Cutâneo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , NomogramasRESUMO
BACKGROUND: Primary cutaneous CD30+ lymphoproliferative diseases are the second most common group of cutaneous T-cell lymphomas, including lymphomatoid papulosis (LyP), primary cutaneous anaplastic large-cell lymphoma (pcALCL), and borderline cases. These diseases form a spectrum and may show overlapping histopathological, phenotypic, and genetic features. In the 2016 WHO classification, LyP with 6p25.3 rearrangement was introduced as a rare new subtype of LyP and showed distinctive clinicopathological features. The striking biphasic histopathologic pattern presented with larger transformed lymphocytes diffusely infiltrating the dermis and smaller atypical cells infiltrating the epidermis as in pagetoid reticulosis. METHODS: Herein we report two cases of pcALCL with rearrangement involving the DUSP22-IRF4 locus on 6p25.3 that show the same particular biphasic histopathologic pattern. We review the literature regarding five similar reported cases and discuss the clinical, pathologic immunotype and follow-up features. RESULTS: Our findings suggest that the biphasic histopathologic pattern is not a unique characteristic of LyP with 6p25.3 rearrangement. CONCLUSION: Cutaneous CD30+ lymphoproliferative diseases with 6p25.3 rearrangement may have the same biphasic histopathological pattern and favorable prognosis, although a variety of clinical manifestations ranging from LyP to pcALCL and even anaplastic lymphoma kinase negative systemic ALCL with secondary cutaneous involvement may be observed.
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Linfoma Anaplásico Cutâneo Primário de Células Grandes/genética , Linfoma Anaplásico Cutâneo Primário de Células Grandes/patologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Idoso , Cromossomos Humanos Par 6/genética , Fosfatases de Especificidade Dupla/genética , Rearranjo Gênico , Humanos , Fatores Reguladores de Interferon/genética , Masculino , Pessoa de Meia-Idade , Fosfatases da Proteína Quinase Ativada por Mitógeno/genéticaRESUMO
Voltage-gated sodium channels are crucial mediators of neuronal damage in ischemic and excitotoxicity disease models. Fenamates have been reported to have anti-inflammatory properties following a decrease in prostaglandin synthesis. Several researches showed that fenamates appear to be ion channel modulators and potential neuroprotectants. In this study, the neuroprotective effects of tolfenamic acid, flufenamic acid, and mefenamic acid were tested by glutamate-induced injury in SH-SY5Y cells. Following this, fenamates' effects were examined on both the expression level and the function of hNav1.1 and hNav1.2, which were closely associated with neuroprotection, using Western blot and patch clamp. Finally, the effect of fenamates on the expression of apoptosis-related proteins in SH-SY5Y cells was examined. The results showed that both flufenamic acid and mefenamic acid exhibited neuroprotective effects against glutamate-induced injury in SH-SY5Y cells. They inhibited peak currents of both hNav1.1 and hNav1.2. However, fenamates exhibited decreased inhibitory effects on hNav1.1 when compared to hNav1.2. Correspondingly, the inhibitory effect of fenamates was found to be consistent with the level of neuroprotective effects in vitro. Fenamates inhibited glutamate-induced apoptosis through the modulation of the Bcl-2/Bax-dependent cell death pathways. Taken together, Nav1.2 might play a part in fenamates' neuroprotection mechanism. Nav1.2 and NMDAR might take part in the neuroprotection mechanism of the fenamates. The fenamates inhibited glutamate-induced apoptosis through modulation of the Bcl-2/Bax-dependent cell death pathways.
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Fenamatos/farmacologia , Ácido Glutâmico/farmacologia , Receptores de N-Metil-D-Aspartato/metabolismo , ortoaminobenzoatos/farmacologia , Ácido Glutâmico/metabolismo , Humanos , Fármacos Neuroprotetores , Técnicas de Patch-Clamp/métodos , Canais de Sódio Disparados por Voltagem/metabolismoRESUMO
Ginsenoside Rg1 (GsRg1), derived from the herb Ginseng, was found to exert protective effects in nerve injury; however, the mechanisms underlying these effects remain to be determined. Oxidant stress and apoptosis are known to be involved in sciatic nerve injury. Thus, the aim of this study was to examine whether GsRg1 was able to modify sciatic nerve injury in a rat model. The following parameters were measured: (1) number of spinal cord motoneurons by Nissl staining, (2) oxidation parameters including spinal cord malondialdehyde (MDA) levels and activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) as well as (3) involvement of apoptosis by determining caspase-3 and X-linked inhibitor of apoptosis protein (XIAP) by immunohistochemistry and Western blot. The number of spinal cord motoneurons was significantly reduced after sciatic nerve injury, while treatment with GsRg1 markedly elevated cell number. Sciatic nerve injury markedly increased spinal cord MDA content concomitant with reduced activities of SOD and GSH-Px. GsRg1 significantly decreased MDA content accompanied by elevated activities of SOD and GSH-Px. Further nerve injury significantly diminished protein expression levels of XIAP accompanied by elevated protein expression levels of caspase-3 in the spinal cord. GsRg1 markedly increased protein expression levels of XIAP, but significantly reduced protein expression levels of caspase-3. Data suggest that the protective effects of GsRg1 in sciatic nerve injury may be associated with reduced oxidative stress involving anti-apoptotic pathways.
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Apoptose/efeitos dos fármacos , Ginsenosídeos/farmacologia , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Nervo Isquiático/lesões , Animais , Masculino , Distribuição Aleatória , Ratos , Ratos Wistar , Nervo Isquiático/efeitos dos fármacosRESUMO
We report a case of cutaneous anaplastic lymphoma kinase-positive anaplastic large-cell lymphoma (ALCL) with linear distributional lesions and sarcomatoid histologic features. A sarcomatoid variant is the rarest morphological pattern of ALCL. Interestingly, the morphology of tumor cells in the present case transitioned from a sarcomatoid variant of ALCL at first diagnosis to a classic variant at relapse. The case is a diagnostic challenge considering both the clinical and histologic aspects. Awareness of the sarcomatoid variant of ALCL and its morphological changes can lead to a correct diagnosis.
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Biomarcadores Tumorais/análise , Linfoma Anaplásico de Células Grandes/enzimologia , Receptores Proteína Tirosina Quinases/análise , Sarcoma/enzimologia , Neoplasias Cutâneas/enzimologia , Adulto , Quinase do Linfoma Anaplásico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biópsia , Quimiorradioterapia , Feminino , Humanos , Imuno-Histoquímica , Linfoma Anaplásico de Células Grandes/genética , Linfoma Anaplásico de Células Grandes/patologia , Linfoma Anaplásico de Células Grandes/terapia , Sarcoma/genética , Sarcoma/patologia , Sarcoma/terapia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/terapiaRESUMO
Cognitive dysfunction is known to be influenced by circulating sex steroidal hormones. The aim of this study was to examine the protective effect and possible protective mechanism of testosterone (T) on cognitive performance in male rats induced by intrahippocampal injections of beta amyloid 1-42 oligomers (Aß1-42). Treatment with T as evidenced by the Morris water maze (MWM) test significantly shortened escape latency and reduced path length to reach the platform compared to the control (C). During probe trials, the T group displayed a significantly greater percent of time in the target quadrant and improved the number of platform crossings compared with C, flutamide (F), an antiandrogen, and a combined F and T group. Flutamide markedly inhibited the influence of T on cognitive performance. Following Nissl staining, the number of intact pyramidal cells was significantly elevated in the T group, and the effect of T was blocked by F. Immunohistochemisty and Western blot analysis showed that the protein expression level of Aß 1-42 was markedly decreased and expression levels of synaptophysin (SYN) significantly increased with T, while F inhibited all T-mediated effects. Our data suggest that the influence of T on cognitive performance was mediated via androgen receptors (AR) to remove beta amyloid, which leads to enhanced synaptic plasticity.
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Doença de Alzheimer , Peptídeos beta-Amiloides , Antagonistas de Androgênios/farmacologia , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/etiologia , Hipocampo/efeitos dos fármacos , Fragmentos de Peptídeos , Testosterona , Doença de Alzheimer/complicações , Animais , Flutamida/farmacologia , Flutamida/uso terapêutico , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Distribuição Aleatória , Ratos , Sinaptofisina/farmacologia , Sinaptofisina/uso terapêutico , Testosterona/farmacologia , Testosterona/uso terapêuticoRESUMO
PURPOSE: Advanced glycation end products (AGEs) play an important role in the pathogenesis of diabetic vascular complications. Recently, growing evidence has shown that AGEs could be involved in the pathogenesis of insulin resistance. It has also been suggested that circulating AGE are associated with insulin resistance in nondiabetic patients. This study investigated whether serum AGEs levels are associated with insulin resistance in nondiabetic patients with obstructive sleep apnea (OSA). METHODS: A total of 139 male nondiabetic patients with OSA were recruited for participation in the study. Serum AGE levels were examined using an enzyme-linked immunosorbent assay. Insulin resistance was determined using the homeostasis model assessment index (HOMA-IR). RESULTS: There was a significant correlation between serum AGEs and the apnea-hypopnea index (AHI) (r = 0.281, p = 0.014), duration of SaO2 < 90% (r = 0.267, p = 0.018), minimum SaO2 (r = -0.188, p = 0.046), high-sensitivity C-reactive protein (hsCRP) (r = 0.274, p = 0.012), and HOMA-IR (r = 0.303, p < 0.001). Multiple regression analysis showed that serum AGEs (p = 0.011), AHI (p = 0.024), waist circumference (p = 0.040), and hsCRP (p = 0.046) were independently associated with HOMA-IR (R(2) = 0.392). In addition, the strength of the correlation between serum AGEs and HOMA-IR was related to the severity of OSA. CONCLUSIONS: The present study indicated that serum AGE levels were associated with insulin resistance in male nondiabetic patients with OSA. These findings suggest that AGEs may play a role in insulin resistance in OSA and may also be a biomarker for patients with OSA with high risk of developing type 2 diabetes.
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Produtos Finais de Glicação Avançada/sangue , Resistência à Insulina/fisiologia , Apneia Obstrutiva do Sono/fisiopatologia , Adulto , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Oxigênio/sangue , Polissonografia , Fases do Sono/fisiologia , Estatística como AssuntoRESUMO
Congenital hemidysplasia with ichthyosiform erythroderma and limb defects (CHILD) syndrome is a rare X-linked dominant disease characterized by peculiar cutaneous presentations and skeletal abnormalities. Verruciform xanthoma (VX)-like histologic changes occasionally occur in CHILD syndrome, but typical VX-like lesions coexisting with CHILD syndrome are rare. In this study we report a rare case of multiple, coexisting VXs on the vulva and left lower limb of an 11-year-old Chinese girl who also exhibited the typical clinical presentations and limb defects of CHILD syndrome. Histologic and immunohistochemical analyses showed that the lesions were typical VXs.
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Anormalidades Múltiplas/patologia , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Eritrodermia Ictiosiforme Congênita/patologia , Deformidades Congênitas dos Membros/patologia , Verrugas/patologia , Xantomatose/patologia , Criança , Comorbidade , Feminino , HumanosAssuntos
Artrite/complicações , Comunicação Interatrial/complicações , Sinovite/complicações , Uveíte/complicações , Artrite/diagnóstico , Artrite/tratamento farmacológico , Artrite/genética , Criança , Feminino , Predisposição Genética para Doença , Glucocorticoides/uso terapêutico , Comunicação Interatrial/diagnóstico por imagem , Humanos , Mutação de Sentido Incorreto , Proteína Adaptadora de Sinalização NOD2/genética , Fenótipo , Sarcoidose , Sinovite/diagnóstico , Sinovite/tratamento farmacológico , Sinovite/genética , Uveíte/diagnóstico , Uveíte/tratamento farmacológico , Uveíte/genéticaAssuntos
Antituberculosos/administração & dosagem , Infecções por Mycobacterium não Tuberculosas/diagnóstico , Infecções por Mycobacterium não Tuberculosas/tratamento farmacológico , Micobactérias não Tuberculosas/isolamento & purificação , Dermatopatias Bacterianas/diagnóstico , Adulto , Biópsia por Agulha , Seguimentos , Humanos , Imuno-Histoquímica , Masculino , Infecções por Mycobacterium não Tuberculosas/patologia , Pneumonia/diagnóstico por imagem , Pneumonia/microbiologia , Medição de Risco , Índice de Gravidade de Doença , Dermatopatias Bacterianas/tratamento farmacológico , Dermatopatias Bacterianas/patologia , Resultado do TratamentoAssuntos
Heterozigoto , Proteínas de Homeodomínio/genética , Transtornos Linfoproliferativos/genética , Mutação , Imunodeficiência Combinada Severa/genética , Pré-Escolar , Predisposição Genética para Doença , Humanos , Transtornos Linfoproliferativos/diagnóstico , Transtornos Linfoproliferativos/imunologia , Transtornos Linfoproliferativos/terapia , Masculino , Fenótipo , Imunodeficiência Combinada Severa/diagnóstico , Imunodeficiência Combinada Severa/imunologia , Imunodeficiência Combinada Severa/terapia , Pele/patologiaAssuntos
Linfadenopatia Imunoblástica/patologia , Linfoma Difuso de Grandes Células B/patologia , Linfoma de Células T/patologia , Segunda Neoplasia Primária/patologia , Neoplasias Cutâneas/patologia , Infecções por Vírus Epstein-Barr/complicações , Evolução Fatal , Feminino , Humanos , Linfadenopatia Imunoblástica/tratamento farmacológico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/virologia , Linfoma de Células T/tratamento farmacológico , Pessoa de Meia-Idade , Segunda Neoplasia Primária/tratamento farmacológico , Segunda Neoplasia Primária/virologia , Células de Reed-Sternberg/patologia , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/virologiaRESUMO
AIMS: Preferentially expressed antigen in melanoma (PRAME) recently is a reliable immunohistochemistry (IHC) marker for distinguishing melanoma from other lesions. However, there are few articles focused on PRAME use in acral malignant melanoma, the most common type in Asians. This study investigated PRAME IHC expression in a large series of acral malignant melanoma in situ to add to the body of clinical knowledge. METHODS: PRAME IHC was performed in unequivocal cases of primary acral lentiginous melanoma in situ (ALMIS), subungual melanoma in situ (SMIS) and acral recurrent nevi as the control. PRAME tumour cell percentage positivity and intensity were expressed as categorised in a cumulative score by adding the quartile of positive tumour cells to intensity labelling. The final IHC expression was interpreted as negative (0-1), weak (2-3), moderate (4-5) or strong (6-7). RESULTS: In 91 ALMIS patients, 32 cases (35.16%) were strong, 37 (40.66%) were moderate and 22 (24.18%) were weak. In 18 SMIS patients, strong positivity of PRAME was observed in 4 (22.22%) cases, moderate in 10 (55.56%) and weak in the remaining 4 (22.22%). No melanoma sample was negative for PRAME. By comparison, only 2 of the 40 acral recurrent nevi cases were positive. CONCLUSIONS: Our study supports the ancillary value of PRAME for diagnosing ALMIS and SMIS with high sensitivity and specificity.
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Background: Skin cutaneous melanoma (SKCM) is the deadliest dermatology tumor. Ongoing researches have confirmed that the NOD-like receptors (NLRs) family are crucial in driving carcinogenesis. However, the function of NLRs signaling pathway-related genes in SKCM remains unclear. Objective: To establish and identify an NLRs-related prognostic signature and to explore its predictive power for heterogeneous immune response in SKCM patients. Methods: Establishment of the predictive signature using the NLRs-related genes by least absolute shrinkage and selection operator-Cox regression analysis (LASSO-COX algorithm). Through univariate and multivariate COX analyses, NLRs signature's independent predictive effectiveness was proven. CIBERSORT examined the comparative infiltration ratios of 22 distinct types of immune cells. RT-qPCR and immunohistochemistry implemented expression validation for critical NLRs-related prognostic genes in clinical samples. Results: The prognostic signature, including 7 genes, was obtained by the LASSO-Cox algorithm. In TCGA and validation cohorts, SKCM patients with higher risk scores had remarkably poorer overall survival. The independent predictive role of this signature was confirmed by multivariate Cox analysis. Additionally, a graphic nomogram demonstrated that the risk score of the NLRs signature has high predictive accuracy. SKCM patients in the low-risk group revealed a distinct immune microenvironment characterized by the significantly activated inflammatory response, interferon-α/γ response, and complement pathways. Indeed, several anti-tumor immune cell types were significantly accumulated in the low-risk group, including M1 macrophage, CD8 T cell, and activated NK cell. It is worth noting that our NLRs prognostic signature could serve as one of the promising biomarkers for predicting response rates to immune checkpoint blockade (ICB) therapy. Furthermore, the results of expression validation (RT-qPCR and IHC) were consistent with the previous analysis. Conclusion: A promising NLRs signature with excellent predictive efficacy for SKCM was developed.
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Cutaneous and systemic plasmacytosis (CSP) is a rare disorder characterized by disseminated reddish brown plaques and polyclonal hypergammaglobulinemia. The lesions of CSP are histologically characterized by an infiltration of mature polyclonal plasma cells, which display similar pathological features to the plasma cell-type Castleman disease (CD). The relationship between CSP and CD is controversial. Herein, we described a 43-year-old man from China with disseminated reddish brown plaques and nodules on the cheek and temple. The serum level of immunoglobulin G and immunoglobulin A were higher than normal. In addition to mature plasma cell perivascular infiltrate in the dermis, the biopsy of the lesions showed small to medium-sized germinal follicles with hyalinized vessels and a concentrically arranged mantle zone. The patient had clinical features of CSP, but the biopsy revealed changes resembling mixed-type CD. To the best of our knowledge, this is the first case of CSP with the pathological features of mixed-type CD reported from China.
Assuntos
Hiperplasia do Linfonodo Gigante/diagnóstico , Hipergamaglobulinemia/diagnóstico , Plasmócitos/patologia , Dermatopatias/diagnóstico , Pele/patologia , Adulto , Biomarcadores/sangue , Biópsia , Hiperplasia do Linfonodo Gigante/tratamento farmacológico , Hiperplasia do Linfonodo Gigante/imunologia , Hiperplasia do Linfonodo Gigante/patologia , Quimioterapia Combinada , Humanos , Hipergamaglobulinemia/tratamento farmacológico , Hipergamaglobulinemia/imunologia , Hipergamaglobulinemia/patologia , Imunoglobulina A/sangue , Imunoglobulina G/sangue , Imunossupressores/uso terapêutico , Masculino , Plasmócitos/imunologia , Pele/imunologia , Dermatopatias/tratamento farmacológico , Dermatopatias/imunologia , Dermatopatias/patologia , Resultado do TratamentoRESUMO
BACKGROUND: Actinic keratosis (AK) is a precancerous disease, caused by ultraviolet radiation (UV). OBJECTIVE: To analyze the clinical and pathological characteristics of AK in four areas with different ultraviolet radiation intensities. METHODS: 1188 diagnosed AK patients, from January 2000 to July 2015, in dermatology department of four hospitals were collected. The UV intensity of hospital located cities from high to low is Kunming, Yinchuan, Shenyang and Nanjing. The information comes from medical records, and the pathological types and Keratinocyte Intraepithelial Neoplasia (KIN) grades were checked by two experienced pathologists. All information was conducted a retrospective multicenter research. RESULTS: The patients were mainly middle-aged and elderly female, which was in direct contrast to the majority of men in European. The age of onset in Kunming group was lower than that in Yinchuan Group (p = 0.013) and Nanjing Group (p < 0.01). The course of disease in Kunming group was significantly shorter than that in Nanjing Group (p < 0.001). The lesions were almost located in the exposed area. The proportion of unexposed areas in Shenyang group was significantly higher than that in other groups (p < 0.001). There were statistical differences in pathological morphological classification among the four groups. These differences were not affected by age and gender. The number of KIN III grade patients in Shenyang group was significantly higher than that in other three groups (p < 0.05). CONCLUSION: The Asian patients were mainly female. The clinical characteristics of AK are closely related to UV intensity, and environmental pollution, lifestyle, religious beliefs and other factors are also related.
Assuntos
Ceratose Actínica , Neoplasias Cutâneas , Idoso , Povo Asiático , China/epidemiologia , Feminino , Humanos , Ceratose Actínica/epidemiologia , Ceratose Actínica/patologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Neoplasias Cutâneas/patologia , Raios Ultravioleta/efeitos adversosRESUMO
Background: Hypopigmented mycosis fungoides (hMF) is gradually acknowledged by more dermatologists, yet a consensus regarding its characteristics is not reached. The profile of Chinese hMF patients has not been deeply reviewed previously. Our research may contribute to the understanding of hMF, especially the Chinese patients with Fitzpatrick phototypes of III and IV. Aim: To have a better understanding of hMF in terms of clinical, histopathological and immunohistochemical features in the Chinese population and to determine if there are differences between the Chinese population and other ethnic groups. Methods: We made a retrospective analysis of clinical, histopathological and immunohistochemical features of 32 hMF patients in our hospital from 2010 to 2020. These features were then summarized and compared with previous reports. Results: All patients belonged to Fitzpatrick phototypes of III or IV. Twenty-one male (65.63%) patients and 11 female (34.37%) patients were analyzed, and the male to female ratio was 1.9:1. The age at diagnosis of patients ranged from 4 to 39 years, and the average age at diagnosis of these patients was 18 years, the median age was 16.5. Back was the most frequent site (34.37%). The clinical and histological results of lesions had no distinctive points. Immunohistochemically, among these 32 patients, there were 30 patients whose information was complete, there was 19 patients (63.33%) who were CD8 positive lymphocytes predominance, 9 patients (30%) had CD8 and CD4 positive lymphocyte mixed infiltration, and other 2 patients (6.67%) had CD4 positive lymphocytes predominance. Partial loss of CD7 was only observed in 1 patient (3.33%). Nearly all patients adopted topical nitrogen mustard and topical steroid and most of them had an excellent prognosis. Conclusion: The clinical profiles of hMF in Chinese population shared differences with other ethnic groups, but its histopathological, immunohistochemical results and prognosis condition were resembled with other previous reports. Hence, more patients were needed to find the characteristics of hMF.
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BACKGROUND: A number of studies have demonstrated that N6-methyladenosine (m6A) plays a vital role in the pathological process of various tumours. Recently, it was found that m6A writers or erasers affect the tumourigenesis of melanoma. However, the relationship between m6A readers such as YTH domain family (YTHDF) proteins and melanoma was still elusive. METHODS: RT-qPCR, Western blot and immunohistochemistry were conducted to measure the expression level of YTH N6-methyladenosine RNA binding protein 3 (YTHDF3) and lysyl oxidase-like 3 (LOXL3) in melanoma tissues and cells. The effects of YTHDF3 and LOXL3 on melanoma were verified in vitro and in vivo. Multi-omics analysis including RNA-seq, MeRIP-seq, RIP-seq and mass spectrometry analyses was performed to identify the target. The interaction between YTHDF3 and LOXL3 was verified by RT-PCR, Western blot, MeRIP-qPCR, RIP-qPCR and CRISPR-Cas13b-based epitranscriptome engineering. RESULTS: In this study, we found that m6A reader YTHDF3 could affect the metastasis of melanoma both in vitro and in vivo. The downstream targets of YTHDF3, such as LOXL3, phosphodiesterase 3A (PDE3A) and chromodomain helicase DNA-binding protein 7 (CHD7) were identified by means of RNA-seq, MeRIP-seq, RIP-seq and mass spectrometry analyses. Besides, RT-qPCR, Western blot, RIP-qPCR and MeRIP-qPCR were performed for subsequent validation. Among various targets of YTHDF3, LOXL3 was found to be the optimal target of YTHDF3. With the application of CRISPR-Cas13b-based epitranscriptome engineering, we further confirmed that the transcript of LOXL3 was captured and regulated by YTHDF3 via m6A binding sites. YTHDF3 augmented the protein expression of LOXL3 without affecting its mRNA level via the enrichment of eukaryotic translation initiation factor 3 subunit A (eIF3A) on the transcript of LOXL3. LOXL3 downregulation inhibited the metastatic ability of melanoma cells, and overexpression of LOXL3 ameliorated the inhibition of melanoma metastasis caused by YTHDF3 downregulation. CONCLUSIONS: The YTHDF3-LOXL3 axis could serve as a promising target to be interfered with to inhibit the metastasis of melanoma.