An in vitro nevus explant model for studying the effects of ultraviolet radiation.

Ultraviolet radiation (UVR) has been recognized as a potential trigger for the transformation of benign melanocytic nevi into melanoma. However, the mechanisms governing the formation and progression of melanocytic nevi remain poorly understood. This lack of understanding is partly due to the difficulty in isolating and culturing nevus tissues in vitro, resulting in a dearth of robust ex vivo models for nevi. Therefore, the establishment of a reliable melanocytic nevus model is imperative. Such a model is essential for elucidating nevus pathogenesis and facilitating the development of effective therapeutic interventions. Therefore, we have sought to establish an ex vivo nevus explant model to study UVR stimulation. And the structural integrity and tissue activity of the ex vivo nevi explant model was evaluated. We then observed melanogenesis and proliferation activity of the explants after UVR stimulation. There was less blister formation after Day 3 in nevi explants under our modified medium conditions. The nevi explant was able to maintain almost the same morphological structure and tissue activity as in vivo tissue within 24 h. Following UVR stimulation, we observed increased melanogenesis and proliferation activity in nevi explants. Nevi explants could serve as an ex vivo model for UVR-induced nevi stimulation research.

Clinical Misdiagnosis of Cutaneous Malignant Tumors as Melanocytic Nevi or Seborrheic Keratosis: A Retrospective Analysis of a Chinese Population.

Purpose: The rising incidence and mortality associated with cutaneous malignant tumours highlight the importance of early diagnosis of these tumors. In clinical practice, these tumors are often misdiagnosed as benign skin lesions such as melanocytic nevi (MN) and seborrheic keratosis (SK) because of their similar morphologic features. The incidence and clinicopathological subtypes of cutaneous malignancies in East Asia populations significantly differ from those in fair-skinned groups. However, studies on misdiagnoses in Eastern countries are lacking. Therefore, this study focused on the clinical and pathological features of cutaneous malignant tumors misdiagnosed as MN or SK in a Chinese population. Patients and Methods: A total of 4592 samples clinically diagnosed as MN (n = 3503) or SK (n = 1089) from July 2014 to June 2022 were collected and evaluated retrospectively. The clinical and pathological data were analyzed to identify associated factors. Results: Pathological assessments showed that 2.5% (86/3503) of the specimens clinically diagnosed as MN were malignancies, predominantly basal cell carcinoma (BCC, 84.9%, 73/86), followed by malignant melanoma (MM, 8.1%, 7/86) and squamous cell carcinoma (SCC, 7.0%, 6/86). Similarly, 5.7% (62/1089) of the specimens clinically diagnosed as SK were malignant tumors, of which BCC (50.0%, 31/62) was the most common, followed by SCC (41.9%, 26/62) and MM (8.1%, 5/62). In both types of specimens, advanced age and facial lesions were risk factors for malignancy misdiagnosis. The malignancy rate, mean age, and proportion of SCC in the specimens clinically diagnosed as SK were higher than those in the specimens clinically diagnosed as MN. Dermoscopy significantly reduced the rate of misdiagnosis of these tumors as MN or SK. Conclusion: In China, cutaneous malignant tumors misdiagnosed as MN or SK are not uncommon in clinical practice, and active introduction of noninvasive diagnostic techniques is essential to distinguish them.

Dickkopf-1 is an immune infiltration-related prognostic biomarker of head and neck squamous cell carcinoma.

Immunotherapy is currently one of the most viable therapies for head and neck squamous cell carcinoma (HNSCC), characterized by high immune cell infiltration. The Wnt-signaling inhibitor and immune activation mediator, Dickkopf-1 (DKK1), has a strong correlation with tumor growth, tumor microenvironment, and, consequently, disease prognosis. Nevertheless, it is still unclear how DKK1 expression, HNSCC prognosis, and tumor-infiltrating lymphocytes are related. To better understand these associations, we examined how DKK1 expression varies across different tumor and normal tissues. In our study, we investigated the association between DKK1 mRNA expression and clinical outcomes. Next, we assessed the link between DKK1 expression and tumor immune cell infiltration. Additionally, using immunohistochemistry, we evaluated the expression of DKK1 in 15 healthy head and neck tissue samples, and the expression of CD3, CD4, and DKK1 in 27 HNSCC samples. We also explored aberrant DKK1 expression during tumorigenesis. DKK1 expression was remarkably higher in HNSCC tissues than in healthy tissues, and was shown to be associated with tumor stage, grade, lymph node metastasis, histology, and a dismal clinical prognosis in HNSCC. DKK1 expression in HNSCC tissues was inversely correlated with CD3+ (P < 0.0001) and CD4+ (P < 0.0001) immune cell infiltration, while that in immune cells was inversely associated with HNSCC prognosis. These findings offer a bioinformatics perspective on the function of DKK1 in HNSCC immunotherapy and provide justification for clinical research on DKK1-targeted HNSCC treatments. DKK1 is a central target for improving the efficacy of HNSCC immunotherapy.

Expression Analysis of Retinal G Protein-coupled Receptor and its Correlation with Regulation of the Balance between Proliferation and Aberrant Differentiation in Cutaneous Squamous Cell Carcinoma.

Retinal G protein-coupled receptor (RGR), a photosensitive protein, functions as a retinal photoisomerase under light conditions in humans. Cutaneous squamous cell carcinoma (cSCC) is linked to chronic ultraviolet exposure, which suggests that the photoreceptor RGR may be associated with tumorigenesis and progression of squamous cell carcinoma (SCC). However, the expression and function of RGR remain uncharacterized in SCC. This study analysed RGR expression in normal skin and in lesions of actinic keratosis, Bowen's disease and invasive SCC of the skin with respect to SCC initiation and development. A total of 237 samples (normal skin (n = 28), actinic keratosis (n = 42), Bowen's (n = 35) and invasive SCC (n = 132) lesions) were examined using immunohistochemistry. Invasive SCC samples had higher expression of RGR protein than the other samples. A high immunohistochemical score for RGR was associated with increased tumour size, tumour depth, Clark level, factor classification, and degree of differentiation and a more aggressive histological subtype. In addition, RGR expression was inversely correlated with involucrin expression and positively correlated with proliferating cell nuclear antigen (PCNA) and Ki67 expression. Furthermore, RGR regulates SCC cell differentiation through the PI3K-Akt signalling pathway, as determined using molecular biology approaches in vitro, suggesting that high expression of RGR is associated with aberrant proliferation and differentiation in SCC.

In vitro differentiation of human amniotic epithelial stem cells into keratinocytes regulated by OPN3.

Human amniotic epithelial stem cells (hAESCs) are regarded as potential alternatives to keratinocytes (KCs) used for skin wound healing. Light is an alternative approach for inducing stem cell differentiation. Opsins (OPNs), a family of light-sensitive, G protein-coupled receptors, play a multitude of light-dependent and light-independent functions in extraocular tissues. However, it remains unclear whether the light sensitivity and function of OPNs are involved in light-induced differentiation of hAESCs to KCs. Herein, we determine the role of OPNs in differentiation of hAESCs into KCs through cell and molecular biology approaches in vitro. It is shown that mRNA expression of OPN3 in the amniotic membrane and hAESCs was higher than the other four primary OPNs by RT-qPCR analysis. Changes in OPN3 gene expression had a significant impact on cell proliferation, stemness and differentiation capability of hAESCs. Furthermore, we found a significant upregulation of OPN3, KRT5 and KRT14 with hAESCs treated at 3 × 33 J/cm2 irradiation from blue-light LED. Taken together, these results suggest that OPN3 acts as a positive regulator of differentiation of hAESCs into KCs. This study provides a novel insight into photosensitive OPNs associated with photobiomodulation(PBM)-induced differentiation in stem cells.

A pan-cancer analysis of RGR opsin expression and its downregulation associated with poor prognosis in glioma.

Retinal G protein-coupled receptor (RGR) serves a retinal photoisomerase function to mediate retinoid metabolism and visual chromophore regeneration in the human eyes. Retinoids display critical functions in cell proliferation, differentiation, and apoptosis. Abnormal retinoid metabolism may contribute to tumor development. However, in human tumor tissues, the expression of RGR remains uncharacterized. Herein, we performed the analysis of RGR expression in 620 samples from 24 types of tumors by immunohistochemistry (IHC) and 33 cancer types from the Cancer Genome Atlas (TCGA), the Chinese Glioma Genome Atlas (CGGA), and Gene Expression Omnibus (GEO) databases by bioinformatic analyses. Furthermore, the biological role of RGR in glioma cells was investigated using molecular biology approaches in vitro. Notably, we found that brain lower grade glioma (LGG), in contrast to other tumor types, had the highest median score of IHC and RNA level of RGR expression. Survival analysis showed that low RGR expression was associated with worse overall survival in LGG (p<0.0001). RGR expression levels in glioma were also associated with pathological subtypes, grades, and isocitrate dehydrogenase (IDH) mutations. Moreover, its molecular function was closely associated with cadherin-related family member 1 (CDHR1), a tumor suppressive protein in glioma, suggesting that RGR might negatively regulate the tumorigenesis and progression of LGG through interacting with CDHR1. Our findings provide new insight into the role of RGR in human cancer, especially in glioma.

Opsin 3 expression in human Langerhans cell histiocytosis and its mediation of ELD-1 cellular function.

BACKGROUND: Langerhans cell histiocytosis (LCH) is a type of -histiocytic disorder characterized by aberrant function, differentiation or proliferation of mononuclear phagocyte system cells, however, the pathogenesis is not fully understood. Opsin 3 (OPN3) plays an important role in regulating cell function. OBJECTIVES: We aimed to investigate OPN3 expression in LCH and Langerhans cells and evaluate its possible regulation of cellular function in a Langerhans cell-like cell line (ELD-1). MATERIALS & METHODS: Expression of OPN3 in LCH and paired adjacent healthy skin tissue was determined using microscopic tools (immunohistochemical and immunofluorescence staining) and RNA scope. OPN3 protein and mRNA levels in primary dendritic cells and ELD-1 were measured by real-time quantitative PCR and western blotting, respectively. The effects of reduced or over-expressed OPN3 mRNA level, via a lentiviral vector, were examined on ELD-1 proliferation, migration, cell cycle and apoptosis using the Cell Counting Kit 8, EdU-594 kit, Transwell assays and Cell Cycle Analysis Kit and Annexin V-PE apoptosis kit, respectively. Lastly, the signalling pathway mediating these functions was investigated via RNA sequencing and western blotting. RESULTS: OPN3 was highly expressed in human LCH tissue compared to healthy tissue, and was expressed in primary dendritic cells and ELD-1. Knockdown of OPN3 in ELD-1 inhibited cell proliferation, the cell cycle, and cell migration, while over-expression reversed these processes. These functions correlated with induction of the MAPK (p38/JNK/ERK) signalling pathway. CONCLUSION: Our results provide insight into the role of OPN3 in LCH which may become a molecular target for the clinical treatment of LCH.

'Seaweed appearance' in squamous cell carcinoma of the penis: A new dermoscopic finding.

Squamous cell carcinoma of the penis is an uncommon cancer. Vascular feature on dermoscopy is common in all forms of invasive squamous cell carcinoma, and the presence of the specific vascular features is often used to aid diagnosis. Here, we reported a new dermoscopic finding-seaweed-like vascular pattern in squamous cell carcinoma of the penis.

The necessity for popularizing varicella-zoster virus vaccine programs worldwide: An age-period-cohort analysis for the Global Burden of Disease study 2019.

BACKGROUND: Varicella-zoster virus (VZV) causes varicella and herpes zoster (VHZ), which is endemic worldwide. Although infection with VZV represents a considerable health threat, the global, regional and national burden of VZV infection, especially the probable relationship between VZV vaccines and the epidemiology of VZV infection, is poorly known. We sought to estimate the global spatial patterns and temporal trends of VHZ burden in 204 countries and territories from 1990 to 2019. METHODS: Numbers and age-standardized rates (ASR) of VHZ incidence, and disability-adjusted life years (DALYs) were estimated using data from the Global Burden of Diseases Study (GBD) 2019. Spatiotemporal trends in ASR were evaluated by estimated annual percentage change (EAPC). RESULTS: Worldwide, in 2019, there were approximately 84.0 million incidence and 0.9 million DALYs due to VHZ. The corresponding ASIR (age-standardized incidence rate) and ASDR (age-standardized DALY rate) drastically decreased in children (aged <20 years old), while the ASIR and ASDR of VHZ significantly increased in middle- and old-aged adults (aged >50 years old), with highest ASIR and ASDR in the High-income Asia Pacific and Western Sub-Saharan Africa, respectively. From 1990-2019, the corresponding EAPC in ASIR were 0.03 (95% uncertainty interval [UI]: 0.02-0.04). Whereas the global EAPC in ASDR decreased in all regions (-1.59, 95% UI: -1.64 to -1.55), expect for Australasia (0.46, [0.05, 0.88]). Notably, in 2019, age-specific rates of VHZ DALYs presented a rapid growth trend after 70 years old. CONCLUSION: The spatiotemporal trends of VHZ were heterogeneous across countries from 1990 to 2019. The spatiotemporal trend in ASIR is highest in the High sociodemographic index (SDI) region, however the EAPC in ASDR is lowest, in part probably due to VHZ vaccination. Therefore, reducing morbidity and burden strategies such as vaccines programs for the prevention of VHZ should be promoted in those regions with high growth incidence and/or burden, especially for the population after 70 years old.

The effects of missense OPN3 mutations in melanocytic lesions on protein structure and light-sensitive function.

Opsin 3 (OPN3), a member of the light-sensitive, retinal-dependent opsin family, is widely expressed in a variety of human tissues and plays a multitude of light-dependent and light-independent roles. We recently identified five missense variants of OPN3, including p. I51T, p. V134A, p. V183I, p. M256I and p. C331Y, in human melanocytic tumours. However, it remains unclear how these OPN3 variants affect OPN3 protein structure and function. Herein, we conducted structural and functional studies of these variant proteins in OPN3 by molecular docking and molecular dynamics simulations. Moreover, we performed in vitro fluorescence calcium imaging to assess the functional properties of five single-nucleotide variant (SNV) proteins using a site-directed mutagenesis method. Notably, the p. I51T variant was not able to effectively dock with 11-cis-retinal. Additionally, in vitro, the p. I51T SNVs failed to induce any detectable changes in intracellular Ca2+ concentration at room temperature. Taken together, these results reveal that five SNVs in the OPN3 gene have deleterious effects on protein structure and function, suggesting that these mutations, especially the p. I51T variant, significantly disrupt the canonical function of the OPN3 protein. Our findings provide new insight into the role of OPN3 variants in the loss of protein function.

Identification and functional assays of single-nucleotide variants of opsins genes in melanocytic tumors.

Epidermal melanocytes sense solar light via the opsin-coupled signaling pathway which is involved in a range of biological functions, including regulating pigmentation, proliferation, apoptosis, and tumorigenesis. However, it remains unclear whether there are genetic variants within these opsins that affect opsin protein structure and function, and further melanocyte biological behaviors. Here, we examined single-nucleotide variants (SNVs) of five opsin (RGR, OPN1SW, OPN2, OPN4, and OPN5) genes in MM (malignant melanoma; n = 76) and MN (melanocytic nevi; n = 157), using next-generation sequencing. The effects of these pathogenic single-nucleotide variants (SNVs) on opsin structure and function were further investigated using molecular dynamics (MD) simulations, dynamic cross-correlation (DCC), and site-directed mutagenesis. In total, 107 SNV variants were identified. Of these variants, 14 nonsynonymous SNVs (nsSNVs) of opsin genes were detected, including three mutations in the RGR gene, three mutations in the OPN1SW gene, two mutations in the OPN2 gene, and six mutations in the OPN4 gene. The effect of these missense mutations on opsin function was then assessed using eight prediction tools to estimate the potential impact of an amino acid substitution. The impact of each nsSNV was investigated using MD simulations and DCC analysis. Furthermore, we performed in vitro fluorescence calcium imaging to assess the functional properties of nsSNV proteins using a site-directed mutagenesis method. Taken together, these results revealed that p.A103V (RGR), p.T167I (RGR), p.G141S (OPN1SW), p.R144C (OPN1SW), and p.S231F (OPN4) had more deleterious effects on protein structure and function among the 14 nsSNVs. Opsin gene alterations showed the low frequency of missense mutations in melanocytic tumors, and although rare, some mutations in these opsin genes disrupt the canonical function of opsin. Our findings provide new insight into the role of opsin variants in the loss of function.

OPN3 Regulates Melanogenesis in Human Congenital Melanocytic Nevus Cells through Functional Interaction with BRAFV600E.

OPN3, as a member of the opsin family, has various nonlight-dependent functions. Congenital melanocytic nevus (CMN) is a skin lesion with dark pigmentation that appears at birth and can be initiated by the BRAFV600E mutation in melanocytes. However, the role of OPN3 in BRAFV600E CMN cell melanogenesis has never been reported. In this study, we show that OPN3 acts as a negative regulator of melanin production by modulating BRAFV600E signaling in BRAFV600E CMN cells. Knocking down OPN3 expression can inhibit the BRAFV600E/extracellular signal‒regulated kinase signaling pathway and upregulate the expression of microcephaly-related transcription factors, tyrosinase, and TRP1 and TRP2, thus increasing melanin levels in BRAFV600E CMN cells. More remarkably, OPN3 and BRAFV600E were found to form a physical complex. Furthermore, a three-dimensional nevus model was used to further prove the negative regulatory effect of OPN3 on BRAFV600E CMN cell melanogenesis. Our study reveals a mechanism for OPN3-mediated melanogenesis in BRAFV600E CMN cells, and these results may lead to a more personalized and economically viable approach to treating BRAFV600E CMN.

Expression of Retinal G Protein-Coupled Receptor, a Member of the Opsin Family, in Human Skin Cells and Its Mediation of the Cellular Functions of Keratinocytes.

Background: Photoreceptive proteins play critical physiological roles in human skin cells. The retinal G protein-coupled receptor (RGR) is a photoisomerase in the human retina, but its expression and cellular functions in human skin cells have not been reported. Objectives: We aimed to detect RGR expression in various skin cells and evaluate its regulation of the cellular functions of keratinocytes. Methods: The expression, distribution, and subcellular location of the RGR in normal human epidermal keratinocytes and cells with pathological conditions including psoriasis, seborrheic keratosis, and squamous cell carcinoma were determined using microscopic tools (immunohistochemical staining, immunofluorescence staining, and immunoelectron microscopy) and Western blotting (WB). The protein levels of the RGR in primary human melanocytes, keratinocytes, and fibroblasts isolated from the neonatal foreskin were measured by WB. The expression and subcellular localization of the RGR in these cells were detected by immunofluorescence staining under a fluorescence microscope and laser scanning confocal microscope. Additionally, the levels of RGR expression in normal keratinocytes exposed to ultraviolet (UV)-A or total ultraviolet radiation (UVR) in the presence or absence of all-trans-retinal were measured by WB. Furthermore, the effects of the RGR on human keratinocyte functions including proliferation, migration, and apoptosis were evaluated using the Cell Counting Kit 8, wound healing, and Transwell assays after reducing the RGR mRNA level in keratinocytes using small interfering RNA technology. Results: The RGR was primarily located in the epidermal basal and spinous layers and skin appendages. Its expression increased in psoriatic lesions, seborrheic keratosis, and squamous cell carcinoma. Confocal microscopy showed that the RGR was located in the cell membrane and nucleus of keratinocytes, melanocytes, and fibroblasts. Keratinocytes had a higher expression of the RGR than melanocytes and fibroblasts, as well as nuclear expression, according to nuclear/cytoplasmic fractionation. Colloidal gold immunoelectron microscopy technology further confirmed that the RGR is mainly located in the nucleoplasm and mitochondria and is scattered in the cytoplasm and other organelles in the epidermal keratinocytes. Notably, RGR knockdown in keratinocytes led to the inhibition of cell proliferation and migration, augmenting cell apoptosis. Conclusions: This study is the first to demonstrate the presence of RGR in the human skin. Our findings indicate that the RGR may play a critical role in the physiological function of epidermal keratinocytes.

Integrated analysis of the prognostic and oncogenic roles of OPN3 in human cancers.

BACKGROUND: Emerging cell- or tissue-based evidence has demonstrated that opsin 3 (OPN3) mediates a variety of pathological processes affecting tumorigenesis, clinical prognosis, and treatment resistance in some cancers. However, a comprehensive analysis of OPN3 across human cancers is unavailable. Therefore, a pancancer analysis of OPN3 expression was performed and its potential oncogenic roles were explored. METHODS: The expression and characterization of OPN3 were evaluated among 33 tumour types using The Cancer Genome Atlas (TCGA) dataset. Additionally, the OPN3 RNA level and overall survival (OS) in relation to its expression level in 33 cancer types were estimated. Based on the analysis above, 347 samples from 5 types of tumours were collected and detected for the protein expression of OPN3 by immunohistochemical assay. Furthermore, the biological role of OPN3 in cancers was evaluated via gene set enrichment analysis (GSEA). RESULTS: The OPN3 expression level was heterogeneous across cancers, yet a remarkable difference existed between OPN3 expression and patient overall survival among the 7 types of these 33 cancers. Consistently, a high immunohistochemical score of OPN3 was significantly associated with a poor prognosis among patients with 5 types of tumours. Additionally, OPN3 expression was involved in cancer-associated fibroblast infiltration in 5 types of tumours, and promoter hypomethylation of OPN3 was observed in 3 tumour types. Additionally, OPN3 protein phosphorylation sites of Tyr140 and Ser380 were identified via posttranscriptional modification analysis, suggesting the potential function of Tyr140 and Ser380 phosphorylation in tumorigenesis. Furthermore, the enrichment analysis was mainly concentrated in C7orf70, C7orf25 and the "ribosome" pathway by GSEA in 5 types of cancers, indicating that OPN3 might affect tumorigenesis and progression by regulating gene expression and ribosome biogenesis. CONCLUSIONS: High expression of OPN3 was significantly associated with a poor clinical prognosis in five types of cancers. Its molecular function was closely associated with the ribosomal pathway.

Characterization of Single Nucleotide Variants of OPN3 Gene in Melanocytic Nevi and Melanoma.

In this study, we examined single nucleotide variants (SNVs) of the OPN3 gene in malignant melanoma and melanocytic nevi. A total of 20 variants of SNVs were detected. Of these variants, five nonsynonymous mutations of OPN3 were identified, including c.T152C, c.T401C, c.G547A, c.G768A, and c.G992A. Three prediction tools, MutationTaster2, Polymorphism Phenotyping version 2, and PROVEAN (Protein Variation Effect Analyzer), which predict possible impact of an amino acid substitution, suggested that the mutations could be deleterious. Nine SNVs occurred in 3' untranslated regions, whereas two were observed in 5' untranslated regions. In all cases, four intronic variants were identified. In addition, we identified nine 3' untranslated region SNVs in OPN3; one of them (OPN3[NM_014322:c.∗83C>T]) is predicted to disrupt a conserved microRNA (has-miR-376c-3p) target site, located in position 86-93 of OPN3 3' untranslated region. Our findings suggest that there is a strong possibility that OPN3 SNVs play a role in the pathogenesis of melanocytic tumors via prediction of functional phenotype.

Global, regional and national incidence, mortality and disability-adjusted life-years of skin cancers and trend analysis from 1990 to 2019: An analysis of the Global Burden of Disease Study 2019.

BACKGROUND: Information about global and local epidemiology and trends of skin cancers is limited, which increases the difficulty of cutaneous cancer control. METHODS: To estimate the global spatial patterns and temporal trends of skin cancer burden. Based on the GBD 2019, we collected and analyzed numbers and age-standardized rates (ASR) of skin cancer incidence, disability-adjusted life years (DALYs) and mortality (ASIR, ASDR, and ASMR) in 204 countries from 1990 through 2019 were estimated by age, sex, subtype (malignant skin melanoma [MSM], squamous-cell carcinoma [SCC], and basal-cell carcinoma [BCC]), Socio-demographic Index (SDI), region, and country. Temporal trends in ASR were also analyzed using estimated annual percentage change. RESULTS: Globally, in 2019, there were 4.0 million BCC, 2.4 million SCC, and 0.3 million MSM. There were approximately 62.8 thousand deaths and 1.7 million DALYs due to MSM, and 56.1 thousand deaths and 1.2 million DALYs were attributed to SCC, respectively. The men had higher ASR of skin cancer burden than women. The age-specific rates of global skin cancer burden were higher in the older adults, increasing trends observed from 55 years old. Geographically, the numbers and ASR of skin cancers varied greatly across countries, with the largest burden of ASIR in high SDI regions. However, an unexpected increase was observed in some regions from 1990 to 2019, such as East Asia, and Sub-Saharan Africa. Although there was a slight decrease of the ASMR and ASDR, the global ASIR of MSM dramatically increased, 1990-2019. Also, there was a remarkable increase in ASR of BCC and SCC burden. CONCLUSIONS: Skin cancer remains a major global public health threat. Reducing morbidity and mortality strategies such as primary and secondary prevention should be reconsidered, especially in the most prevalent and unexpected increased regions, especially for those areas with the greatest proportions of their population over age 55.

Expression of OPN3 in acral lentiginous melanoma and its associated with clinicohistopathologic features and prognosis.

BACKGROUND: OPN3 upregulation associated with metastasis was recently described in two subtypes of lung cancers. And OPN3 identified in light-independent functions in epidermal melanocytes has already shown promise. However, in malignant melanocytic tissues, the expression and characterization of OPN3 remain uncharacterized. OBJECTIVES: We investigated the clinico-histopathologic features in relation to OPN3 expression of acral lentiginous melanoma (ALM), which is a rare cutaneous melanoma subtype and not associated with prior sunlight exposure. METHODS: In all, 84 samples of junctional melanocytic nevi (JMN, n = 12), primary ALMs (n = 39) and inguinal lymph node metastasis (ILNM, n = 23) from ALMs were evaluated for the immunohistochemical expression of OPN3. OPN3 messenger RNA and protein level were further determined in melanocytic tumors using quantitative real-time PCR, multiimmunofluorescence and Western blot assays. We also estimated the associations OPN3 expression between clinicopathological features and prognosis. RESULTS: ILNMs, in contrast to JMN and ALMs, had higher OPN3 expression scores (p < .001) by immunohistochemistry analysis. High OPN3 score was associated with presence of ulceration, increased Breslow depth and Clark level (p = .025, p = .042, and p = .012, respectively). Furthermore, a remarkable difference (p = .037) of patient overall survival was found when comparing the OPN3 expression of immunohistochemical score between equal to or larger than 100 and below 100 groups. Also, Cox regression models showed that high OPN3 scores were associated with worse melanoma survival. CONCLUSION: High OPN3 expression is significantly associated with ALMs and metastatic phenotype as well as a poor prognosis.

Z-VRPR-FMK can inhibit the growth and invasiveness of diffuse large B-cell lymphoma by depressing NF-κB activation and MMP expression induced by MALT1.

This study aimed to investigate the therapeutic effect of the mucosa-associated lymphoid tissue lymphoma translocation gene 1 (MALT1) on diffuse large B-cell lymphoma (DLBCL) and its underlying molecular mechanism through the application of Z-Val-Arg-Pro-DL-Arg-fluoromethyl ketone (Z-VRPR-FMK). Cultured OCI-LY10 cells and their xenografts in nude mice were treated with Z-VRPR-FMK. The growth and invasiveness of the tumor were observed. The components of the NF-κB signaling pathways, such as P65, MALT1, A20, matrix metalloproteinase 2 (MMP2) and MMP9, were detected using a real-time fluorescent quantitative polymerase chain reaction, immunohistochemical staining, and a Western blot analysis. Z-VRPR-FMK inhibited the growth and invasiveness of OCI-LY10 cells and their xenografts. The increase in the tumor volume was slower in the experimental group than it was in the control group, and the weight of the nude mice was significantly different between the two groups on the 11th and 13th days of treatment. The expression of P65 was significantly lower at the gene level in cultured OCI-LY10 cells and transplanted tumors than in the controls after treatment with Z-VRPR-FMK. The nuclear expression of the P65 protein of xenografts also decreased, but the nuclear expression of the A20 protein followed a reverse pattern. The expressions of the MALT1, MMP2, and MMP9 proteins were lower in the OCI-LY10 cells and transplanted tumors treated with Z-VRPR-FMK compared with the controls. This study indicates that MALT1 might serve as an effective therapeutic target for activated B-cell (ABC)-like DLBCL. Z-VRPR-FMK inhibits the growth and invasiveness of ABC-like DLBCL by depressing the proteolysis of A20, the activation of NF-κB, and the expression of MMP9 and MMP2 induced by the MALT1 protein.