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Cutaneous melanoma (CM, hereafter referred to as melanoma) is a highly malignant tumor that typically undergoes early metastasis. Pyroptosis, as a special programmed cell death process that releases inflammatory factors and has been widely studied in tumors, but its role in melanoma has not been fully elucidated. In this study, we examined the relationship between pyroptosis and the prognosis of melanoma through bioinformatic analysis of RNA-sequencing data. Our results demonstrated that pyroptosis is a protective factor associated with melanoma prognosis. A higher pyroptosis score was associated with a more favorable overall survival. We used weighted gene co-expression networks analysis (WGCNA) to establish an effective prognosis model based on 12 pyroptosis-related genes. We then validated it in two independent cohorts. Furthermore, a nomogram combining clinicopathological characteristics and a pyroptosis-related gene signature (PGS) score was designed to effectively evaluate the prognosis of melanoma. Additionally, we analyzed the potential roles of pyroptosis in the tumor immune microenvironment and drug response. Interestingly, we found that the elevated infiltration of multiple immune cells, such as CD4 + T cells, CD8 + T cells, dendritic cells, and M1 macrophages, may be associated with the occurrence of pyroptosis. Pyroptosis was also related to a better response of melanoma to interferon-α, paclitaxel, cisplatin and imatinib. Through Spearman correlation analysis of the 12 pyroptosis-related genes and 135 chemotherapeutic agents in the Genomics of Drug Sensitivity in Cancer database, we identified solute carrier family 31 member 2 (SLC31A2) and collagen type 4 alpha 5 chain (COL4A5) as being associated with resistance to most of these drugs. In conclusion, this PGS is an effective and novelty prognostic indicator in melanoma, and also has an association with the melanoma immune microenvironment and melanoma treatment decision-making., (© 2022. The Author(s).)

Melanoma is a highly heterogeneous tumor. The incidence of melanoma increases with age and its long-term prognosis is poor. The treatment of melanoma includes surgical removal, chemotherapy and immunotherapy; however, the effect of these treatments is limited on mutated melanoma. Osteopontin is an extracellular protein which is expressed in numerous kinds of cells; it is related to the proliferation and invasion of cancer cells as well as the development of tumor microenvironment. The relationship between osteopontin and metastasis of melanoma has been clarified in recent years. This review focuses on the expression of osteopontin in patients with melanoma and associated signaling pathways involved in development and metastasis of melanoma; the potential role of osteopontin in immune modulation and prognosis prediction is also discussed here., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Melanoma is one of the most aggressive skin cancers with an increasing rate of morbidity. Umbilicaria esculenta is an edible lichen and its main component of extracts-polysaccharide (PUE) has shown significant antitumor effects in a variety of cancer types such as stomach adenocarcinoma. However, whether it has an anti-melanoma effect and the underlying mechanism has not been revealed. In this article, we showed that PUE extracted from Umbilicaria esculenta could inhibit the growth of A875 and A375 melanoma cells but without obvious toxicity to normal vascular endothelial cells. The generation of reactive oxygen species (ROS) in A875 cells was significantly elevated when treated with PUE for 24h. In addition, the expression of caspase-3 and -9 also increased as compared to the controlled group which resulted in the apoptosis of A875 melanoma cells. In the meantime, when pre-treated with N-acetylcysteine (NAC), the ROS scavenger, PUE induced apoptosis and cell death could be reversed via suppression of elevated generation of ROS and ROS-mediated caspase-9 expression. In summary, our study demonstrated that PUE extracts from Umbilicaria esculenta have a potent anti-melanoma effect through the induction of ROS and caspases-3 and -9. It could provide a promising strategy of melanoma therapy with the components from the extracts of natural and edible plants such as lichen Umbilicaria esculenta.

Background: The extracellular protein collagen triple helix repeat containing 1 (CTHRC1) is aberrantly upregulated in melanoma and most human solid cancers. However, its role in cancer remains unknown., Objective: In this study, we investigated the functional impact of CTHRC1 on melanoma cells in vitro., Methods: Stable clones of cultured melanoma cells expressing different amounts of CTHRC1 protein were generated and evaluated to characterize their growth, survival, and attachment ability as well as their sensitivity to chemotherapy., Results: In cultured MMAN and MMRU melanoma cells, increased expression of CTHRC1 protein resulted in morphologic cell changes, enhanced cell adhesion to culture surfaces, increased cell proliferation, and decreased apoptosis. Furthermore, decreased CTHRC1 expression through antisense inhibition enhanced temozolomide sensitivity., Conclusion: CTHRC1 expression influences cellular processes, including cell adhesion and survival. Additionally, CTHRC1 inhibition may represent a potential method for decreasing melanoma resistance to conventional chemotherapy.

Malignant melanoma (MM) is a major public health problem. The development of effective, systemic therapies for MM is highly desired. We showed here that the transferrin receptor (TfR) was a suitable surface marker for targeting of gene therapy in MM and that the hypoxia-inducible factor-1alpha (HIF-1alpha) was an attractive therapeutic molecular target in MM. We observed that inhibition of HIF-1alpha blocked cell proliferation and induced cell apoptosis in vitro. We then showed that a transferrin-polyethylenimine-HIF-1alpha-short-hairpin RNA (Tf-PEI-HIF-1alpha-shRNA) complex could target MM specifically and efficiently both in vivo and in vitro, exploiting the high expression of the TfR in MM. The systemic delivery of sequence-specific small-interfering RNA (siRNA) against HIF-1alpha by the Tf- PEI-HIF-1alpha-shRNA complex dramatically inhibited tumor growth in the A375 MM xenograft model. The underlying concept of transfecting a HIF-1alpha shRNA expression vector complexed with Tf-PEI to block HIF-1alpha holds promise as a clinical approach to gene therapy for MM.

Background: Endothelin-3 (ET-3) is an essential paracrine factor for the proliferation, migration, and survival of embryonic melanocytes during fetal development. Its expression is tightly regulated, being completely turned off in adult skin., Objective: In this study, results are presented that demonstrate abnormal expression of ET-3 by metastatic melanoma cells in both tissue biopsies and cell culture. Further, in vitro experiments showed that metastatic melanoma cells have the capacity to respond to ET-3 stimulation by increasing survival., Conclusion: Therefore, an abnormal autocrine stimulation pathway involving ET-3 is present in metastatic melanoma cells. Blocking this signal transduction pathway may prove useful for the treatment of metastatic melanoma.

To establish an animal model of benign lymphangiomas of C57BL/6 mouse in vitro and to observe the effect of mouse ascites melanoma cell B16-F1 on the lymphangiogenesis, 16 C57BL/6 mice aged 8 weeks were given two intraperitoneal injections of incomplete Freund's adjuvant at a 15-day interval. The induced neoplasms were studied histopathologically and the neoplasms specimens were immunohistochemically examined for the expressions of VEGF-C (vascular endothelial growth factor-C) and Flt-4 (VEGFR-3, vascular endothelial growth factor receptor-3). The neoplasms were harvested and embedded in fibrin gel for culture in conditioned medium of B16-F1 cells in vitro and observed under inverted microscope. Our results showed that white solid tumor masses developed in peritoneal cavity after the induction. The tumors were confirmed to be lymphangioma by gross and histological examination. The tumor cells expressed both VEGF-C and Flt-4. Lymphatic capillaries coming from lymphangioma specimen grew into the gel and the conditioned medium of B16-F1 cells was found to be able to promote the growth of the vessels. It is concluded that intraperitoneal injection of incomplete Freund's adjuvant is a good method for inducing benign lymphangiomas in mouse and B16-F1 cells can promote lymphangiogenesis.

In order to investigate the expression of endothelin receptor B (ETR-B) in human malignant melanoma (MM) cells A375 and SK-mel-1 and the proliferative effects of endothelin 3 (ET3) on A375 cells, RT-PCR was applied to detect the expression of ETR-B gene in human MM cells A375 and SK-mel-1. MTT method was used to evaluate the growth enhancing effects of ET3 on A375 cell line in vitro. The results showed that ETR-B gene was expressed in both MM A375 and SK-mel-1 cells. ET3 had stronger ability to enhance the proliferation of A375 cells in vitro in a concentration-dependent manner. It was suggested that ET3/ETR-B might play an important proliferative role in MM.

Purpose: Integrin-linked kinase (ILK), a key component of the extracellular matrix adhesion, has been studied extensively in recent years. Overexpression of ILK in epithelial cells results in anchorage-independent cell growth with increased cell cycle progression. Furthermore, increased ILK expression is correlated with progression of several human tumor types, including breast, prostate, and colon carcinomas. However, the role of ILK overexpression in human melanoma pathogenesis is not known. To investigate whether ILK plays a role in melanoma progression, we measured ILK expression in primary melanoma biopsies at various stages of invasion and evaluated the prognostic value of ILK expression in human melanoma., Experimental Design: We used tissue microarray and immunohistochemistry to determine ILK expression in 67 primary melanomas and analyzed the correlation between ILK expression and melanoma progression and 5-year patient survival., Results: We show that strong ILK expression is significantly associated with melanoma thickness. Strong ILK expression was observed in 0, 22, 33, and 63% in melanoma biopsies 3.0 mm in thickness, respectively. Furthermore, strong ILK expression was detected in 83% of the tumors with lymph node invasion compared with only 18% for tumors without lymph node invasion (P < 0.01). Strikingly, our data revealed that strong ILK expression is inversely correlated with 5-year patient survival (P < 0.05)., Conclusion: ILK expression increases dramatically with melanoma invasion and progression and is inversely correlated with patient survival.

Background: Melanoma is one of the most malignant and aggressive skin tumors, and its incidence is increasing worldwide. However, few studies have investigated the process of tumorigenesis from normal skin to melanoma. Methods: Several bioinformatics analyses, including GEO databases, Oncomine database, TCGA database, STRING, MCODE and cytoHubba plug-ins, GEPIA, TIMER and TRRUST and DGIdb, were performed to disclose the hub genes and immunology implicated in primary melanoma tumorigenesis. Finally, immunohistochemistry (IHC) and quantitative real-time PCR (qPCR) were used to validate the results of bioinformatics analysis in vitro. Results: A total of 295 overlapping DEGs (ODEGs) (157 upregulated and 138 downregulated) and 9 hub genes were identified between primary melanoma and normal skin tissues. Functional analysis of these 9 hub genes indicated that the genes were primarily enriched in cell chemotaxis, the chemokine-mediated signaling pathway, the extracellular region, the extracellular space, chemokine activity and CXCR3 chemokine receptor binding. KEGG pathway enrichment showed that these genes were primarily involved in the chemokine signaling pathway, cytokine–cytokine receptor interaction, the toll-like receptor signaling pathway, the cytosolic DNA-sensing pathway and the TNF signaling pathway. Upregulated CCL5, CCL4, CXCL9 and CXCL10 demonstrated good overall survival (OS), and most of them have a higher expression in stage 0 and 1 of melanoma. Moreover, immune infiltration analysis showed that the above hub genes showed a strong positive correlation between their expression and infiltration of the six immune cell subsets. Transcription factor regulation network suggested that RELA and NFKB1 are the transcription factors of CCL4, CCL5, CXCL10 and CXCL2, while IRF7, IRF3 and IRF1 are the transcription factors of CCL5 and CXCL10. Drug–gene interaction analysis identified 46 drug–gene interactions. In vitro data demonstrated that the level of CCL4, CCL5, CXCL9 and CXCL10 is higher in melanoma than that in normal skin tissues, either at tissue or cell lines level. Conclusion: In summary, we identified 4 key chemokine members related to tumorigenesis and progression in primary melanoma, and these results may help to elucidate melanoma tumorigenesis and facilitate its treatment. [ABSTRACT FROM AUTHOR]