Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.2 (focal adhesion kinase)
 44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Melanoma is one of the most aggressive cancers. Hypoxic microenvironment affects multiple cellular pathways and contributes to tumor progression. The purpose of the research was to investigate the association between hypoxia and melanoma, and identify the prognostic value of hypoxia-related genes. Based on the GSVA algorithm, gene expression profile collected from The Cancer Genome Atlas (TCGA) was used for calculating the hypoxia score. The Kaplan-Meier plot suggested that a high hypoxia score was correlated with the inferior survival of melanoma patients. Using differential gene expression analysis and WGCNA, a total of 337 overlapping genes associated with hypoxia were determined. Protein-protein interaction network and functional enrichment analysis were conducted, and Lasso Cox regression was performed to establish the prognostic gene signature. Lasso regression showed that seven genes displayed the best features. A novel seven-gene signature (including ABCA12, PTK6, FERMT1, GSDMC, KRT2, CSTA, and SPRR2F) was constructed for prognosis prediction. The ROC curve inferred good performance in both the TCGA cohort and validation cohorts. Therefore, our study determined the prognostic implication of the hypoxia score in melanoma and showed a novel seven-gene signature to predict prognosis, which may provide insights into the prognosis evaluation and clinical decision making.
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PMID:Identification of Signatures of Prognosis Prediction for Melanoma Using a Hypoxia Score. 3313 57

Melanoma is one of the most serious forms of skin cancer, and its increasing incidence coupled with non-lasting therapeutic options for metastatic disease highlight the need for additional novel approaches for its management. In this study, we determined the potential interactions between polo-like kinase 1 (PLK1, a serine/threonine kinase involved in mitotic regulation) and NOTCH1 (a type I transmembrane protein deciding cell fate during development) in melanoma. Employing an in-house human melanoma tissue microarray (TMA) containing multiple cases of melanomas and benign nevi, coupled with high-throughput, multispectral quantitative fluorescence imaging analysis, we found a positive correlation between PLK1 and NOTCH1 in melanoma. Further, TCGA database analysis of melanoma patients showed an association of higher mRNA levels of PLK1 and NOTCH1 with poor overall as well as disease-free survival. Next, utilizing small-molecule inhibitors of PLK1 and NOTCH (BI 6727 and MK-0752, respectively), we found a synergistic anti-proliferative response of combined treatment in multiple human melanoma cells. To determine the molecular targets of the overall and synergistic responses of combined PLK1-NOTCH inhibition, we conducted RNA-sequencing analysis employing a unique regression model with interaction terms. We identified the modulations of several key genes relevant to melanoma progression/metastasis, including MAPK, PI3K, and RAS, as well as some new genes such as Apobec3G, BTK and FCER1G which have not been well-studied in melanoma. In conclusion, our study demonstrated a synergistic anti-proliferative response of a concomitant targeting of PLK1 and NOTCH in melanoma, unraveling a potential novel therapeutic approach for detailed preclinical/clinical evaluation.
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PMID:PLK1 and NOTCH Positively Correlate in Melanoma and their Combined Inhibition Results in Synergistic Modulations of Key Melanoma Pathways. 3317 55

Melanoma is a skin malignancy with a high mutation frequency of genetic alterations. MicroRNA (miR)-200b-3p is involved in various cancers, while in melanoma its bio-function remains unknown. In this study, we found that miR-200b-3p was down-regulated in melanoma tissues and cell lines compared to benign nevus cells. Overexpression of miR-200b-3p significantly inhibited the proliferation and invasion of melanoma cells. According to bioinformatics analysis and sequencing data, we supposed that SMAD family member 2 (SMAD2) was the target gene and nuclear enriched abundant transcript 1 (NEAT1) was the upstream long non-coding RNA (lncRNA) of miR-200b-3p. These predictions were verified by western blotting and quantitative real-time reverse transcription PCR (RT-qPCR). Luciferase reporter assays revealed that NEAT1 up-regulated SMAD2 by directly sponging miR-200b-3p. In vitro and in vivo, we demonstrated that both NEAT1 and SMAD2 could promote the proliferation and invasion of melanoma cells, and these effects were reversed by up-regulating miR-200b-3p. In addition, NEAT1/miR-200b-3p/SMAD2 axis promoted melanoma progression by activating EMT signaling pathway and immune responses. Taken together, the NEAT1/miR-200b-3p/SMAD2 signaling pathway promotes melanoma via activation of EMT, cell invasion and is related with immune responses, which provides new insights into the molecular mechanisms and therapeutic targets for melanoma.
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PMID:NEAT1/miR-200b-3p/SMAD2 axis promotes progression of melanoma. 3320 80


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