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KIT and Melanoma: Biological Insights and Clinical Implications
Duc (Daniel) M. Pham,Samantha Guhan,Hensin Tsao 연세대학교의과대학 2020 Yonsei medical journal Vol.61 No.7
Melanoma, originating from epidermal melanocytes, is a heterogeneous disease that has the highest mortality rate among alltypes of skin cancers. Numerous studies have revealed the cause of this cancer as related to various somatic driver mutations, includingalterations in KIT—a proto-oncogene encoding for a transmembrane receptor tyrosine kinase. Although accounting foronly 3% of all melanomas, mutations in c-KIT are mostly derived from acral, mucosal, and chronically sun-damaged melanomas. As an important factor for cell differentiation, proliferation, and survival, inhibition of c-KIT has been exploited for clinical trialsin advanced melanoma. Here, apart from the molecular background of c-KIT and its cellular functions, we will review the widedistribution of alterations in KIT with a catalogue of more than 40 mutations reported in various articles and case studies. Additionally,we will summarize the association of KIT mutations with clinicopathologic features (age, sex, melanoma subtypes, anatomiclocation, etc.), and the differences of mutation rate among subgroups. Finally, several therapeutic trials of c-KIT inhibitors, includingimatinib, dasatinib, nilotinib, and sunitinib, will be analyzed for their success rates and limitations in advanced melanomatreatment. These not only emphasize c-KIT as an attractive target for personalized melanoma therapy but also propose therequirement for additional investigational studies to develop novel therapeutic trials co-targeting c-KIT and other cytokines suchas members of signaling pathways and immune systems.
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P200 Beta-catenin causes fibrotic changes in the ECM via upregulation of collagen I transcription
( Mi Ryung Roh ),( Ji Young Choi ),( Raj Kumar ),( Apunchelvi Rajadurai ),( Jenny Njauw ),( Un Hee Ryoo ),( Kee Yang Chung ),( Hensin Tsao ) 대한피부과학회 2016 대한피부과학회 학술발표대회집 Vol.68 No.2
<div style="display:none">fiogf49gjkf0d</div><div style="display:none">fiogf49gjkf0d</div><div style="display:none">fiogf49gjkf0d</div><div style="display:none">fiogf49gjkf0d</div><div style="display:none">fiogf49gjkf0d</div><div style="display:none">fiogf49gjkf0d</div><div style="display:none">fiogf49gjkf0d</div> Background: Keloid scars represent a pathological response to cutaneous injury. They are characterized by increased proliferation of fibroblasts, especially in the active growth phase, as well as an abnormally increased production of collagen. The Wnt/β-catenin signaling pathway is a multifunctional network that plays an essential role in embryonic development, organogenesis, and tissue homeostasis. Objectives: We hypothesized that expression of stabilized β-catenin in fibroblasts is sufficient to cause fibrotic changes in the ECM via upregulation of collagen I transcription. Methods: First, we identified the expression of β-catenin and collagen in keloid tissues and cell lines. Then, we generated a tetracycline controlled stable immortalized fibroblast cell line expressing β-catenin to explore the role of stabilized β-catenin in collagen I transcription and synthesis. Results: By immunohistochemical staining, fibroblasts in keloid tissues showed significantly higher expression of β -catenin (p=0.046) and collagen I (p=0.002) than those of normal tissues. Immortalized fibroblasts with β-catenin overexpression (IF β-catenin) showed increased β -catenin, collagen I, and collagen III expression. Measurement of mRNA level by RT-PCR showed that β -catenin (p=0.02), col I (p=0.007), and col III (p=0.019) were markedly expressed in IF β-catenin compared to IF control. To determine if β-catenin had a direct transcriptional effect on the collagen I promoter, we generated a COL1A2-luciferase reporter and observed a dose-dependent increase in luciferase activity with increasing amounts of β-catenin. Conclusion: We found that the increased expression of β -catenin in fibroblasts is sufficient for increased collagen I synthesis, with concomitant increases in the COL1A2 luciferase activity. The highly increased levels of β -catenin together with its potent pro-fibrotic effects suggest that β-catenin might be a candidate for anti-fibrotic approaches.
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Promoter Methylation of PTEN Is a Significant Prognostic Factor in Melanoma Survival
Roh, Mi Ryung,Gupta, Sameer,Park, Kyu-Hyun,Chung, Kee Yang,Lauss, Martin,Flaherty, Keith T.,Jö,nsson, Gö,ran,Rha, Sun Young,Tsao, Hensin Elsevier 2016 The Journal of investigative dermatology Vol.136 No.5
<P>Structural compromise of the tumor suppressor gene, phosphatase and tensin homolog (PTEN), occurs in 10% of melanoma specimens, and loss of PTEN expression through DNA methylation of the PTEN promoter region has also been reported in a number of other malignancies. However, the role of PTEN promoter methylation in melanoma is not well understood. We thus sought to elucidate the prevalence of PTEN promoter methylation in melanoma specimens, its relationship to clinical features, and its impact on the outcome of patients with melanoma. PTEN promoter methylation data were acquired from an archived primary Korean melanoma cohort (KMC) of 158 patients and, for validation, 234 patients from The Cancer Genome Atlas melanoma (TCGA-MEL) cohort. Hierarchical clustering was performed to identify PTEN 'high methylated' and 'low methylated' samples. Subsequently, differences in clinical features and outcomes based on PTEN promoter methylation status were then analyzed using SPSS and R. In the KMC, all tumors were acquired from primary tumors and 65.7% (n = 105) were acral or mucosal by site, whereas in the TCGA-MEL cohort, 90.5% of the tumors were from regional lymph node and distant metastatic lesions. Overall, 17.7% and 45.7% of the specimens harbored BRAF mutations in the KMC and TCGA-MEL cohort, respectively. Neuroblastoma RAS viral oncogene homolog was mutated in 12.2% and 26.9% of the tumors in the KMC and TCGA-MEL cohort, respectively. In the KMC, 31 cases (19.6%) were included in the high methylated group versus 142 cases (60.7%) in the TCGA-MEL cohort (P < 0.001). Multivariate Cox-regression analysis revealed promoter methylation of PTEN to be an independent negative prognostic factor for survival in both the KMC (hazard ratio 3.76, 95% confidence interval = 1.24-11.12, P = 0.017) and TCGA-MEL cohort (HR 1.88, 95% confidence interval = 1.13-3.12, P = 0.015). Our results indicate that PTEN promoter methylation is an independent predictor for impaired survival in patients with melanoma.</P>
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