Promotion effects of mono-2-ethyhexyl phthalate (MEHP) on migration and invasion of human melanoma cells via activation of TGF-β signals.
邻苯二甲酸mono-2-ethyhexyl (MEHP) 通过激活TGF-β 信号对人黑色素瘤细胞迁移和侵袭的促进作用。
- 作者列表："Fan P","Li Z","Zuo C","Fang M
:Malignant melanoma is one of the most leading forms of skin cancer associated with a low patient survival rate. There is an urgent need to illustrate risk factors that can trigger the motility of melanoma cancer cells. Our present study revealed that mono-(2-ethylhexyl)phthalate (MEHP) exposure can significantly increase the in vitro migration and invasion of WM983A and A375 cells. Among the tested cytokines, MEHP can increase the expression of transforming growth factor β (TGF-β). Inhibition of TGF-β via its neutralization antibody can attenuate MEHP-induced cell migration and invasion. Further, upregulation of TGF-β mediated MEHP-induced activation of Smad signals and upregulation of Snail in melanoma cells. Blocking the TGF-β/Smad signal pathway can attenuate MEHP-induced cell migration. Estrogen receptor α (ERα) was essential for MEHP-induced expression of TGF-β. In addition, MEHP can increase the expression of ERα in melanoma cells. Collectively, our study found that MEHP can stimulate the progression of melanoma via TGF-β signals. SIGNIFICANCE: Mono-(2-ethylhexyl)phthalate (MEHP) is the active and most toxic metabolite of di(2-ethylhexyl)phthalate (DEHP). Our present study revealed that MEHP can trigger the in vitro migration and invasion of melanoma cells via upregulation of TGF-β/Snail signals. It revealed that daily exposure to MEHP might be a risk factor for melanoma patients.
: 恶性黑色素瘤是与低患者生存率相关的最主要形式的皮肤癌之一。迫切需要说明能够触发黑色素瘤癌细胞运动的危险因素。我们目前的研究揭示了邻苯二甲酸单-(2-乙基己基) 酯 (MEHP) 暴露可显著增加WM983A和A375 细胞的体外迁移和侵袭。在所检测的细胞因子中，MEHP能增加转化生长因子 β (TGF-β) 的表达。通过其中和抗体抑制TGF-β 可减弱MEHP诱导的细胞迁移和侵袭。此外，TGF-β 的上调介导了MEHP诱导的Smad信号的激活和黑色素瘤细胞中Snail的上调。阻断TGF-β/Smad信号通路可减弱MEHP诱导的细胞迁移。雌激素受体 α (er α) 对MEHP诱导的TGF-β 表达至关重要。此外，MEHP可增加黑色素瘤细胞er α 的表达。总的来说，我们的研究发现MEHP可以通过TGF-β 信号刺激黑色素瘤的进展。意义: 邻苯二甲酸单 (2-乙基己基) 酯 (MEHP) 是邻苯二甲酸二 (2-乙基己基) 酯 (DEHP) 的活性和毒性最强的代谢产物。我们目前的研究揭示了MEHP可以通过上调TGF-β/Snail信号触发黑色素瘤细胞的体外迁移和侵袭。它揭示了每天暴露于MEHP可能是黑色素瘤患者的一个危险因素。
METHODS::Blue rubber bleb naevus syndrome (BRBNS) is an extremely rare venous malformation that often manifests as multiple haemangioma-like lesions in the skin and gastrointestinal tract. The drug sirolimus plays a key role in the signalling pathway of angiogenesis and subsequent development of BRBNS and its use has been described in several case reports. We present a case series of four patients with BRBNS who exhibited good treatment response to sirolimus. All four patients were administered oral sirolimus at doses of 1.0-1.5 mg/m2 /day with a target drug level of 5-10 ng/mL and median treatment duration of 20 months. All patients had a reduction in the size of the lesions and a normalization of coagulopathy with tolerable drug adverse reactions at follow-up. Sirolimus may be effective and safe in paediatric patients with BRBNS. Further prospective studies are suggested to evaluate the long-term effectiveness of this drug.
METHODS:BACKGROUND:Human papillomavirus (HPV) infections are associated with common dermatologic and nondermatologic diseases. Although HPV vaccines are well established as preventive measures for genital warts and cervical neoplasia, their use as therapeutic agents deserves greater attention. OBJECTIVE:To evaluate the use of HPV vaccine(s) as a treatment modality for cutaneous and/or mucosal disease. METHODS:A primary literature search using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines was conducted in January 2019 by using the PubMed and Cochrane databases. RESULTS:A total of 63 articles with 4439 patients were included. The majority of patients with cutaneous warts, recurrent respiratory papillomatosis, and squamous and basal cell carcinomas were successfully treated with HPV vaccination. Preliminary data on patients with pre-existing anogenital warts, cervical intraepithelial neoplasia, anal intraepithelial neoplasia, and vulvar intraepithelial neoplasia is promising. LIMITATIONS:This review was limited by the lack of controls, patients' previous HPV vaccination status, and publication bias. CONCLUSION:The commercially available three-dose, quadrivalent HPV vaccine is a potential therapeutic option for the treatment of cutaneous warts, recurrent respiratory papillomatosis, and squamous and basal cell carcinomas. Noncommercially available HPV vaccines demonstrate therapeutic response for treating anogenital warts, cervical intraepithelial neoplasia, anal intraepithelial neoplasia, and vulvar intraepithelial neoplasia. The vaccine's efficacy as an adjunct therapy for HPV-associated cutaneous and/or mucosal disease warrants further exploration.
METHODS::Our understanding of melanoma precursors and progression to melanoma has developed as a result of advances in the field of molecular diagnostics. We now better understand the potential for genetic heterogeneity within a single lesion. Combined tumors can pose a diagnostic challenge when deciding the line between benign and malignant, which in turn has direct implications for patient management. Primary cilia (PC) are ubiquitous sensory organelles that have essential functions in cellular proliferation, differentiation, and development. The ciliation index (percentage of ciliated melanocytes) has been shown to reliably differentiate melanoma, which fail to ciliate, from melanocytic nevi, which retain PC. We therefore analyzed the potential for using the ciliation index to differentiate benign and malignant components in combined melanocytic lesions. We collected patient samples (n = 10) of unequivocal combined lesions with both melanoma and associated nevus components. Melanocytes were highlighted with SOX10 and costained with gamma-Tubulin and acetylated alpha-Tubulin to highlight the basal body and cilium, respectively. The number of melanocytes retaining cilia under high-power microscopy was examined. The melanoma component had average of 4% ciliation (SD: 7%), whereas the associated nevus component was significantly higher with 59% ciliation (SD: 17%). These data show that PC may be a reliable means of distinguishing benign from malignant components within a single tumor. The ciliation index may be a helpful tool in distinguishing challenging cases of combined lesions of melanoma in situ with a dermal nevus component from invasive melanoma, thus promoting improved staging and clinical management.