The Effect Of Genistein On Uveal Melonama And The Meta Analysis Of Age-related Macular Degeneration Risk Factor

Eye disease has complex etiological factor, including genetic and environmental factors (chronic light damage, malnutrition, toxicosis, dysimmunity, hypertension, arteriosclerosis, and so on). Pathogenic mechanism is related to abnormal blood supply, oxidative stress. The reseach about pathogenesis and mechanism have significance on prevention and treatment of eye disease.Uveal melanoma is the most common primary intra-ocular malignancy in adults. More than half of these patients will eventually develop hematogenous metastases. The median survival of patients with metastasis is less than 6 months. The treatment options are limited. Vasculogenic mimicry (VM), a new form of blood supply, has been recognized firstly in uveal melanoma. It is correlated with poor prognosis in patients with uveal melanoma tumors. VM is a possibly therapeutic target. At present there are insufficient researches targeting VM.Age-related macular degeneration (AMD) is the most important cause of adult blindness in developed countries. AMD was estimated to affect 8 million in the world by the year of 2020. AMD is also becoming a significant social problem in China due to the rapid aging of the population. However, there is no curative treatment for AMD at present. Therefore, more and more attention has been given to identification of modifiable factors related to this disease.In present study, we examine the the effect of anticancer drug Genistein on VM formation by human uveal melanoma cells and the possible molecular mechanism. In addition,we also evaluated the association of smoking and the risk of AMD. PartⅠEffect of Genistein on vasculogenic mimicry formation by human uveal melanoma cellsVasculogenic mimicry (VM) is network of vascular channels forming by aggressive melanoma tumor cells instead of endothelial cells. It is different from classical angiogenesis. The patterned microcirculation characteristic was first described in uveal melanoma. Uveal melanoma cells form VM channels and could express some endothelial-associated genes, including vascular endothelial cadherin (VE-cadherin). VM, new form of blood supply, is correlated with poor prognosis in patients with uveal melanoma tumors. Genistein is a predominant isoflavone in soybeans and has been shown to inhibit the invasion and growth of various cancer cells. This study was performed to evaluate the effect of Genistein on the VM channels formation of highly aggressive melanoma cells and explore the underlying molecular mechanisms.The cells viability was measured by MTT assay and morphological changes of the cells were recorded. Three dimension cultural and periodic acid–Schiff (PAS) staining were conducted to examine the effect of Genistein on the formation of VM by human uveal melanoma C918 cells. The nude mice models of human uveal melanoma C918 cells were established to assess the number of VM using immunohistochemical and PAS double-staining. We used reverse transcription polymerase chain reaction (RT-PCR) and Western blot to determine the VE-cadherin mRNA and protein expression. The result showed Genistein inhibited the cell survival in dose-dependent manner and the 50% inhibitory concentration of Genistein within 48 after incubation was 67.5μM. C918 cells cultruled on three dimension matrix formed VM in control, 25μM and 50μM Genistein groups; but not in 100μM and 200μM groups. In addition, the ectopic mode study also showed that VM in tumor tissue sections were significantly reduced by Genistein (P<0.05). Genistein also down regulated the VE-cadherin mRNA and protein expression. 25μM and 50μM of Genistein down regulated the VE-cadherin mRNA and protein levels but no statistics significant (P>0.05). However, VE-cadherin levels were significantly decreased by 100 and 200μM of Genistein (P < 0.05, P < 0.01, respectively).PartⅡSmoking and the risk of age-related macular degeneration: a meta-analysisThe pathogenesis of age-related macular degeneration (AMD) is relatively complicated. The exact mechanism is still unclear. Age and other various factors commonly induced the incidence of AMD which is closely related to oxidative stress. Many epidemiological studies investigated the association of smoking and the risk of AMD. Though most studies suggested smoking increase the risk of AMD, the results were inconsistent. Therefore, we undertook this meta-analysis to further clarify the association of smoking with AMD risk.Five prospective studies met the inclusion criteria. The results showed the ever smoking was associated with increased risk of AMD (RR=1.61, 95% CI=1.01–2.57). No evidence of publication bias was observed with a nonsignificant Egger test (P=0.852). Compared with individuals who never smoking, current smokers had a significant higher risk of AMD (RR=2.06, 95% CI=1.12–3.77). Past smoker had boldline risk of AMD (RR=1.40, 95% CI=0.96–2.06). Furthermore, we analyzed the the relationship of smoking to both subtype of AMD. Results showed smoking increased the geographic atrophy (GA) risk. However, for those with neovascular AMD (NV), the association was not statistically significant (RR=1.48, 95% CI=0.92–2.37).Eight case-control studies were included. Compared individuals who never smoking, the pooled estimate of AMD was 1.76 (95% CI=1.56–1.99) for ever smokers. No evidence of publication bias was observed with a nonsignificant Egger test (P=0.412). Current smokers and past smokers had significant risk of AMD. But the risk was higher among current smokers (OR=2.38, 95% CI=1.74–3.26) than among past smokers (OR=1.66, 95% CI=1.35–2.04). In the subtype analysis, we found smoking significant increased the risks of both GA (RR=1.71, 95% CI=1.23–2.39) and NV (RR=1.96, 95% CI=1.69–2.27). In addition, we separated the population-based case-control studies from their hospital-based case-control studies, and found no apparent difference between hospital-based case-control studies (OR=1.85, 95% CI=1.58–2.16) and population-based case-control studies (OR=1.62, 95% CI=1.33–1.98).