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C. Martins, E. Antecka, B. F. Fernandes, S. Di Cesare, S. Malloney, M. N. Burnier, Jr.; Expression of Metastasis Suppressor Genes Kiss1 and Mkk4 in Retinoblastoma. Invest. Ophthalmol. Vis. Sci. 2008;49(13):25.
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Retinoblastoma is the most common primary intraocular malignant tumor in children. Despite success in the treatment of primary retinoblastoma, there is a significant incidence of recurrence, metastatic disease and subsequent death in affected individuals. Metastasis Suppressor Genes (MSGs) have recently emerged as putative therapeutic targets in numerous malignancies. Specifically, MKK4 and KISS1 are MSGs thought to be involved in tumor dormancy. The purpose of this study was to investigate the expression of KISS1 and MKK4 in human retinoblastoma samples and cell lines and correlate this expression with known histopathological prognostic factors.
Paraffin-embedded sections from forty-two retinoblastoma patients were immunostained with KISS1 and MKK4 antibodies. The immunostaining was evaluated semi-quantitatively based on extent and intensity. Additionally, expression of KISS1 and MKK4 was analyzed in two retinoblastoma cell lines (WERY1 and Y79) using real-time PCR and immunocytochemistry. Finally, expression of the KISS1 receptor GPR54 was assessed in the two cell lines via real-time PCR
Immunostaining of KISS1 and MKK4 was positive in 88% (37 / 42) and 84% (35 / 42) of retinoblastoma cases, respectively. Staining was cytoplasmic in all positive cases, with KISS1 expression being strong while MKK4 staining was notably weak. KISS1 expression was positive in 86% (19 / 22) of cases with choroidal invasion and 88% (14 / 16) of cases with optic nerve invasion. Furthermore, expression of KISS1 was positive only in the most aggressive cell line, Y79, while MKK4 expression was moderate in WERY1 and weak in Y79. Quantitative real-time PCR analysis confirmed the expression of KISS1 and GPR54 mRNA in both retinoblastoma cell lines. Expression of KISS1 was 25 times higher in Y79 than WERY1, which was consistent with immunostaining results. GPR54 expression was low in both cell lines. Expression of MKK4 was shown to be low in both cell lines; expression in WERY1 was almost twice as high as the Y79 cell line
To the best of our knowledge, this is the first time that KISS1 and MKK4 expression has been characterized in retinoblastoma. The strong expression of KISS1 compared to the weak expression of MKK4 in primary tumors suggests that these MSGs play different roles in the progression of retinoblastoma. Further studies may yield valuable insight into the prognostic value of KISS1 and MKK4 in retinoblastoma
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