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Vinodh Kakkassery, Natalie Wagner, Marvin Jarocki, Stephanie C Joachim, H Burkhard Dick, Andreas Faissner, Jacqueline Reinhard; Extracellular matrix remodelling in an Etoposide resistant WERI-Rb1 subclone. Invest. Ophthalmol. Vis. Sci. 2018;59(9):1630.
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Chemotherapy resistance is still a significant problem in retinoblastoma (Rb). Studies indicate that extracellular matrix (ECM) remodelling plays a crucial role in tumour malignancy. Therefore, objective of this study was to analyze the ECM of two human retinoblastoma cell lines, Etoposide sensitive WERI-Rb1 and an Etoposide resistant subclone (WERI-ETOR).
Quantitative RT-PCR analyses were performed for the proteoglycans Aggrecan, Brevican, Neurocan and Versican in both cell lines, WERI-Rb1 and WERI-ETOR. Also, the glycoproteins Fibronectin, α1-Laminin, Tenascin-C and Tenascin-R, the matrix metalloproteinases MMP-2, -7 and -9, the tissue inhibitor of metalloproteinases TIMP-1 and -2 as well as the integrins α5, β1, αv, α4 and α6 were evaluated. Additionally, proliferation analyses via video microscopy were performed after WERI-Rb1 and WERI-ETOR cell cultivation on Fibronectin, Laminin, Tenascin-C and Collagen IV. Data were analyzed by using Student`s t-test for pair-wise or ANOVA for multiple comparisons followed by Scheffés post-hoc test.
Quantitative RT-PCR analysis showed a reduced Brevican (p < 0.001), Neurocan (p = 0.003) and Versican (p < 0.001) mRNA expression in the resistant WERI-ETOR compared to the sensitive WERI-Rb1. Furthermore, reduced expression levels of α1-Laminin (p = 0.001), Fibronectin (p < 0.001), Tenascin-C (p = 0.001) and Tenascin-R (p < 0.001) were observed in the resistant cell line. A significant down-regulation was shown for MMP-2, -7, -9 and TIMP-2 (all p < 0.001). Lower levels of the α5-, β1- and α4-Integrins were observed, whereas an up-regulation was detected for α6-Integrin in the resistant cell line (p < 0.001).Interestingly, proliferation of resistant cells was enhanced on Tenascin-C, while an anti-proliferative effect was observed on Fibronectin (p = 0.014).
Our results indicate a different ECM expression and cell-substrate interaction in chemotherapy resistant Rb cells. This mechanism might be a step towards chemotherapeutic resistance transformation in Rb patients.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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