L1-CAM expression in ccRCC correlates with shorter patients survival times and confers chemoresistance in renal cell carcinoma cells

Kai Doberstein, Anja Wieland, Sophia B Boyoung Lee, Roman A Alexander Blaheta, Steffen Wedel, Holger Moch, Peter Schraml, Josef Pfeilschifter, Glen Kristiansen, Paul Gutwein
Carcinogenesis 2011, 32 (3): 262-70
Conflicting data exist about the expression of L1 cell adhesion molecule (L1-CAM) in clear cell renal cell carcinoma (ccRCC). To determine the clinical usefulness of L1-CAM as a therapeutic or prognostic marker molecule in renal cancer patients, we analyzed its expression on a cohort of 282 renal cell carcinoma (RCC) patients. L1-CAM expression was found in 49.5% of 282 renal cancer tissues. Importantly, L1-CAM expression in patients with ccRCC was associated with significantly shorter patient survival time. We further present evidence that L1-CAM was involved in the resistance against therapeutic reagents like rapamycin, sunitinib and cisplatin. The downregulation of L1-CAM expression decreased renal cancer cell proliferation and reduced the expression of cyclin D1. In addition, we found out that Von Hippel-Lindau (VHL) deficiency was accompanied by a downregulation of the transcription factor PAX8 and L1-CAM. In normal renal tissue, PAX8 and L1-CAM were co-expressed in collecting duct cells. Importantly, the downregulation of PAX8 by small interfering RNA increased the expression of L1-CAM and concomitantly induced the migration of renal cancer cells. Furthermore, we observed in 65.3% of 282 RCC patients a downregulation of PAX8 expression. With chromatin immunoprecipitation analysis, we additionally demonstrate that PAX8 can bind to the promoter of L1-CAM and we further observed that the downregulation of PAX8 was accompanied by increased L1-CAM expression in a high fraction of ccRCC patients. In summary, we show that VHL and PAX8 are involved in the regulation of L1-CAM in renal cancer and L1-CAM represents an important therapeutic and prognostic marker protein for the treatment of ccRCC.

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