Abstract
Conflicting data exist about the expression of L1 cell adhesion molecule (L1-CAM) in clear cell renal cell carcinoma (ccRCC). To determine the clinical usefullness of L1-CAM as a therapeutic or prognostic marker molecule in renal cancer patients, we analyzed its expression on a cohort of 282 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 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 siRNA 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 promotor 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.
Doberstein, K