Analysis of the tumour-associated genes BCL9L and SLC35F2 in the progression of bladder cancer

The molecular mechanisms of progression remain poorly understood. From DNA sequencing analysis of non-muscle invasive (NMIBC) and corresponding muscle-invasive bladder cancer (MIBC) patients, the solute carrier family 35 member F2 (SLC35F2) and B-Cell Lymphoma 9-Like (BCL9L) were exclusively mutated in the 5′ and 3′ untranslated region (UTR). This study shows that the C>T mutation at 3′ UTR of SLC35F2 increases luciferase reporter activity in bladder cancer cells, suggesting a promoting role in protein expression in bladder cancer. The A>T mutation at 3′ UTR of BCL9L reduces the mRNA expression and activity of luciferase reporter, suggesting an inhibitory effect on mRNA and protein expression of BCL9L in bladder cancer. Expression analysis of NMIBC and MIBC show that SLC35F2 and BCL9L are increased in MIBC compared to NIMBC. Especially tumour cells at the border of tumour islands in MIBC show a stronger expression. Knockdown of SLC35F2 and BCL9L significantly suppress the growth, migration and invasion of T24 and Cal29 cells independent of apoptosis, suggesting an oncogenic role of BCL9L and SLC35F2 and an involvement in bladder cancer progression. BCL9L knockdown reduces a subset of Wnt/β-catenin target genes and active β-catenin protein in Cal29 but not in T24. Furthermore, inhibition of Wnt/β-catenin signalling by the specific inhibitor iCRT3 represses growth, migration and invasion of both Cal29 and T24 cells, suggesting that Wnt/β-catenin signalling has an oncogenic effect on bladder cancer cells, however, the function of the β-catenin cofactor BCL9L could act dependent or independent of Wnt/β-catenin signalling. In conclusion, the tumour-associated genes SLC35F2 and BCL9L as well as the Wnt/β-catenin signalling seems to be associated with bladder cancer progression. Suppression of the oncogenic effect mediated by SLC35F2, BCL9L and Wnt/β-catenin signalling pathways might provide a potential therapeutic strategy against bladder cancer.