Abstract
Growing evidence indicates that Rab GTPases, key regulators of intracellular transport in eukaryotic cells, play an important role in cancer. We analysed the deregulation at the transcriptional level of the genes encoding Rab proteins and Rab-interacting proteins in bladder cancer pathogenesis, distinguishing between the two main progression pathways so far identified in bladder cancer: the Ta pathway characterized by a high frequency of FGFR3 mutation and the carcinoma in situ pathway where no or infrequent FGFR3 mutations have been identified. A systematic literature search identified 61 genes encoding Rab proteins and 223 genes encoding Rab-interacting proteins. Transcriptomic data were obtained for normal urothelium samples and for two independent bladder cancer data sets corresponding to 152 and 75 tumors. Gene deregulation was analysed with the SAM (significant analysis of microarray) test or the binomial test. Overall, 30 genes were down-regulated, and 13 were up-regulated in the tumor samples. Five of these deregulated genes (LEPRE1, MICAL2, RAB23, STXBP1, SYTL1) were specifically deregulated in FGFR3-non-mutated muscle-invasive tumors. No gene encoding a Rab or Rab-interacting protein was found to be specifically deregulated in FGFR3-mutated tumors. Cluster analysis showed that the RAB27 gene cluster (comprising the genes encoding RAB27 and its interacting partners) was deregulated and that this deregulation was associated with both pathways of bladder cancer pathogenesis. Finally, we found that the expression of KIF20A and ZWINT was associated with that of proliferation markers and that the expression of MLPH, MYO5B, RAB11A, RAB11FIP1, RAB20 and SYTL2 was associated with that of urothelial cell differentiation markers. This systematic analysis of Rab and Rab effector gene deregulation in bladder cancer, taking relevant tumor subgroups into account, provides insight into the possible roles of Rab proteins and their effectors in bladder cancer pathogenesis. This approach is applicable to other group of genes and types of cancer.
Highlights
Intracellular trafficking is an essential process in eukaryotic cells
Briefly: 1. an exhaustive list of genes coding for Rab and Rab-interacting was established from public databases, 2. deregulated genes in each of the two pathways were identified from two transcriptome datasets, 3. deregulated genes possibly because of tumor stroma or tumor – stroma interactions were identified and omitted from further analysis (analysis of transcriptome data in bladder tumor cell lines compared to normal cells in culture (NHU)), 4. for each deregulated gene, a specific association either with the FGFR3mutated tumor group or the non-mutated tumor group was investigated as well as an association with a differentiation or proliferation phenotype
We investigated for each Rab cluster whether it could be associated with bladder cancer pathogenesis
Summary
Intracellular trafficking is an essential process in eukaryotic cells. It relies on vesicular or tubular transport carriers that shuttle between cell compartments facilitating the constant exchange of proteins and lipids. The active GTP-bound form of the Rab is membranebound whereas hydrolysis of the GTP to GDP results in its dissociation into the cytosol. These two cycles are controlled by a complex regulatory network of proteins that includes guanine nucleotide exchange factors (GEFs), GTPase activating proteins (GAPs) and guanine nucleotide dissociation inhibitors (GDI). In their active form Rab GTPases interact with a diverse range of effector proteins, such as molecular motors, lipid kinases, tethering factors and scaffolding proteins (see [1] for review)
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