Rab15 alternative splicing is altered in spheres of neuroblastoma cells

Abstract

Abstract. Neuroblastoma is an aggressive pediatric tumor that accounts for 15% of cancer-related deaths in children. More than half of high-risk neuroblastoma patients develop tumor relapse that is lethal in most cases. A small population of tumor-initiating cells (TICs), recently identified from high-risk neuroblastoma patients as spheres, is believed to be responsible for tumor relapse. Rab family small G proteins are essential in controlling membrane traffic and their misregulation results in several cancers. Rab15 was originally isolated as a brain-specific Rab protein regulating the endocytic recycling pathway and was recently identified as a downstream target of the neural transcription factor Atoh1. Previously, we identified two alternatively spliced Rab15 isoforms in neuroblastoma cells and showed a significant correlation between Rab15 expression and neuronal differentiation. As aberrant alternative splicing is intimately associated with an increasing number of cancers, its use as a new diagnostic and/or prognostic biomarker has attracted considerable attention. In the present study, we explored cancer-associated changes of Rab15 alternative splicing in neuroblastoma TICs. We found that Rab15 alternative splicing generated two novel isoforms designated as Rab15 AN2 and Rab15 AN3 in addition to two known isoforms designated as Rab15 CN and Rab15 AN1. Although both Rab15 AN2 and Rab15 AN3 contained premature termination codons, they were detected in not only neuroblastoma cells but also in normal human tissues.One isoform was predominantly expressed in the brain and testis, while the other isoform was more specifically expressed in the brain. In neuroblastoma, Rab15 isoform balance measured by the Rab15 CN /Rab15 AN1+AN2+AN3 ratio was significantly decreased in spheres compared to parental cells. These results suggest that Rab15 alternative splicing may serve as a biomarker to discriminate TICs from non-TICs in neuroblastoma.

Constitutive resistance to viral infection in human CD141 + dendritic cells

“…S3B). Of note, expression of RAB15 AN1, a splicing variant of RAB15 that lacks the CXC domain required for membrane binding (49), completely and specifically abrogated infection and fusion by influenza virus H1N1 and H1N1-pseudotyped virus (Fig. S3C, S3D, S3E, S3F, S3G, S3H, S3I, S3J).…”

A New Mutation of the Atoh1 Gene in Mice with Normal Life Span Allows Analysis of Inner Ear and Cerebellar Phenotype in Aging

“…However, there was no significant difference in mRNA levels of Rab15 in inner ear tissue between mutant mice and wild-type mice. It is widely acceptedthat Barhl1 is one direct target of Atoh1 in the developing neural tube or cerebellum [5] , [12] , [19] , which is sufficient for the initial generation of those hair cells even in the absence of Barhl1 expression. The expression of Selm was down-regulated in trhl/trhl samples, though not significant, which were in accordance with previously report [13] , indicating a G-Atransition mutation affects the regulating target genes of Atoh1.…”

“…These characteristics may reflect a crucial requirement for Atoh1 in the lifelong maintenance of cochlear hair cells. Conceivably, an understanding of this requirement at the molecular level will provide significant insights into the pathology of aging-related deafness, creating further demand for this model as a significant tool to explore human diseases including lung cancers [19] , intestinal tumorigenesis, [5] and neuroblastomaformation [19] , [28] .…”

Knockdown of estrogen receptor β increases proliferation and affects the transcriptome of endometrial adenocarcinoma cells

“…Though originally being a transcriptional repressor, this protein is known to interact with other molecules like SS18, thereby deregulating developmental programs to drive transformation leading to irreversible mesenchymal differentiation [43]. The 2-fold upregulated gene RAB15 is known as a member of RAS oncogene family, but to judge, to what extent it acts as an oncogene itself or might be able to affect proliferation of cancer cells, more research on its specific functions is necessary [44, 45]. Nicotinamide phosphoribosyltransferase (NAMPT), in our experiments more than 4-fold upregulated after ESR2 knockdown in HEC-1A cells, is overexpressed in several cancer entities such as ovarian, breast, gastric, colorectal, and prostate cancer, gliomas and B-cell lymphomas [46].…”