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Splicing in gliomas

ABSTRACT: The objective of our study was to determine whether aberrant alternative splicing could play a role in the malignant phenotype of GBM. Patients with GBM were operated with 5-aminolevulinic fluorescence guided surgery. The fluorescent was used to take biopsies from the tumor center, and from adjacent normal-looking tissue. Three paired normal/GBM samples were analyzed in a HJAY J array. We validated our results with conventional PCR and qRT-PCR in those tumor samples and in ten additional GBMs. We performed functional studies using MTT assays (proliferation) and IF qRT-PCR (differentiation). We generated a list of seven genes with differential alternative splicing between central tumor samples and the adjacent normal-looking tissue. DPF-2(BAF45d) was one of our top candidates. Interestingly, DPF-2 is known as a tumor suppressor gene in the context of the SWI/SNF complex and plays a key role in the development of the central nervous system. The inhibition of our DPF-2 isoform resulted in a significative reduction in proliferation and in a morphology changes towards a more differentiated phenotype in GBM cell lines. Interestingly, our DPF2 tumoral isoform was the predominant transcript in early postnatal murine neural precursors and its expression disappeared as these cells were instructed towards neurons. Our results suggest that the alternative splicing of DPF-2 in GBM could participate in the maintenance of an undifferentiated cellular state. In addition, our data suggest that alternative splicing is a mechanism that could be central to GBM development

ORGANISM(S): Homo sapiens

PROVIDER: GSE76070 | GEO | 2016/09/01

SECONDARY ACCESSION(S): PRJNA306150

REPOSITORIES: GEO

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Project description:Background:Breast cancer is the second most frequent type of cancer affecting women. We are increasingly aware that changes in mRNA splicing are associated with various characteristics of cancer. The most deadly aspect of cancer is metastasis, the process by which cancer spreads from the primary tumor to distant organs. However, little is known specifically about the involvement of alternative splicing in the formation of macroscopic metastases. Our study investigates transcript isoform changes that characterize tumors of different abilities to form growing metastases. Results:To identify alternative splicing events (ASEs) that are associated with the fully metastatic phenotype in breast cancer, we used Affymetrix Exon Microarrays to profile mRNA isoform variations genome-wide in weakly metastatic (168FARN and 4T07) and highly metastatic (4T1) mammary carcinomas. Statistical analysis identified significant expression changes in 7606 out of 155,994 (4%) exons and in 1725 out of 189,460 (1%) intronic regions, which affect 2623 out of 16,654 (16%) genes. These changes correspond to putative alternative isoforms - several of which are novel - that are differentially expressed between tumors of varying metastatic phenotypes. Gene pathway analysis showed that 1224 of genes expressing alternative isoforms were involved in cell growth, cell interactions, cell proliferation, cell migration and cell death and have been previously linked to cancers and genetic disorders. We chose ten predicted splice variants for RT-PCR validation, eight of which were successfully confirmed (MED24, MFI2, SRRT, CD44, CLK1 and HNRNPH1). These include three novel intron retentions in CD44, a gene in which isoform variations have been previously associated with the metastasis of several cancers. Conclusions:Our findings reveal that various genes are differently spliced and/or expressed in association with the metastatic phenotype of tumor cells. Identification of metastasis-specific isoforms may contribute to the development of improved breast cancer stage identification and targeted therapies. Keywords: Seek pre-mRNA changes associated with the fully metastatic phenotype in breast cancer We used RNA tumor tissues derived from three murine mammary carcinoma cell lines (168FARN, 4T07 and 4T1); four biological replicates of 168FARN, four biological replicates of 4T07, and four biological replicates of 4T1 were hybridized independently at McGill university site.

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Splicing in gliomas

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