Recurrent Chimeric RNA, CTNNBIP1-CLSTN1 Regulates Cell Proliferation through SERPINE2 in Non-neoplastic Human Cells
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ABSTRACT:
PROVIDER: PRJNA694672 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13523312_1.fastq.gz | Fastqsanger.gz | |||
| SRR13523312_2.fastq.gz | Fastqsanger.gz | |||
| SRR13523313_1.fastq.gz | Fastqsanger.gz | |||
| SRR13523313_2.fastq.gz | Fastqsanger.gz | |||
| SRR13523314_1.fastq.gz | Fastqsanger.gz |
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Project description:Conventional wisdom that chimeric RNAs and proteins being peculiarity of carcinoma is being challenged, as more evidence are accumulated supporting that chimeric RNAs are widely spread in noncancerous tissues and cells. One particular chimeric RNA, CTNNBIP1-CLSTN1 produced by cis-splicing between two neighboring genes, has been detected in a variety of normal tissues. However, the details of its functionality are not clear. Here, we report that this fusion transcript is expressed in almost all tissues, and a wide range of cell types including fibroblasts, epithelial, stem, vascular endothelial cells, and hepatocytes. The expression level in non-cancerous cell lines is also not evidently different from that in the cancer cell lines. Furthermore, silencing CTNNBIP1-CLSTN1 significantly reduces cell proliferation rate, by inducing G2/M arrest in cell cycle progress and apoptosis in at least three cell types. Importantly, rescue experiments confirmed that the cell cycle arrest can be regained by exogenous expression of the chimera, but not the wild type parental gene. Further evidence is provided that CTNNBIP1-CLSTN1 regulates cell proliferation through SERPINE2. In conclusion, CTNNBIP1-CLSTN1 chimeric transcript widely exists in normal physiology, and undertakes essential cellular maintenance roles. It represents an example of a new class of fusion RNA, dubbed “housekeeping chimeric RNAs”.
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Project description:Treating recurrent GBM is a clinical challenge due to its highly resistant and aggressive nature. In order to develop new therapeutic targets for recurrent GBM a better understanding of its molecular landscape is necessary. Here we used a cellular model, developed in our lab which generates paired primary and recurrent samples from GBM cell lines and primary patient samples hence allowing us to compare the molecular differences between the two populations. Total RNA seq analysis of parent and recurrent population of two cell lines and one patient sample revealed a significant upregulation of Extracellular matrix interaction in recurrent population. Since matrix stiffness plays a pivotal role in cell-ECM interaction and downstream signaling, we developed a system that mimicked the brain like substrate stiffness by using collagen coated polyacrylamide-based substrate whose stiffness can be modified from normal brain (0.5kPa) to tumorigenic (10kPa). Using these substrates, we were able to capture the morphological and physiological differences between parent and recurrent GBM which were not evident on plastic surfaces (~1 GPa). On 0.5kPa, unlike circular parent cells, recurrent GBM cells showed two morphologies (circular and elongated). The recurrent cells growing on 0.5kPa also showed higher proliferation, invasion, migration and in-vivo tumorigenicity in orthotropic GBM mouse model, compared to parent cells. Furthermore, recurrent cells exhibited elevated velocity irrespective of substrate stiffness, which indicated that recurrent cells may possess inherent differential mechanosignalling ability which was reflected by higher expression of ECM proteins like Collagen IVA, MMP2 and MMP9. Moreover, mice brain injected with recurrent cells grown on 0.5kPa substrate showed higher Young’s modulus values suggesting that recurrent cells conditioned on 0.5kPa make the surrounding ECM stiffer. Importantly, inhibition of EGFR signaling, that is amplified with tissue stiffening in GBM resulted in decreased invasion, migration and proliferation in 0.5kPa recurrent cells, but interestingly survival remained unaffected, highlighting the importance of mimicking the physiological stiffness of the brain mimicking clinical scenario. Total RNA seq analysis of parent and recurrent cells grown on plastic and 0.5kPa substrate identified PLEKHA7 as significantly upregulated gene specifically in 0.5kPa recurrent sample. Higher protein expression of PLEKHA7 in recurrent GBM as compared to primary GBM was validated in patient biopsies. Accordingly, PLEKHA7 knockdown reduced invasion and survival of recurrent GBM cells. Together, these data provides a model system that captures the differential mechanosensing signals of primary and recurrent GBM cells and identifies a novel potential target specific for recurrent GBM.
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Project description:Interventions: From November 2010 to August 2012 Following the detection of colorectal lesions in WL observation, the lesions were diagnosed for neoplastic or non-neoplastic.
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