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Inference of Low and High-Grade Glioma Gene Regulatory Networks Delineates the Role of Rnd3 in Establishing Multiple Hallmarks of Cancer.

Clarke K, Daubon T, Turan N, Soulet F, Mohd Zahari M, Ryan KR, Durant S, He S, Herbert J, Ankers J, Heath JK, Bjerkvig R, Bicknell R, Hotchin NA, Bikfalvi A, Falciani F - PLoS Genet. (2015)

Bottom Line: Glioblastoma patients have an average survival time of less than 15 months.The first one is involved in maintaining normal glial cell function, while the second is linked to the establishment of multiple hallmarks of cancer.Next, the development and application of a novel data integration methodology reveals novel functions of RND3 in controlling glioma cell migration, invasion, proliferation, angiogenesis and clinical outcome.

View Article: PubMed Central - PubMed

Affiliation: Centre for Computational Biology and Modelling (CCBM), Institute of Integrative Biology, University of Liverpool, Liverpool, United Kingdom; INSERM U1029, University Bordeaux, Pessac, France.

ABSTRACT
Gliomas are a highly heterogeneous group of brain tumours that are refractory to treatment, highly invasive and pro-angiogenic. Glioblastoma patients have an average survival time of less than 15 months. Understanding the molecular basis of different grades of glioma, from well differentiated, low-grade tumours to high-grade tumours, is a key step in defining new therapeutic targets. Here we use a data-driven approach to learn the structure of gene regulatory networks from observational data and use the resulting models to formulate hypothesis on the molecular determinants of glioma stage. Remarkably, integration of available knowledge with functional genomics datasets representing clinical and pre-clinical studies reveals important properties within the regulatory circuits controlling low and high-grade glioma. Our analyses first show that low and high-grade gliomas are characterised by a switch in activity of two subsets of Rho GTPases. The first one is involved in maintaining normal glial cell function, while the second is linked to the establishment of multiple hallmarks of cancer. Next, the development and application of a novel data integration methodology reveals novel functions of RND3 in controlling glioma cell migration, invasion, proliferation, angiogenesis and clinical outcome.

No MeSH data available.


Related in: MedlinePlus

RND3 is up-regulated in grade IV glioma.A. RND3 expression determined by western blot in patient samples from different glioma grades as determined after anatomopathological analysis. B. Densitometric analysis of RND3 protein from western blot shown in (A) presenting the ratio of RND3 to tubulin. C. Immunohistochemical analysis of RND3 expression in grade II, III and grade IV patient tumors (bar 100 μm), magnified images are presented in left panels. Data is representative of 4 or more tumours. *** p < 0.001, ** p < 0.01, * p < 0.05, values +/- SEM.
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pgen.1005325.g004: RND3 is up-regulated in grade IV glioma.A. RND3 expression determined by western blot in patient samples from different glioma grades as determined after anatomopathological analysis. B. Densitometric analysis of RND3 protein from western blot shown in (A) presenting the ratio of RND3 to tubulin. C. Immunohistochemical analysis of RND3 expression in grade II, III and grade IV patient tumors (bar 100 μm), magnified images are presented in left panels. Data is representative of 4 or more tumours. *** p < 0.001, ** p < 0.01, * p < 0.05, values +/- SEM.

Mentions: RND3 and other Rho GTPases are transcriptionally regulated in high-grade glioma (see S2 Fig). However, the expression of RND3 protein in different glioma grades is unknown. We tested the expression of RND3 which on the basis of the numbers of inferred network connections we predicted to have differential activity across glioma grades. Remarkably, western blot analysis of grade II, III and IV human glioma samples confirmed that protein expression correlated with the transcriptional network connectivity. RND3 protein was significantly up-regulated in grade IV gliomas compared to both grade II and grade III (Fig 4A and 4B). We confirmed the difference in RND3 expression in tumour cells by immunohistochemistry analysis of grade II, III and IV gliomas (Fig 4C). RND3 was found in the cytoplasm of tumor cells but also in the nucleus.


Inference of Low and High-Grade Glioma Gene Regulatory Networks Delineates the Role of Rnd3 in Establishing Multiple Hallmarks of Cancer.

Clarke K, Daubon T, Turan N, Soulet F, Mohd Zahari M, Ryan KR, Durant S, He S, Herbert J, Ankers J, Heath JK, Bjerkvig R, Bicknell R, Hotchin NA, Bikfalvi A, Falciani F - PLoS Genet. (2015)

RND3 is up-regulated in grade IV glioma.A. RND3 expression determined by western blot in patient samples from different glioma grades as determined after anatomopathological analysis. B. Densitometric analysis of RND3 protein from western blot shown in (A) presenting the ratio of RND3 to tubulin. C. Immunohistochemical analysis of RND3 expression in grade II, III and grade IV patient tumors (bar 100 μm), magnified images are presented in left panels. Data is representative of 4 or more tumours. *** p < 0.001, ** p < 0.01, * p < 0.05, values +/- SEM.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4488580&req=5

pgen.1005325.g004: RND3 is up-regulated in grade IV glioma.A. RND3 expression determined by western blot in patient samples from different glioma grades as determined after anatomopathological analysis. B. Densitometric analysis of RND3 protein from western blot shown in (A) presenting the ratio of RND3 to tubulin. C. Immunohistochemical analysis of RND3 expression in grade II, III and grade IV patient tumors (bar 100 μm), magnified images are presented in left panels. Data is representative of 4 or more tumours. *** p < 0.001, ** p < 0.01, * p < 0.05, values +/- SEM.
Mentions: RND3 and other Rho GTPases are transcriptionally regulated in high-grade glioma (see S2 Fig). However, the expression of RND3 protein in different glioma grades is unknown. We tested the expression of RND3 which on the basis of the numbers of inferred network connections we predicted to have differential activity across glioma grades. Remarkably, western blot analysis of grade II, III and IV human glioma samples confirmed that protein expression correlated with the transcriptional network connectivity. RND3 protein was significantly up-regulated in grade IV gliomas compared to both grade II and grade III (Fig 4A and 4B). We confirmed the difference in RND3 expression in tumour cells by immunohistochemistry analysis of grade II, III and IV gliomas (Fig 4C). RND3 was found in the cytoplasm of tumor cells but also in the nucleus.

Bottom Line: Glioblastoma patients have an average survival time of less than 15 months.The first one is involved in maintaining normal glial cell function, while the second is linked to the establishment of multiple hallmarks of cancer.Next, the development and application of a novel data integration methodology reveals novel functions of RND3 in controlling glioma cell migration, invasion, proliferation, angiogenesis and clinical outcome.

View Article: PubMed Central - PubMed

Affiliation: Centre for Computational Biology and Modelling (CCBM), Institute of Integrative Biology, University of Liverpool, Liverpool, United Kingdom; INSERM U1029, University Bordeaux, Pessac, France.

ABSTRACT
Gliomas are a highly heterogeneous group of brain tumours that are refractory to treatment, highly invasive and pro-angiogenic. Glioblastoma patients have an average survival time of less than 15 months. Understanding the molecular basis of different grades of glioma, from well differentiated, low-grade tumours to high-grade tumours, is a key step in defining new therapeutic targets. Here we use a data-driven approach to learn the structure of gene regulatory networks from observational data and use the resulting models to formulate hypothesis on the molecular determinants of glioma stage. Remarkably, integration of available knowledge with functional genomics datasets representing clinical and pre-clinical studies reveals important properties within the regulatory circuits controlling low and high-grade glioma. Our analyses first show that low and high-grade gliomas are characterised by a switch in activity of two subsets of Rho GTPases. The first one is involved in maintaining normal glial cell function, while the second is linked to the establishment of multiple hallmarks of cancer. Next, the development and application of a novel data integration methodology reveals novel functions of RND3 in controlling glioma cell migration, invasion, proliferation, angiogenesis and clinical outcome.

No MeSH data available.


Related in: MedlinePlus