Unknown,Transcriptomics,Genomics,Proteomics

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Role of HSP70 in response to (thermo)radiotherapy: analysis of gene expression in canine osteosarcoma cells by RNA-seq

ABSTRACT: The aim of the study was to investigate which genes are up- and down-regulated in response to hyperthermia and combined thermoradiotherapy in HSP70 proficient and deficient canine osteosarcoma cell line. Canine osteosarcoma cell line Abrams was transfected with negative control siRNA or siRNA targeting HSP70. Cells were treated with hyperthermia (42C, 1 hour, HT), radiotherapy (6Gy, RT) and thermoradiotherapy (HTRT). RNA was extracted 24 hours after treatment and used for RNA sequencing. Three independent experiments were performed, each with negative control siRNA (Neg) and HSP70 knockdown (HSP70kd) cells. Cells were treated with radiotherapy (RT), hyperthermia (HT), thermoradiotherapy (HTRT) or untreated (ctrl). One experiment consists of 8 samples (ctrl, RT, HT, HTRT in neg and HSP70kd cells), total 24 samples were sequenced.

INSTRUMENT(S): Illumina HiSeq 4000

ORGANISM(S): Canis lupus familiaris

SUBMITTER: Katarzyna Nytko

PROVIDER: E-MTAB-8652 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:While hyperthermia has been shown to be an effective adjuvant anti-tumor treatment to radiotherapy, we still do not completely understand effects thermoradiotherapy on tumor phenotype or how these effects vary among different tumors. Here, we performed gene expression analysis in 22 spontaneous canine sarcomas before and after the first hyperthermia treatment that was administered as an adjuvant to radiotherapy. Diffusion weighted MRI (DWI) was done prior to the treatment course and at the end of therapy. Using supervised analysis, we identified significant correlation of DWI with several genes involved in VEGF signaling, telomerase, Wnt pathways and fatty acid synthesis. When the change of gene expression caused by treatment was examined, we found that thermoradiotherapy led to the induction of well known cycle regulators p21 and mdm2 and reduced cellular proliferation in most treated tumors. We also identified two tumor subtypes with dramatic differences in the gene expression response and treatment response at the end of therapy. In the subtype with strong expression and increase in DWI, the mRNA level of hsp70, POT1 and centrosomal proteins was significantly higher. In the other subtype with modest response to hyperthermia, levels of CD31, vWF and transferrin was noted to be significantly higher. It is also possible to build a predictive model based on the pre-treatment gene expression to predict the likely treatment response of the tumors. The differential expression between the two tumor subtypes was used to interrogate connectivity map and identify linkages to an HDAC inhibitor and geldanamycin, an HSP90 inhibitor. Both HDAC inhibitors and hsp90 inhibitor geldanamycin are shown to synergerize with thermoradiotherapy in reducing cell survival in clonogenic assays. Taken together, the gene expression studies of hyperthermia-treated spontaneous canine tumors shed mechanistic insights into the heterogeneity of thermoradiotherapy response and identified pathway-targeting compounds with synergistic potential to enhance its therapeutic benefits. To our knowledge, this is one of the first successful attempts to link genomic and functional imaging changes together. This is the first demonstration of using such associations to understand the connection between cellular and physiologic responses to treatment. gene expression analysis in 22 spontaneous canine sarcomas before and after the first hyperthermia treatment that was administered as an adjuvant to radiotherapy.

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Role of HSP70 in response to (thermo)radiotherapy: analysis of gene expression in canine osteosarcoma cells by RNA-seq

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