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MICRORNA RESPONSE TO HYPOXIC STRESS IN SARCOMA CELL LINES - HSA-MIR-485-5P, HSA-MIR-210 AND HIF3A

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MICRORNA RESPONSE TO HYPOXIC STRESS IN SARCOMA CELL LINES - HSA-MIR-485-5P, HSA-MIR-210 AND HIF3A

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Samenvatting

Hypoxia is one of the key features of quickly progressing tumors, as they may outgrow their blood supply resulting in low oxygen tension. A major hypoxic stress response is the upregulation of Hypoxia-Inducible Factor 1A (HIF1A). This gene is a master transcription factor which orchestrates the activation of pathways that are important for the adaption of the cell to low oxygen like angiogenesis and glucose metabolism. Hypoxia-Inducible Factor 3A (HIF3A) is a family member of HIF1A, however not much is known about its regulation and function. It has multiple transcription variants, but only one of them, namely transcription variant 201, has a long 3'UTR containing several binding sites for miRNAs that have been found to be upregulated under hypoxic stress, i.e. 11 binding sites for hsa-miR-485-5p and one binding site for hsa-miR-210.
MicroRNAs (miRNAs) are a specific class of non-protein coding RNAs and are approximately 18-22 nucleotides long. Although they are not protein coding, they seem to be genetically active. They have important roles in normal physiology and can be deregulated in or contribute to diseases such as cancer.
Several miRNAs have already been identified to be differentially expressed under hypoxic stress in sarcomas, i.e. miRNA-210. A pilot study has identified several other miRNAs to be expressed in sarcoma cell lines when exposed to hypoxic conditions, i.e. miRNA-485-5p, miRNA 216a and miRNA-185*. MiRNA-625 has been found to be severely down-regulated under hypoxic stress in sarcoma cell lines. The focus in this report will be on one of the possible target genes of hsa-miR-485-5p and hsa-miR-210, namely the HIF3A transcription variant 201. It is hypothesised that this protein is posttranscriptionally regulated by hsa-miR-485-5p and hsa-miR-210 under hypoxic conditions.
In this report we show that the upregulation of HIF1A is an early response to hypoxic stress as it is already upregulated after the cells have been cultured under hypoxic conditions for 6 hours and its expression is decreasing at 24 and 48 hours of hypoxic stress.
The HIF3A mRNA shows an upregulation as time elapses, but its protein is peaking after 24 hours of hypoxic stress and is decreasing after 48 hours.
In this report HIF3A is validated as a target gene for hsa-miR210 and hsa-miR-485-5p. In this report it is also shown that hypoxia has an effect on the 3'UTR of HIF3A transcription variant 201 and that transfection of mimics of hsa-miR-210 and hsa-miR-485-5p has an effect on the hypoxia response pathway.

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OrganisatieAvans Hogeschool
AfdelingATGM Academie voor de technologie van Gezondheid en Milieu
PartnersDaniel Den Hoed Cancer Center; Dept of Medical Oncology
Datum2012-05
TypeBachelor
TaalEngels

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