IDENTIFICATION OF TRANSCRIPTOME-WIDE CHANGES DURING HYPOXIA - EVIDENCE OF HYPOXIA INDUCED EME1 ISOFORMS IN PROMOTING CELL GROWTH, MIGRATION AND CISPLATIN RESISTANCE

Abstract

CANCER PATIENTS WITH HYPOXIC TUMORS OFTEN HAVE UNFAVORABLE OUTCOMES AND DRUG RESISTANCE. HOWEVER THE HYPOXIA-MEDIATED TRANSCRIPTOME FACILITATING TUMORIGENESIS REMAINS POORLY UNDERSTOOD. MICROARRAYS AND RNA SEQUENCING OF NEUROBLASTOMA CELLS RESULTED IN THE IDENTIFICATION OF HYPOXIA-INDUCIBLE CODING, NON-CODING RNA, MICRORNA, ALTERNATIVE PROMOTER USAGE AND SPLICING TARGETS THAT MAY BE IMPORTANT IN TUMOR BIOLOGY. EME1 EXPRESSION IS SIGNIFICANTLY HIGHER IN LUNG, BREAST, OVARY, URINARY ORGANS AND SKIN CARCINOMAS COMPARED TO MATCHED NORMAL TISSUES. TWO HYPOXIA-INDUCIBLE EME1 ISOFORMS IMPORTANT FOR DNA DAMAGE REPAIR WERE IDENTIFIED. EXON 2 DELETION ISOFORMS WERE LOCALISED TO THE CYTOPLASM WHILE OTHER ISOFORMS WERE PREDOMINANTLY NUCLEAR. OVEREXPRESSION OF THE DEL2C, 4, 6N ISOFORM IN MCF10A CELLS WITH LOW EME1 LEVELS ENHANCES CELL GROWTH AND MIGRATION, WHILE HINEPC CELLS SHOWED INCREASED GROWTH BUT REDUCED MIGRATION. THE INDUCTION OF EME1 ISOFORMS IN MCF10A CELLS RESULTED IN GRADUAL CISPLATIN R