Increasing the relative expression of endogenous non-coding Steroid Receptor RNA Activator (SRA) in human breast cancer cells using modified oligonucleotides.
Products of the Steroid Receptor RNA Activator gene (SRA1) have the unusual property to modulate the activity of steroid receptors and other transcription factors both at the RNA (SRA) and the protein (SRAP) level. Balance between these two genetically linked entities is controlled by alternative splicing of intron-1, whose retention alters SRAP reading frame. We have previously found that both fully-spliced SRAP-coding and intron-1-containing non-coding SRA RNAs co-exist in breast cancer cell lines. Herein, we report a significant (Student's t-test, P < 0.003) higher SRA-intron-1 relative expression in breast tumors with higher progesterone receptor contents. Using an antisense oligoribonucleotide, we have successfully reprogrammed endogenous SRA splicing and increased SRA RNA-intron-1 relative level in T5 breast cancer cells. This increase is paralleled by significant changes in the expression of genes such as plasminogen urokinase activator and estrogen receptor beta. Estrogen regulation of other genes, including the anti-metastatic NME1 gene, is also altered. Overall, our results suggest that the balance coding/non-coding SRA transcripts not only characterizes particular tumor phenotypes but might also, through regulating the expression of specific genes, be involved in breast tumorigenesis and tumor progression.
Cooper
Charlton
C
Department of Biochemistry & Medical Genetics, Manitoba Institute of Cell Biology, University of Manitoba, Winnipeg, Manitoba R3E0W3, Canada.
Guo
Jimin
J
Yan
Yi
Y
Chooniedass-Kothari
Shilpa
S
Hube
Florent
F
Hamedani
Mohammad K
MK
Murphy
Leigh C
LC
Myal
Yvonne
Y
Leygue
Etienne
E
D017398:Alternative Splicing; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007438:Introns; D020320:Oligoribonucleotides, Antisense / Q000737:chemistry; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011980:Receptors, Progesterone / Q000378:metabolism
D020320:Oligoribonucleotides, Antisense; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; D011980:Receptors, Progesterone; C405423:steroid receptor RNA activator; D004958:Estradiol