DDX5 lncRNA and encoded miRNAs- potential roles in cell motility and invasion and implications in Melanoma

Background : The RNA helicase p68 is an important transcriptional coactivator of several proteins that play key roles in cancer development. p68 is aberrantly expressed/modified in several cancers, suggesting that alteration in p68 expression/function may be key events in tumour development. The DDX5 (p68) gene encodes an evolutionarily conserved, alternatively spliced, intron the function of which has to date remained unclear.The fully spliced mRNA encodes for the p68 protein; however several studies have demonstrated the presence of two predominant p68 RNAs in cell lines and tissues, resulting from alternative splicing of this intron, and shown that their expression is differentially regulated, suggesting that the intron-containing RNA is not only stable but may also be functional [1, 2] Inclusion of the intron introduces a stop codon, but, to date, there is no evidence for the presence of a truncated protein, suggesting that the intron-containing RNA is a long-non-coding RNA (lncRNA). Additionally, this intron encodes three novel miRNAs [3, 4], providing other mechanisms by which the lncRNA or the intronic RNA itself could have additional functions.

Our recent work has shown that high levels lncRNA and at least one of the encoded miRNAs are associated with poor disease-free survival in HER2-positive breast cancer. Furthermore siRNAs studies have shown that the lncRNA promotes cell motility a range of breast cancer cell lines, providing a possible mechanism by which high levels of this RNA could promote disease progression.

Specific aims for Ph.D. project:

  1. The importance of the lncRNA and encoded miRNAs in breast cancer: Potential role in motility,  invasion/anchorage-independent growth.
  2. Identification of miRNA targets and inhibitory pathways.
  3. Investigate the expression profile of the lncRNA and miRNAs in melanoma.

References

  1. Stevenson RJ et al. Expression of the 'DEAD box' RNA helicase p68 is developmentally and growth regulated and correlates with organ differentiation/maturation in the fetus. J Pathol, 1998. 184: 351-359.
  2. Rossler OG et al. Structure and expression of the human p68 RNA helicase gene. Nucleic Acids Res, 2000. 28: 932-939.
  3. Moore HC et al. An evolutionarily conserved, alternatively spliced, intron in the p68/DDX5 DEAD-box RNA helicase gene encodes a novel miRNA. RNA, 2011. 17: 555-62.
  4. Persson H et al. Identification of New MicroRNAs in Paired Normal and Tumor Breast Tissue Suggests a Dual Role for the ERBB2/Her2 Gene. Cancer Res. 2011. 71: 78-86.
Supervisor: 
Dr Frances Fuller-Pace
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Eligible PhD students from the University of Dundee will spend 1 to 2 years of their PhD at an A*STAR research institute under the joint supervision of staff at the University of Dundee and an A*STAR research institute