Oral Presentation The Joint Annual Scientific Meetings of the Endocrine Society of Australia and the Society for Reproductive Biology 2017

The lncRNA GHSROS mediates tumour growth and expression of genes associated with metastasis and adverse outcome (#30)

Patrick Thomas 1 2 3 , Penny Jeffery 1 2 3 , Manuel Gahete 4 5 6 7 , Eliza Whiteside 8 , Carina Maree Walpole 1 , Michelle Maugham 1 2 3 , Jennifer Gunter 2 , Colleen Nelson 2 , Adrian Herington 1 , Raul Luque 4 5 6 7 , Rakesh Veedu 9 , Lisa Chopin 1 2 3 , Inge Seim 1 2 3
  1. Ghrelin Research Group, Translational Research Institute/ Institute of Health and Biomedical Innovation - Queensland University of Technology, Brisbane, Queensland, Australia
  2. Australian Prostate Cancer Research Centre-Queensland, Queensland University of Technology (QUT)/ Princess Alexandra Hospital, Brisbane, Queensland, Australia
  3. Comparative and Endocrine Biology Laboratory, Translational Research Institute/ Institute of Health and Biomedical Innovation - Queensland University of Technology, Brisbane, Queensland, Australia
  4. Maimonides Institute of Biomedical Research of Cordoba (IMIBIC), Córdoba, Spain
  5. Department of Cell Biology, Physiology and Immunology, University of Córdoba, Córdoba, Spain
  6. Hospital Universitario Reina Sofía (HURS), Córdoba, Spain
  7. CIBER de la Fisiopatología de la Obesidad y Nutrición (CIBERobn), Córdoba, Spain
  8. Centre for Health Research, University of Southern Queensland, Toowoomba, Queensland, Australia
  9. Center for Comparative Genomics, Murdoch University/ Western Australian Neurosciences Research Institute, Perth, Western Australia, Australia

Long non-coding RNAs (lncRNAs) play key regulatory roles in cancer progression and are novel therapeutic targets. We recently discovered an lncRNA termed GHSROS (GHSR opposite strand) on the antisense strand of the ghrelin receptor gene (GHSR). Using quantitative RT-PCR, we demonstrated that GHSROS is highly expressed in a subset of high-grade prostate cancers. GHSROS over-expression significantly increased cell proliferation and migration in the PC3 (1.76 ± 0.18 fold, P<0.01; 1.54 ± 0.35 fold, P<0.05) and DU145 prostate cancer cell lines (1.74 fold ± 0.73 P<0.01; 1.94 ± 0.43 fold, P<0.01). Tumour volumes were significantly increased in both PC3 and DU145 GHSROS over-expressing prostate cancer cell line xenografts in NOD/SCID mice (P<0.05). Preliminary studies indicate that up-regulation of GHSROS confers resistance to the androgen receptor (AR) antagonist enzalutamide and the chemotherapeutic drug docetaxel, both of which are used to treat advanced prostate cancer. Through high-throughput transcriptome sequencing (RNA-seq) ~400 differentially expressed genes were identified in GHSROS over-expressing PC3 cells, demonstrating enrichment of genes associated with motility, survival, and regulation of cell growth. From this gene set, concept mapping and interrogation of publicly-available clinical prostate cancer data sets revealed a 34-gene signature associated with poorer disease outcome and metastatic progression in patients. Analysis of The Cancer Genome Atlas (TCGA) data suggests that the signature has potential as a prognostic indicator for disease free- or overall survival for numerous cancers. Finally, locked nucleic acid antisense oligonucleotide (LNA-ASO) inhibition of endogenous GHSROS expression reciprocally regulated cell growth (RNV124: -1.14 ± 0.06, P = 0.049 and RNV104L: -1.18 ± 0.05, P = 0.030), migration (RNV124: -1.96 ± 0.11, P = 0.004) and gene expression changes. Taken together, we therefore propose that GHSROS has clinical significance as a potential target for novel antisense therapy.