A functional variant in HOXA 11-AS, a novel long non-coding RNA, inhibits the oncogenic phenotype of epithelial ovarian cancer

Edward J. Richards, Jennifer Permuth-Wey, Yajuan Li, Y. Ann Chen, Domenico Coppola, Brett M. Reid, Hui Yi Lin, Jamie K. Teer, Andrew Berchuck, Michael J. Birrer, Kate Lawrenson, Alvaro N.A. Monteiro, Joellen M. Schildkraut, Ellen L. Goode, Simon A. Gayther, Thomas A. Sellers, Jin Q. Cheng

Research output: Contribution to journalArticle

77 Scopus citations

Abstract

The homeobox A (HOXA) region of protein-coding genes impacts female reproductive system embryogenesis and ovarian carcinogenesis. The 5-prime end of HOXA includes three long non-coding RNAs (lncRNAs) (HOXA10-AS, HOXA11-AS, and HOTTIP) that are underexplored in epithelial ovarian cancer (EOC). We evaluated whether common genetic variants in these lncRNAs are associated with EOC risk and/or have functional roles in EOC development. Using genome-wide association study data from 1,201 serous EOC cases and 2,009 controls, an exonic variant within HOXA11-AS, rs17427875 (A>T), was marginally associated with reduced serous EOC risk (OR = 0.88 (95% CI: 0.78-1.01, p = 0.06). Functional studies of ectopic expression of HOXA11-AS minor allele T in EOC cells showed decreased survival, proliferation, migration, and invasion compared to common allele A expression. Additionally, stable expression of HOXA11-AS minor allele T reduced primary tumor growth in mouse xenograft models to a greater extent than common allele A. Furthermore, HOXA11-AS expression levels were significantly lower in human EOC tumors than normal ovarian tissues (p < 0.05), suggesting that HOXA11-AS has a tumor suppressor function in EOC which may be enhanced by the T allele. These findings demonstrate for the first time a role for HOXA11-AS in EOC with effects that could be modified by germline variants.

Original languageEnglish (US)
Pages (from-to)34745-34757
Number of pages13
JournalOncotarget
Volume6
Issue number33
DOIs
StatePublished - 2015

Keywords

  • Genetic susceptibility
  • HOX cluster
  • Long non-coding RNAs
  • Ovarian cancer
  • Single nucleotide polymorphisms

ASJC Scopus subject areas

  • Oncology

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    Richards, E. J., Permuth-Wey, J., Li, Y., Ann Chen, Y., Coppola, D., Reid, B. M., Lin, H. Y., Teer, J. K., Berchuck, A., Birrer, M. J., Lawrenson, K., Monteiro, A. N. A., Schildkraut, J. M., Goode, E. L., Gayther, S. A., Sellers, T. A., & Cheng, J. Q. (2015). A functional variant in HOXA 11-AS, a novel long non-coding RNA, inhibits the oncogenic phenotype of epithelial ovarian cancer. Oncotarget, 6(33), 34745-34757. https://doi.org/10.18632/oncotarget.5784