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

63 Citations (Scopus)

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

Fingerprint

Long Noncoding RNA
Homeobox Genes
Phenotype
Alleles
Ovarian epithelial cancer
Neoplasms
Genome-Wide Association Study
Heterografts
Open Reading Frames
Embryonic Development
Carcinogenesis

Keywords

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

ASJC Scopus subject areas

  • Oncology

Cite this

Richards, E. J., Permuth-Wey, J., Li, Y., Ann Chen, Y., Coppola, D., Reid, B. M., ... 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

A functional variant in HOXA 11-AS, a novel long non-coding RNA, inhibits the oncogenic phenotype of epithelial ovarian cancer. / Richards, Edward J.; Permuth-Wey, Jennifer; Li, Yajuan; Ann Chen, Y.; Coppola, Domenico; Reid, Brett M.; Lin, Hui Yi; Teer, Jamie K.; Berchuck, Andrew; Birrer, Michael J.; Lawrenson, Kate; Monteiro, Alvaro N A; Schildkraut, Joellen M.; Goode, Ellen L; Gayther, Simon A.; Sellers, Thomas A.; Cheng, Jin Q.

In: Oncotarget, Vol. 6, No. 33, 2015, p. 34745-34757.

Research output: Contribution to journalArticle

Richards, EJ, Permuth-Wey, J, Li, Y, Ann Chen, Y, Coppola, D, Reid, BM, Lin, HY, Teer, JK, Berchuck, A, Birrer, MJ, Lawrenson, K, Monteiro, ANA, Schildkraut, JM, Goode, EL, Gayther, SA, Sellers, TA & Cheng, JQ 2015, 'A functional variant in HOXA 11-AS, a novel long non-coding RNA, inhibits the oncogenic phenotype of epithelial ovarian cancer', Oncotarget, vol. 6, no. 33, pp. 34745-34757. https://doi.org/10.18632/oncotarget.5784
Richards, Edward J. ; Permuth-Wey, Jennifer ; Li, Yajuan ; Ann Chen, Y. ; Coppola, Domenico ; Reid, Brett M. ; Lin, Hui Yi ; Teer, Jamie K. ; Berchuck, Andrew ; Birrer, Michael J. ; Lawrenson, Kate ; Monteiro, Alvaro N A ; Schildkraut, Joellen M. ; Goode, Ellen L ; Gayther, Simon A. ; Sellers, Thomas A. ; Cheng, Jin Q. / A functional variant in HOXA 11-AS, a novel long non-coding RNA, inhibits the oncogenic phenotype of epithelial ovarian cancer. In: Oncotarget. 2015 ; Vol. 6, No. 33. pp. 34745-34757.
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AU - Monteiro, Alvaro N A

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