A functional variant in HOXA11-AS, a novel long non-coding RNA, inhibits the oncogenic phenotype of epithelial ovarian cancer.

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.

• Authors: 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
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 33 Pg. 34745-57 (Oct 27 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 26430965 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• HOXA11 protein, human
• Homeodomain Proteins
• RNA, Long Noncoding

Topics

• Animals
• Blotting, Western
• Carcinoma, Ovarian Epithelial
• Female
• Genes, Tumor Suppressor
• Genome-Wide Association Study
• Genotype
• Heterografts
• Homeodomain Proteins (genetics)
• Humans
• Mice
• Mice, Nude
• Neoplasms, Glandular and Epithelial (genetics, pathology)
• Ovarian Neoplasms (genetics, pathology)
• Phenotype
• Polymorphism, Single Nucleotide
• RNA, Long Noncoding (genetics)
• Reverse Transcriptase Polymerase Chain Reaction