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

作者：Richards Edward J; Permuth Wey Jennifer; Li Yajuan; Chen Y Ann; 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^*

来源：Oncotarget, 2015, 6(33): 34745-34757.

DOI：10.18632/oncotarget.5784

• ovarian cancer
• genetic susceptibility
• HOX cluster
• long non-coding RNAs
• single nucleotide polymorphisms

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.

• 出版日期2015-10-27