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A functional variant in HOXA11-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 and Jin Q. Cheng _

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Oncotarget. 2015; 6:34745-34757. https://doi.org/10.18632/oncotarget.5784

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Abstract

Edward J. Richards1,*, Jennifer Permuth-Wey2,*, Yajuan Li1,*, Y. Ann Chen3, Domenico Coppola4, Brett M. Reid2, Hui-Yi Lin3, Jamie K. Teer3, Andrew Berchuck5, Michael J. Birrer6, Kate Lawrenson7, Alvaro N.A. Monteiro2, Joellen M. Schildkraut8, Ellen L. Goode9, Simon A. Gayther7, Thomas A. Sellers2 and Jin Q. Cheng1

1 Department of Molecular Oncology, Moffitt Cancer Center, Tampa, FL, USA

2 Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL, USA

3 Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, FL, USA

4 Department of Anatomic Pathology, Moffitt Cancer Center, Tampa, FL, USA

5 Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, North Carolina, USA

6 Massachusetts General Hospital, Boston, MA, USA

7 Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Norris Comprehensive Cancer Center, Los Angeles, California, USA

8 School of Medicine, Public Health Sciences, University of Virginia, Charlottesville, VA, USA

9 Department of Health Science Research, Division of Epidemiology, Mayo Clinic, Rochester, MN, USA

* These authors have contributed equally to this manuscript

Correspondence to:

Jin Q. Cheng, email:

Thomas A. Sellers, email:

Keywords: ovarian cancer, genetic susceptibility, HOX cluster, long non-coding RNAs, single nucleotide polymorphisms

Received: June 14, 2015 Accepted: August 31, 2015 Published: September 22, 2015

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.


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