Abstract 1103: Tumor suppressive role of a novel microRNA at frequently deleted chromosomal locus 8p21 in prostate cancer
Abstract Background: A frequent genomic alteration in prostate cancer (PCa) is the loss of chromosome (chr) 8p21 in approximately 30%-50% of cases. Genomic deletions of this region increase significantly with tumor grade and are associated with tumor progression and poor prognosis suggesting its rol...
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Published in | Cancer research (Chicago, Ill.) Vol. 76; no. 14_Supplement; p. 1103 |
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Main Authors | , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
15.07.2016
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Online Access | Get full text |
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Summary: | Abstract
Background: A frequent genomic alteration in prostate cancer (PCa) is the loss of chromosome (chr) 8p21 in approximately 30%-50% of cases. Genomic deletions of this region increase significantly with tumor grade and are associated with tumor progression and poor prognosis suggesting its role in PCa progression. A common region of loss of heterozygosity (LOH) has been mapped to the chr8p21 locus that harbors prostate-specific NKX3.1 homeobox gene. Recent genomic studies suggest that this region harbors alternative tumor suppressor genes apart from NKX3.1 that have largely remained elusive. We propose a novel, paradigm shifting hypothesis that this frequently deleted locus is associated with a cluster of microRNA genes- miR-3622a/b- that are lost in prostate cancer and play an important mechanistic role in PCa progression and metastasis. We previously demonstrated that miR-3622a plays a crucial role in PCa epithelial-to-mesenchymal transition by direct targeting of ZEB1 and SNAI2. Here we demonstrate the role of miR-3622b in prostate cancer.
Methods: miRNA expression profiling was performed in microdissected prostate cancer tissues and matched adjacent normal regions by real-time PCR. To assess the functional significance of miR-3622b in PCa, we overexpressed miR-3622b/ control miRNA (miR-CON) in PCa cell lines (Du145, PC3, LNCaP) followed by functional assays.We also examined the therapeutic potential of synthetic miR-3622b mimics in vivo in a prostate cancer xenograft mouse model.
Results: Expression analyses in a cohort of prostate cancer clinical specimens showed that miR-3622b expression is frequently lost in prostate cancer. Further, loss of miR-3622b expression significantly correlated with poor survival outcome and tumor progression. miR-3622b overexpression significantly decreased cellular viability and clonogenicity in PCa cell lines supporting an anti-proliferative role for this microRNA. miR-3622b overexpression also led to significant reduction of invasiveness and migration in PCa cell lines. In vivo studies demonstrated that miR-3622b overexpression induced regression of established prostate tumor xenografts.
Conclusions: Collectively, these data suggest that miR-3622b plays a tumor suppressive role in PCa. We propose that frequent loss of miR-3622a/b at chr8p21 region by genetic and epigenetic mechanisms promotes prostate cancer progression and metastasis. This study supports a novel concept that connects a long standing observation of frequent loss of a chromosomal region with a novel miRNA cluster in prostate cancer.
Citation Format: Nathan Bucay, Kiran Sekhon, Shahana Majid, Varahram Shahryari, Soichiro Yamamura, Z. Laura Tabatabai, Kirsten Greene, Yuichiro Tanaka, Rajvir Dahiya, Guoren Deng, Sharanjot Saini. Tumor suppressive role of a novel microRNA at frequently deleted chromosomal locus 8p21 in prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1103. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0008-5472 1538-7445 |
DOI: | 10.1158/1538-7445.AM2016-1103 |