Abstract
Abstract Background and Hypothesis The 3q26.2 loci amplification is present in at least 35% of high grade serous ovarian cancer (HGSEOC). Recently we identified a microRNA, MIR551B located in the 3q26 amplicon. However, the potential role of microRNAs amplified at 3q26 amplicon and their functions in ovarian tumorigenesis has not been studied previously. Thus, our studies have the potential to provide novel mechanism underlying MIR551B oncogenesis in ovarian cancer. Results The 3q26.2 locus is large and structurally complex suggesting that multiple coding genes located in the amplicon could contribute to tumor initiation and progression alone or through cooperative activity. High-resolution SNP-based copy number analysis of 533 high-grade serous ovarian cancer samples demonstrated that MIR551B is highly amplified as a consequence of the 3q26.2 amplicon. Expression analysis in the Cancer Genome Atlas (TCGA) data sets showed that amplification of MIR551B is associated with increased expression of maturedmicroRNA miR551b in the recently defined proliferative subtype of ovarian cancer. Reverse phase protein array (RPPA) demonstrated that enforced expression of miR551b-5p increased the expression c-KIT oncogene and activated the ERK signaling pathway. Our target search analysis identified a potential novel mechanism whereby miR551b-5p could bind to a target site in the promoter of c-KIT oncogene and increase the transcription of c-Kit mRNA. Strikingly, enforced expression of miR551b-5p induced the survival and proliferation of ovarian surface epithelial cells detached from extracellular matrix. Of note, miR551b-5p expression in recurrent ovarian tumors are higher than the primary ovarian cancers. Summary Our results show that copy number alterations (CNAs) of MIR551B are associated with increased levels of mature microRNA, miR551b. Mechanistic studies revealed a novel role of microRNA miR-551b-5p to induce transcriptional activation by interacting with the promoter of the c-Kit oncogene, which in turn renders cells resistant to anokis a critical component of the survival and spread of ovarian cancer in the peritoneal cavity. Our results propose the c-KIT transcriptional activation induced by miR551b-5p is a key mechanism of survival of ovarian cancer cells in the ascitic fluid in the peritoneal cavity. Citation Format: Pradeep Chaluvally-Raghavan, Fan Zhang, Wenbin Liu, Moss Tyler, Shuangxing Yu, Sunila Pradeep, Prahlad Ram, Yiling Lu, Anil Sood, Gordon Mills. MicroRNA MIR551B amplified at 3q26.2 locus activate c-KIT expression and causes resistance to anoikis of ovarian cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4396. doi:10.1158/1538-7445.AM2014-4396
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