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Abstract 2011: Expression analysis of transcribed-ultraconserved regions in cancer stem cell population using colorectal cancer organoids

Background: The transcribed-ultraconserved regions (T-UCRs) are a novel class of long noncoding RNAs transcribed from ultraconserved regions (UCRs) that are located in both intra- and intergenic regions and absolutely conserved among the orthologous regions in most of the vertebrates. There are at least 481 UCRs, and these regions can produce 962 T-UCRs. T-UCRs have distinct signatures in human cancers. However, little has been known about the correlation between T-UCRs and tissue/cancer stem cells so far. Organoid is a novel 3D in vitro stem cell culture technology, which sustains stem cell-driven formation of near-physiologic, self-renewing tissues through using the specific niche factors in a dish. As it can be established from patient-derived tissue samples and recapitulates the genetic diversity of the original tissues, patient-derived tumor organoids could be a reliable model of disease. Because of its biologic features, organoid is assumed to harbor many stem and progenitor cells, so that it is suitable for stem cell analysis. In this study, we aimed to identify T-UCRs that are specifically expressed in cancer stem cell of colorectal cancer (CRC) and validate their functional role in CRC stem cells. Methods: We focused on 61 T-UCRs that were reported as the dysregulated T-UCRs in CRC by microarray analysis. We examined them using RNA samples isolated from 3 pairs of CRC and non-neoplastic organoids by qRT-PCR. Biologic roles of the T-UCRs upregulated in CRC organoids were analyzed using a vector containing the whole sequences of the T-UCRs. Results: Through the validation, we found that Uc.91+, Uc.182+, Uc.249+A and Uc.266+A were specifically upregulated in CRC organoids compared to those in normal organoids. We also validated the T-UCRs expression in several CRC cases using both primary tumors and organoids, which further supported the validity of CRC stem cell specific signature. Each of the expression of the 4 T-UCRs was highly upregulated in 2 CRC cell lines, HCT-116 and SW480, while we did not see any similarities in representative genetic abnormalities between the 2 CRC cell lines. Further in-depth in vitro studies are ongoing to clarify the solid evidences, especially the direct effect of T-UCRs onto the stem cells features such as dormancy and sphere-forming ability. Conclusion: We identified that Uc.91+, Uc.182+, Uc.249+A and Uc.266+A were specifically upregulated in CRC organoids, and the 4 T-UCRs showed similar trend of expression in several CRC cell lines. These 4 T-UCRs are promising candidates that could potentially have an important role in cancer stem cell biology. Citation Format: Ririno Honma, Naoya Sakamoto, Akira Ishikawa, Daiki Taniyama, Kaho Fukada, Yohei Sekino, Shoichiro Mukai, Kazuhiro Sentani, Naohide Oue, Takao Hinoi, Hiroyuki Egi, Hideki Ohdan, Wataru Yasui. Expression analysis of transcribed-ultraconserved regions in cancer stem cell population using colorectal cancer organoids [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2011.