Browsing by Author "Bayraktar, Emine"

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    PRKAR1B-AS2 Long Noncoding RNA Promotes Tumorigenesis, Survival, and Chemoresistance via the PI3K/AKT/mTOR Pathway
    (MDPI, 2021-02-13) Elsayed, Abdelrahman M.; Bayraktar, Emine; Amero, Paola; Salama, Salama A.; Abdelaziz, Abdelaziz H.; Ismail, Raed S.; Zhang, Xinna; Ivan, Cristina; Sood, Anil K.; Lopez-Berestein, Gabriel; Rodriguez-Aguayo, Cristian; Medical and Molecular Genetics, School of Medicine
    Many long noncoding RNAs have been implicated in tumorigenesis and chemoresistance; however, the underlying mechanisms are not well understood. We investigated the role of PRKAR1B-AS2 long noncoding RNA in ovarian cancer (OC) and chemoresistance and identified potential downstream molecular circuitry underlying its action. Analysis of The Cancer Genome Atlas OC dataset, in vitro experiments, proteomic analysis, and a xenograft OC mouse model were implemented. Our findings indicated that overexpression of PRKAR1B-AS2 is negatively correlated with overall survival in OC patients. Furthermore, PRKAR1B-AS2 knockdown-attenuated proliferation, migration, and invasion of OC cells and ameliorated cisplatin and alpelisib resistance in vitro. In proteomic analysis, silencing PRKAR1B-AS2 markedly inhibited protein expression of PI3K-110α and abrogated the phosphorylation of PDK1, AKT, and mTOR, with no significant effect on PTEN. The RNA immunoprecipitation detected a physical interaction between PRKAR1B-AS2 and PI3K-110α. Moreover, PRKAR1B-AS2 knockdown by systemic administration of 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine nanoparticles loaded with PRKAR1B-AS2–specific small interfering RNA enhanced cisplatin sensitivity in a xenograft OC mouse model. In conclusion, PRKAR1B-AS2 promotes tumor growth and confers chemoresistance by modulating the PI3K/AKT/mTOR pathway. Thus, targeting PRKAR1B-AS2 may represent a novel therapeutic approach for the treatment of OC patients.
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    The mutational landscape and functional effects of noncoding ultraconserved elements in human cancers
    (American Association for the Advancement of Science, 2025) Bayraktar, Recep; Tang, Yitao; Dragomir, Mihnea P.; Ivan, Cristina; Peng, Xinxin; Fabris, Linda; Zhang, Jianhua; Carugo, Alessandro; Aneli, Serena; Liu, Jintan; Chen, Mei-Ju M.; Srinivasan, Sanjana; Sahnoune, Iman; Bayraktar, Emine; Akdemir, Kadir C.; Chen, Meng; Narayanan, Pranav; Huang, Wilson; Ott, Leonie Florence; Eterovic, Agda Karina; Villarreal, Oscar Eduardo; Mohammad, Mohammad Moustaf; Peoples, Michael D.; Walsh, Danielle M.; Hernandez, Jon Andrew; Morgan, Margaret B.; Shaw, Kenna R.; Davis, Jennifer S.; Menter, David; Tam, Constantine S.; Yeh, Paul; Dawson, Sarah-Jane; Rassenti, Laura Z.; Kipps, Thomas J.; Kunej, Tanja; Estrov, Zeev; Joosse, Simon A.; Pagani, Luca; Alix-Panabières, Catherine; Pantel, Klaus; Ferajoli, Alessandra; Futreal, Andrew; Wistuba, Ignacio I.; Radovich, Milan; Kopetz, Scott; Keating, Michael J.; Draetta, Giulio F.; Mattick, John S.; Liang, Han; Calin, George A.; Surgery, School of Medicine
    The mutational landscape of phylogenetically ultraconserved elements (UCEs), especially those in noncoding DNAs (ncUCEs), and their functional relevance in cancers remain poorly characterized. Here, we perform a systematic analysis of whole-genome and in-house targeted UCE sequencing datasets from more than 3000 patients with cancer of 13,736 UCEs and demonstrate that ncUCE somatic alterations are common. Using a multiplexed CRISPR knockout screen in colorectal cancer cells, we show that the loss of several altered ncUCEs significantly affects cell proliferation. In-depth functional studies in vitro and in vivo further reveal that specific ncUCEs can be enhancers of tumor suppressors (such as ARID1B) and silencers of oncogenic proteins (such as RPS13). Moreover, several miRNAs located in ncUCEs are recurrently mutated. Mutations in miR-142 locus can affect the Drosha-mediated processing of precursor miRNAs, resulting in the down-regulation of the mature transcript. These results provide systematic evidence that specific ncUCEs play diverse regulatory roles in cancer.