Browsing by Author "Calin, George A."

Now showing 1 - 7 of 7
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    Allele-Specific Reprogramming of Cancer Metabolism by the Long Non-coding RNA CCAT2
    (Elsevier, 2016-02-18) Redis, Roxana S.; Vela, Luz E.; Lu, Weiqin; de Oliveira, Juliana Ferreira; Ivan, Cristina; Rodriguez-Aguayo, Cristian; Adamoski, Douglas; Pasculli, Barbara; Taguchi, Ayumu; Chen, Yunyun; Fernandez, Agustin F.; Valledor, Luis; Van Roosbroeck, Katrien; Chang, Samuel; Shah, Maitri; Kinnebrew, Garrett; Han, Leng; Atlasi, Yaser; Cheung, Lawrence H.; Huang, Gilbert Yuanjay; Monroig, Paloma; Ramirez, Marc S.; Ivkovic, Tina Catela; Van, Long; Ling, Hui; Gafà, Roberta; Kapitanovic, Sanja; Lanza, Giovanni; Bankson, James A.; Huang, Peng; Lai, Stephan Y.; Bast, Robert C.; Rosenblum, Michael G.; Radovich, Milan; Ivan, Mircea; Bartholomeusz, Geoffrey; Liang, Han; Fraga, Mario F.; Widger, William R.; Hanash, Samir; Berindan-Neagoe, Ioana; Lopez-Berestein, Gabriel; Ambrosio, Andre L.B.; Dias, Sandra M Gomes; Calin, George A.; Department of Surgery, IU School of Medicine
    Altered energy metabolism is a cancer hallmark as malignant cells tailor their metabolic pathways to meet their energy requirements. Glucose and glutamine are the major nutrients that fuel cellular metabolism, and the pathways utilizing these nutrients are often altered in cancer. Here, we show that the long ncRNA CCAT2, located at the 8q24 amplicon on cancer risk-associated rs6983267 SNP, regulates cancer metabolism in vitro and in vivo in an allele-specific manner by binding the Cleavage Factor I (CFIm) complex with distinct affinities for the two subunits (CFIm25 and CFIm68). The CCAT2 interaction with the CFIm complex fine-tunes the alternative splicing of Glutaminase (GLS) by selecting the poly(A) site in intron 14 of the precursor mRNA. These findings uncover a complex, allele-specific regulatory mechanism of cancer metabolism orchestrated by the two alleles of a long ncRNA.
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    Author Correction: Hypoxia-mediated downregulation of miRNA biogenesis promotes tumour progression
    (Nature, 2020-06-03) Rupaimoole, Rajesha; Wu, Sherry Y.; Pradeep, Sunila; Ivan, Cristina; Pecot, Chad V.; Gharpure, Kshipra M.; Nagaraja, Archana S.; Armaiz-Pena, Guillermo N.; McGuire, Michael; Zand, Behrouz; Dalton, Heather J.; Filant, Justyna; Miller, Justin Bottsford; Lu, Chunhua; Sadaoui, Nouara C.; Mangala, Lingegowda S.; Taylor, Morgan; van den Beucken, Twan; Koch, Elizabeth; Rodriguez-Aguayo, Cristian; Huang, Li; Bar-Eli, Menashe; Wouters, Bradly G.; Radovich, Milan; Ivan, Mircea; Calin, George A.; Zhang, Wei; Lopez-Berestein, Gabriel; Sood, Anil K.; Medicine, School of Medicine
    This Article contains an error in Fig. 4. During the preparation of Fig. 4d, the image representing showing E-CADHERIN expression under hypoxia conditions in A2780 cells was inadvertently taken from the image in Supplementary Fig. 15C showing E-CADHERIN expression under hypoxia conditions in SKOV3 cells. The correct version of Fig. 4 is shown below. The error has not been corrected in the PDF or HTML versions of the Article.
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    Classic and targeted anti-leukaemic agents interfere with the cholesterol biogenesis metagene in acute myeloid leukaemia: Therapeutic implications
    (Wiley, 2020-05-25) Chen, Fangli; Wu, Xue; Niculite, Cristina; Gilca, Marilena; Petrusca, Daniela; Rogozea, Adriana; Rice, Susan; Guo, Bin; Griffin, Shawn; Calin, George A.; Boswell, H. Scott; Konig, Heiko; Medicine, School of Medicine
    Despite significant advances in deciphering the molecular landscape of acute myeloid leukaemia (AML), therapeutic outcomes of this haematological malignancy have only modestly improved over the past decades. Drug resistance and disease recurrence almost invariably occur, highlighting the need for a deeper understanding of these processes. While low O2 compartments, such as bone marrow (BM) niches, are well‐recognized hosts of drug‐resistant leukaemic cells, standard in vitro studies are routinely performed under supra‐physiologic (21% O2, ambient air) conditions, which limits clinical translatability. We hereby identify molecular pathways enriched in AML cells that survive acute challenges with classic or targeted therapeutic agents. Experiments took into account variations in O2 tension encountered by leukaemic cells in clinical settings. Integrated RNA and protein profiles revealed that lipid biosynthesis, and particularly the cholesterol biogenesis branch, is a particularly therapy‐induced vulnerability in AML cells under low O2 states. We also demonstrate that the impact of the cytotoxic agent cytarabine is selectively enhanced by a high‐potency statin. The cholesterol biosynthesis programme is amenable to additional translational opportunities within the expanding AML therapeutic landscape. Our findings support the further investigation of higher‐potency statin (eg rosuvastatin)–based combination therapies to enhance targeting residual AML cells that reside in low O2 environments.
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    Epstein–Barr Virus MicroRNAs are Expressed in Patients with Chronic Lymphocytic Leukemia and Correlate with Overall Survival
    (ScienceDirect, 2015-06) Ferrajoli, Alessandra; Ivan, Cristina; Ciccone, Maria; Shimizu, Masayoshi; Kita, Yoshiaki; Ohtsuka, Masahisha; D'Abundo, Lucilla; Qiang, Jun; Lerner, Susan; Nouraee, Nazila; Rabe, Kari G.; Rassenti, Laura Z.; Van Roosbroeck, Katrien; Manning, John T.; Yuan, Yuan; Zhang, Xinna; Shanafelt, Tait D.; Wierda, William G.; Sabbioni, Silvia; Tarrand, Jeffrey J.; Estrov, Zeev; Radovich, Milan; Liang, Han; Negrini, Massimo; Kipps, Thomas J.; Kay, Neil E.; Keating, Michael; Calin, George A.; Department of Surgery, IU School of Medicine
    Although numerous studies highlighted the role of Epstein–Barr Virus (EBV) in B-cell transformation, the involvement of EBV proteins or genome in the development of the most frequent adult leukemia, chronic lymphocytic leukemia (CLL), has not yet been defined. We hypothesized that EBV microRNAs contribute to progression of CLL and demonstrated the presence of EBV miRNAs in B-cells, in paraffin-embedded bone marrow biopsies and in the plasma of patients with CLL by using three different methods (small RNA-sequencing, quantitative reverse transcription PCR [q-RT-PCR] and miRNAs in situ hybridization [miRNA-ISH]). We found that EBV miRNA BHRF1-1 expression levels were significantly higher in the plasma of patients with CLL compared with healthy individuals (p < 0 · 0001). Notably, BHRF1-1 as well as BART4 expression were detected in the plasma of either seronegative or seropositive (anti-EBNA-1 IgG and EBV DNA tested) patients; similarly, miRNA-ISH stained positive in bone marrow specimens while LMP1 and EBER immunohistochemistry failed to detect viral proteins and RNA. We also found that BHRF1-1 plasma expression levels were positively associated with elevated beta-2-microglobulin levels and advanced Rai stages and observed a correlation between higher BHRF1-1 expression levels and shorter survival in two independent patients' cohorts. Furthermore, in the majority of CLL cases where BHRF1-1 was exogenously induced in primary malignant B cells the levels of TP53 were reduced. Our findings suggest that EBV may have a role in the process of disease progression in CLL and that miRNA RT-PCR and miRNAs ISH could represent additional methods to detect EBV miRNAs in patients with CLL.
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    H19 Noncoding RNA, an Independent Prognostic Factor, Regulates Essential Rb-E2F and CDK8-β-Catenin Signaling in Colorectal Cancer
    (Elsevier, 2016-11) Ohtsuka, Masahisa; Ling, Hui; Ivan, Cristina; Pichler, Martin; Matsushita, Daisuke; Goblirsch, Matthew; Stiegelbauer, Verena; Shigeyasu, Kunitoshi; Zhang, Xinna; Chen, Meng; Vidhu, Fnu; Bartholomeusz, Geoffrey A.; Toiyama, Yuji; Kusunoki, Masato; Doki, Yuichiro; Mori, Masaki; Song, Shumei; Gunther, Jillian R.; Krishnan, Sunil; Slaby, Ondrej; Goel, Ajay; Ajani, Jaffer A.; Radovich, Milan; Calin, George A.; Department of Surgery, IU School of Medicine
    The clinical significance of long noncoding RNAs (lncRNAs) in colorectal cancer (CRC) remains largely unexplored. Here, we analyzed a large panel of lncRNA candidates with The Cancer Genome Atlas (TCGA) CRC dataset, and identified H19 as the most significant lncRNA associated with CRC patient survival. We further validated such association in two independent CRC cohorts. H19 silencing blocked G1-S transition, reduced cell proliferation, and inhibited cell migration. We profiled gene expression changes to gain mechanism insight of H19 function. Transcriptome data analysis revealed not only previously identified mechanisms such as Let-7 regulation by H19, but also RB1-E2F1 function and β-catenin activity as essential upstream regulators mediating H19 function. Our experimental data showed that H19 affects phosphorylation of RB1 protein by regulating gene expression of CDK4 and CCND1. We further demonstrated that reduced CDK8 expression underlies changes of β-catenin activity, and identified that H19 interacts with macroH2A, an essential regulator of CDK8 gene transcription. However, the relevance of H19-macroH2A interaction in CDK8 regulation remains to be experimentally determined. We further explored the clinical relevance of above mechanisms in clinical samples, and showed that combined analysis of H19 with its targets improved prognostic value of H19 in CRC.
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    Hypoxia Mediated Downregulation of miRNA Biogenesis Promotes Tumor Progression
    (Nature Publishing Group, 2014-10-29) Rupaimoole, Rajesha; Wu, Sherry Y.; Pradeep, Sunila; Ivan, Cristina; Pecot, Chad V.; Gharpure, Kshipra M.; Nagaraja, Archana S.; Armaiz-Pena, Guillermo N.; McGuire, Michael; Zand, Behrouz; Dalton, Heather J.; Filant, Justyna; Miller, Justin Bottsford; Lu, Chunhua; Sadaoui, Nouara C.; Mangala, Lingegowda S.; Taylor, Morgan; van den Beucken, Twan; Koch, Elizabeth; Rodriguez-Aguayo, Cristian; Huang, Li; Bar-Eli, Menashe; Wouters, Bradly G.; Radovich, Milan; Ivan, Mircea; Calin, George A.; Zhang, Wei; Lopez-Berestein, Gabriel; Sood, Anil K.; Department of Surgery, IU School of Medicine
    Cancer-related deregulation of miRNA biogenesis has been suggested, but the underlying mechanisms remain elusive. Here, we report a previously unrecognized effect of hypoxia in the downregulation of Drosha and Dicer in cancer cells that leads to dysregulation of miRNA biogenesis and increased tumor progression. We show that hypoxia mediated downregulation of Drosha is dependent on ETS1/ELK1 transcription factors. Moreover, mature miRNA array and deep sequencing studies reveal altered miRNA maturation in cells under hypoxic conditions. At a functional level, this phenomenon results in increased cancer progression in vitro and in vivo, and data from patient samples are suggestive of miRNA biogenesis downregulation in hypoxic tumors. Rescue of Drosha by siRNAs targeting ETS1/ELK1 in vivo results in significant tumor regression. These findings provide a new link in the mechanistic understanding of global miRNA downregulation in the tumor microenvironment.
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    The Many Faces of Long Noncoding RNAs in Cancer
    (Mary Ann Liebert, 2018-09-20) Wu, Xue; Tudoran, Oana M.; Calin, George A.; Ivan, Mircea; Medicine, School of Medicine
    SIGNIFICANCE: The emerging connections between an increasing number of long noncoding RNAs (lncRNAs) and oncogenic hallmarks provide a new twist to tumor complexity. Recent Advances: In the present review, we highlight specific lncRNAs that have been studied in relation to tumorigenesis, either as participants in the neoplastic process or as markers of pathway activity or drug response. These transcripts are typically deregulated by oncogenic or tumor-suppressing signals or respond to microenvironmental conditions such as hypoxia. CRITICAL ISSUES: Among these transcripts are lncRNAs sufficiently divergent between mouse and human genomes that may contribute to biological differences between species. FUTURE DIRECTIONS: From a translational standpoint, knowledge about primate-specific lncRNAs may help explain the reason behind the failure to reproduce the results from mouse cancer models in human cell-based systems. Antioxid. Redox Signal. 29, 922-935.