Kovalchuk, Olga

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https://opus.uleth.ca/handle/10133/4539

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Browsing Kovalchuk, Olga by Author "Heyns, Mieke"

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    Genome-wide profiling of transfer RNAs and their role as novel prognostic markers for breast cancer
    (Nature Publishing Group, 2016) Krishnan, Preethi; Ghosh, Sunita; Wang, Bo; Heyns, Mieke; Li, Dongping; Mackey, John R.; Kovalchuk, Olga; Damaraju, Sambasivarao
    Transfer RNAs (tRNAs, key molecules in protein synthesis) have not been investigated as potential prognostic markers in breast cancer (BC), despite early findings of their dysregulation and diagnostic potential. We aim to comprehensively profile tRNAs from breast tissues and to evaluate their role as prognostic markers (Overall Survival, OS and Recurrence Free Survival, RFS). tRNAs were profiled from 11 normal breast and 104 breast tumor tissues using next generation sequencing. We adopted a Case-control (CC) and Case-Only (CO) association study designs. Risk scores constructed from tRNAs were subjected to univariate and multivariate Cox-proportional hazards regression to investigate their prognostic value. Of the 571 tRNAs profiled, 76 were differentially expressed (DE) and three were significant for OS in the CC approach. We identified an additional 11 tRNAs associated with OS and 14 tRNAs as significant for RFS in the CO approach, indicating that CC alone may not capture all discriminatory tRNAs in prognoses. In both the approaches, the risk scores were significant in the multivariate analysis as independent prognostic factors, and patients belonging to high-risk group were associated with poor prognosis. Our results confirmed global up-regulation of tRNAs in BC and identified tRNAs as potential novel prognostic markers for BC.
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    Profiling of small nucleolar RNAs by next generation sequencing: potential new players for breast cancer prognosis
    (Public Library of Science, 2016) Krishnan, Preethi; Ghosh, Sunita; Wang, Bo; Heyns, Mieke; Graham, Kathryn; Mackey, John R.; Kovalchuk, Olga; Damaraju, Sambasivarao
    One of the most abundant,yet least explored,classes of RNA is the small nucleolar RNAs (snoRNAs), which are well known for their involvement in post-transcriptional modifications of other RNAs. Although snoRNAs were only considered to perform housekeeping functions for a long time, recent studies have highlighted their importance as regulators of gene expression and as diagnostic/prognostic markers.However, the prognostic potential of these RNAs has not been interrogated for breast cancer(BC). The objective of the current study was to identify snoRNAs as prognostic markers for BC. Small RNA sequencing (Illumina Genome Analyzer IIx) was performed for 104BC cases and 11 normal breast tissues. Partek Genomics Suite was used for analyzing the sequencing files.Two independent and proven approaches were used to identify prognostic markers: case-control(CC) and case only(CO). For both approaches, snoRNAs significant in the permutation test following univariate Cox proportional hazards regression model were used for constructing risks cores. Risk scores were subsequently adjusted for potential confounders in a multivariate Cox model. For both approaches, thirteen snoRNAs were associated with overall survival and/or recurrence free survival.Patients belonging to the high-risk group were associated with poor outcomes, and the risk score was significant after adjusting for confounders. Validation of representatives no RNAs (SNORD46andSNORD89) using qRT-PCR confirmed the observations from sequencing experiments.We also observed 64 snoRNAs harboring piwi interacting RNAs and/or micro RNAs that were predicted to target genes (mRNAs) involved in tumor igenesis.Our results demonstrate the potential of snoRNAs to serve (i) as novel prognostic markers for BC and (ii) as indirect regulators of gene expression
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    A suppressive role of ionizing radiation-responsive miR-29c in the development of liver carcinoma via targeting WIP1
    (Impact Journals, 2015) Wang, Bo; Li, Dongping; Sidler, Corinne; Rodriquez-Juarez, Rocio; Singh, Natasha; Heyns, Mieke; Ilnytskyy, Yaroslav; Bronson, Roderick T.; Kovalchuk, Olga
    Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths worldwide, and it has been linked to radiation exposure. As a well-defined oncogene, wild-type p53-induced phosphatase 1 (WIP1) plays an inhibitory role in several tumor suppressor pathways, including p53. WIP1 is amplified and overexpressed in many malignancies, including HCC. However, the underlying mechanisms remain largely unknown. Here, we show that low-dose ionizing radiation (IR) induces miR-29c expression in female mouse liver, while inhibiting its expression in HepG2, a human hepatocellular carcinoma cell line which is used as a model system in this study. miR29c expression is downregulated in human hepatocellular carcinoma cells, which is inversely correlated with WIP1 expression. miR-29c attenuates luciferase activity of a reporter harboring the 3’UTR binding motif of WIP1 mRNA. Ectopic expression of miR-29c significantly represses cell proliferation and induces apoptosis and G1 arrest in HepG2. In contrast, the knockdown of miR-29c greatly enhances HepG2 cell proliferation and suppresses apoptosis. The biological effects of miR-29c may be mediated by its target WIP1 which regulates p53 activity via dephosphorylation at Ser-15. Finally, fluorescence in situ hybridization (FISH) and immunohistochemical analyses indicate that miR-29c is downregulated in 50.6% of liver carcinoma tissues examined, whereas WIP1 is upregulated in 45.4% of these tissues. The expression of miR-29c inversely correlates with that of WIP1 in HCC. Our results suggest that the IR-responsive miR-29c may function as a tumor suppressor that plays a crucial role in the development of liver carcinoma via targeting WIP1, therefore possibly representing a target molecule for therapeutic intervention for this disease.