Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Tumor Biology
Published in: Tumor Biology 11/2014

01-11-2014 | Research Article

Hsa-miR-195 targets PCMT1 in hepatocellular carcinoma that increases tumor life span

Authors: Marwa Amer, M. Elhefnawi, Eman El-Ahwany, A. F. Awad, Nermen Abdel Gawad, Suher Zada, F. M. Abdel Tawab

Published in: Tumor Biology | Issue 11/2014

Login to get access

Abstract

MicroRNAs are small 19–25 nucleotides which have been shown to play important roles in the regulation of gene expression in many organisms. Downregulation or accumulation of miRNAs implies either tumor suppression or oncogenic activation. In this study, differentially expressed hsa-miR-195 in hepatocellular carcinoma (HCC) was identified and analyzed. The prediction was done using a consensus approach of tools. The validation steps were done at two different levels in silico and in vitro. FGF7, GHR, PCMT1, CITED2, PEX5, PEX13, NOVA1, AXIN2, and TSPYL2 were detected with high significant (P < 0.005). These genes are involved in important pathways in cancer like MAPK signaling pathway, Jak-STAT signaling pathways, regulation of actin cytoskeleton, angiogenesis, Wnt signaling pathway, and TGF-beta signaling pathway. In vitro target validation was done for protein-l-isoaspartate (d-aspartate) O-methyltransferase (PCMT1). The co-transfection of pmirGLO-PCMT1 and pEGP-miR-195 showed highly significant results. Firefly luciferase was detected using Lumiscensor and t test analysis was done. Firefly luciferase expression was significantly decreased (P < 0.001) in comparison to the control. The low expression of firefly luciferase validates the method of target prediction that we used in this work by working on PCMT1 as a target for miR-195. Furthermore, the rest of the predicted genes are suspected to be real targets for hsa-miR-195. These target genes control almost all the hallmarks of liver cancer which can be used as therapeutic targets in cancer treatment.
Literature
1.
Varnholt H, Drebber U, Schulze F, Wedemeyer I, Schirmacher P, et al. MicroRNA gene expression profile of hepatitis C virus-associated hepatocellular carcinoma. Hepatology. 2008;47:1223–32.PubMedCrossRef
2.
Steel LF, Mattu TS, Mehta A, Hebestreit H, Dwek R, et al. A proteomic approach for the discovery of early detection markers of hepatocellular carcinoma. Dis Markers. 2001;17:179–89.PubMedCentralPubMedCrossRef
3.
Moradpour D, Blum HE. Pathogenesis of hepatocellular carcinoma. Eur J Gastroenterol Hepatol. 2005;17:477–83.PubMedCrossRef
4.
Colombo M, Sangiovanni A. Etiology, natural history and treatment of hepatocellular carcinoma. Antiviral Res. 2003;60:145–50.PubMedCrossRef
5.
Lee JS, Thorgeirsson SS. Comparative and integrative functional genomics of HCC. Oncogene. 2006;25:3801–9.PubMedCrossRef
6.
Lemmer ER, Friedman SL, Llovet JM. Molecular diagnosis of chronic liver disease and hepatocellular carcinoma: the potential of gene expression profiling. Semin Liver Dis. 2006;26:373–84.PubMedCrossRef
7.
Garzon R, Fabbri M, Cimmino A, Calin GA, Croce CM. MicroRNA expression and function in cancer. Trends Mol Med. 2006;12:580–7.PubMedCrossRef
8.
Lee RC, Feinbaum RL, Ambros V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell. 1993;75:843–54.PubMedCrossRef
9.
Berezikov E, Thuemmler F, van Laake LW, Kondova I, Bontrop R, et al. Diversity of microRNAs in human and chimpanzee brain. Nat Genet. 2006;38:1375–7.PubMedCrossRef
10.
Berezikov E, van Tetering G, Verheul M, van de Belt J, van Laake L, et al. Many novel mammalian microRNA candidates identified by extensive cloning and RAKE analysis. Genome Res. 2006;16:1289–98.PubMedCentralPubMedCrossRef
11.
Michael MZ, O’ Connor SM, van Holst Pellekaan NG, Young GP, James RJ. Reduced accumulation of specific microRNAs in colorectal neoplasia. Mol Cancer Res. 2003;1:882–91.PubMed
12.
13.
Volinia S, Calin GA, Liu CG, Ambs S, Cimmino A, et al. A microRNA expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci U S A. 2006;103:2257–61.PubMedCentralPubMedCrossRef
14.
Calin GA, Dumitru CD, Shimizu M, Bichi R, Zupo S, et al. Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc Natl Acad Sci U S A. 2002;99:15524–9.PubMedCentralPubMedCrossRef
15.
Lu J, Getz G, Miska EA, Alvarez-Saavedra E, Lamb J, et al. MicroRNA expression profiles classify human cancers. Nature. 2005;435:834–8.PubMedCrossRef
16.
Yanaihara N, Caplen N, Bowman E, Seike M, Kumamoto K, et al. Unique microRNA molecular profiles in lung cancer diagnosis and prognosis. Cancer Cell. 2006;9:189–98.PubMedCrossRef
17.
Xue C, Li F, He T, Liu GP, Li Y, et al. Classification of real and pseudo microRNA precursors using local structure-sequence features and support vector machine. BMC Bioinforma. 2005;6:310.CrossRef
18.
Berezikov E, Guryev V, van de Belt J, Wienholds E, Plasterk RH, et al. Phylogenetic shadowing and computational identification of human microRNA genes. Cell. 2005;120:21–4.PubMedCrossRef
19.
20.
21.
Melo SA, Esteller M. Dysregulation of microRNAs in cancer: playing with fire. FEBS Lett. 2010;585:2087–99.PubMedCrossRef
22.
23.
Voorhoeve PM, le Sage C, Schrier M, Gillis AJ, Stoop H, et al. A genetic screen implicates miRNA-372 and miRNA-373 as oncogenes in testicular germ cell tumors. Cell. 2006;124:1169–81.PubMedCrossRef
24.
Poy MN, Eliasson L, Krutzfeldt J, Kuwajima S, Ma X, et al. A pancreatic islet-specific microRNA regulates insulin secretion. Nature. 2004;432:226–30.PubMedCrossRef
25.
Huang V, Place RF, Portnoy V, Wang J, Qi Z, et al. Upregulation of cyclin B1 by miRNA and its implications in cancer. Nucleic Acids Res. 2011;40:1695–707.PubMedCentralPubMedCrossRef
26.
Calin GA, Sevignani C, Dumitru CD, Hyslop T, Noch E, et al. Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proc Natl Acad Sci U S A. 2004;101:2999–3004.PubMedCentralPubMedCrossRef
27.
Zhao JJ, Yang J, Lin J, Yao N, Zhu Y, et al. Identification of miRNAs associated with tumorigenesis of retinoblastoma by miRNA microarray analysis. Childs Nerv Syst. 2009;25:13–20.PubMedCrossRef
28.
Klase Z, Winograd R, Davis J, Carpio L, Hildreth R, et al. HIV-1 TAR miRNA protects against apoptosis by altering cellular gene expression. Retrovirology. 2009;6:18.PubMedCentralPubMedCrossRef
29.
Esquela-Kerscher A, Slack FJ. Oncomirs—microRNAs with a role in cancer. Nat Rev Cancer. 2006;6:259–69.PubMedCrossRef
30.
31.
Bernstein E, Kim SY, Carmell MA, Murchison EP, Alcorn H, et al. Dicer is essential for mouse development. Nat Genet. 2003;35:215–7.PubMedCrossRef
32.
Chen CZ, Li L, Lodish HF, Bartel DP. MicroRNAs modulate hematopoietic lineage differentiation. Science. 2004;303:83–6.PubMedCrossRef
33.
Blenkiron C, Goldstein LD, Thorne NP, Spiteri I, Chin SF, et al. MicroRNA expression profiling of human breast cancer identifies new markers of tumor subtype. Genome Biol. 2007;8:R214.PubMedCentralPubMedCrossRef
34.
Verghese ET, Hanby AM, Speirs V, Hughes TA. Small is beautiful: microRNAs and breast cancer-where are we now? J Pathol. 2008;215:214–21.PubMedCrossRef
35.
36.
Gaur A, Jewell DA, Liang Y, Ridzon D, Moore JH, et al. Characterization of microRNA expression levels and their biological correlates in human cancer cell lines. Cancer Res. 2007;67:2456–68.PubMedCrossRef
37.
Nana-Sinkam SP, Croce CM. MicroRNAs as therapeutic targets in cancer. Transl Res. 2011;157:216–25.PubMedCrossRef
38.
Chavous DA, Jackson FR, O'Connor CM. Extension of the Drosophila lifespan by overexpression of a protein repair methyltransferase. Proc Natl Acad Sci U S A. 2001;98:14814–8.PubMedCentralPubMedCrossRef
39.
Lowenson JD, Kim E, Young SG, Clarke S. Limited accumulation of damaged proteins in l-isoaspartyl (d-aspartyl) O-methyltransferase-deficient mice. J Biol Chem. 2001;276:20695–702.PubMedCrossRef
40.
41.
Lewis BP, Burge CB, Bartel DP. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell. 2005;120:15–20.PubMedCrossRef
42.
Schratt GM, Tuebing F, Nigh EA, Kane CG, Sabatini ME, et al. A brain-specific microRNA regulates dendritic spine development. Nature. 2006;439:283–9.PubMedCrossRef
43.
Brennecke J, Hipfner DR, Stark A, Russell RB, Cohen SM. bantam encodes a developmentally regulated microRNA that controls cell proliferation and regulates the proapoptotic gene hid in Drosophila. Cell. 2003;113:25–36.PubMedCrossRef
44.
Johnson SM, Grosshans H, Shingara J, Byrom M, Jarvis R, et al. RAS is regulated by the let-7 microRNA family. Cell. 2005;120:635–47.PubMedCrossRef
45.
O'Donnell KA, Wentzel EA, Zeller KI, Dang CV, Mendell JT. c-Myc-regulated microRNAs modulate E2F1 expression. Nature. 2005;435:839–43.PubMedCrossRef
46.
Medina R, Zaidi SK, Liu CG, Stein JL, van Wijnen AJ, et al. MicroRNAs 221 and 222 bypass quiescence and compromise cell survival. Cancer Res. 2008;68:2773–80.PubMedCentralPubMedCrossRef
47.
Park SM, Gaur AB, Lengyel E, Peter ME. The miR-200 family determines the epithelial phenotype of cancer cells by targeting the E-cadherin repressors ZEB1 and ZEB2. Genes Dev. 2008;22:894–907.PubMedCentralPubMedCrossRef
48.
Su H, Yang JR, Xu T, Huang J, Xu L, et al. MicroRNA-101, down-regulated in hepatocellular carcinoma, promotes apoptosis and suppresses tumorigenicity. Cancer Res. 2009;69:1135–42.PubMedCrossRef
49.
Xu T, Zhu Y, Xiong Y, Ge YY, Yun JP, et al. MicroRNA-195 suppresses tumorigenicity and regulates G1/S transition of human hepatocellular carcinoma cells. Hepatology. 2009;50:113–21.PubMedCrossRef
50.
Robert M, Maluf G, Yanek K, Kong X, Kulik L, et al. Genes involved in viral carcinogenesis and tumor initiation in hepatitis c virus-induced hepatocellular carcinoma. Mol Med. 2009;15:85–94.
51.
Huebscher KJ, Lee J, Rovelli G, Ludin B, Matus A, et al. Protein isoaspartyl methyltransferase protects from Bax-induced apoptosis. Gene. 1999;240:333–41.PubMedCrossRef
52.
Kosugi S, Furuchi T, Katane M, Sekine M, Shirasawa T, et al. Suppression of protein l-isoaspartyl (d-aspartyl) methyltransferase results in hyperactivation of EGF-stimulated MEK-ERK signaling in cultured mammalian cells. Biochem Biophys Res Commun. 2008;371:22–7.PubMedCrossRef
53.
Huang YS, Dai Y, Yu XF, Bao SY, Yin YB, et al. Microarray analysis of microRNA expression in hepatocellular carcinoma and non-tumorous tissues without viral hepatitis. J Gastroenterol Hepatol. 2008;23:87–94.PubMedCrossRef
54.
Pei Y, Zhang T, Renault V, Zhang X. An overview of hepatocellular carcinoma study by omics-based methods. Acta Biochim Biophys Sin (Shanghai). 2009;41:1–15.CrossRef
55.
Ruepp A, Kowarsch A, Schmidl D, Buggenthin F, Brauner B, et al. PhenomiR: a knowledgebase for microRNA expression in diseases and biological processes. Genome Biol. 2010;11:R6.PubMedCentralPubMedCrossRef
56.
57.
Krek A, Grun D, Poy MN, Wolf R, Rosenberg L, et al. Combinatorial microRNA target predictions. Nat Genet. 2005;37:495–500.PubMedCrossRef
58.
Kiriakidou M, Nelson PT, Kouranov A, Fitziev P, Bouyioukos C, et al. A combined computational-experimental approach predicts human microRNA targets. Genes Dev. 2004;18:1165–78.PubMedCentralPubMedCrossRef
59.
60.
61.
ElHefnawi M, Soliman B, Abu-Shahba N, Amer M. An integrative meta-analysis of microRNAs in hepatocellular carcinoma. Genomics Proteomics Bioinforma. 2013;11:354–67.CrossRef
62.
Hsu SD, Lin FM, Wu WY, Liang C, Huang WC, et al. miRTarBase: a database curates experimentally validated microRNA-target interactions. Nucleic Acids Res. 2011;39:D163–169.PubMedCentralPubMedCrossRef
63.
64.
65.
66.
Muckstein U, Tafer H, Hackermuller J, Bernhart SH, Stadler PF, et al. Thermodynamics of RNA-RNA binding. Bioinformatics. 2006;22:1177–82.PubMedCrossRef
67.
68.
Carver T, Bleasby A. The design of Jemboss: a graphical user interface to EMBOSS. Bioinformatics. 2003;19:1837–43.PubMedCrossRef
69.
70.
Okuda S, Yamada T, Hamajima M, Itoh M, Katayama T, et al. KEGG Atlas mapping for global analysis of metabolic pathways. Nucleic Acids Res. 2008;36:W423–426.PubMedCentralPubMedCrossRef
71.
Kono N, Arakawa K, Ogawa R, Kido N, Oshita K, et al. Pathway projector: web-based zoomable pathway browser using KEGG atlas and Google Maps API. PLoS One. 2009;4:e7710.PubMedCentralPubMedCrossRef
72.
Vastrik I, D'Eustachio P, Schmidt E, Gopinath G, Croft D, et al. Reactome: a knowledge base of biologic pathways and processes. Genome Biol. 2007;8:R39.PubMedCentralPubMedCrossRef
73.
da Huang W, Sherman BT, Lempicki RA. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc. 2009;4:44–57.CrossRef
74.
Backes C, Keller A, Kuentzer J, Kneissl B, Comtesse N, et al. GeneTrail—advanced gene set enrichment analysis. Nucleic Acids Res. 2007;35:W186–192.PubMedCentralPubMedCrossRef
75.
McLauchlan J, Lemberg MK, Hope G, Martoglio B. Intramembrane proteolysis promotes trafficking of hepatitis C virus core protein to lipid droplets. EMBO J. 2002;21:3980–8.PubMedCentralPubMedCrossRef
Metadata
Title
Hsa-miR-195 targets PCMT1 in hepatocellular carcinoma that increases tumor life span
Authors
Marwa Amer
M. Elhefnawi
Eman El-Ahwany
A. F. Awad
Nermen Abdel Gawad
Suher Zada
F. M. Abdel Tawab
Publication date
01-11-2014
Publisher
Springer Netherlands
Published in
Tumor Biology / Issue 11/2014
Print ISSN: 1010-4283
Electronic ISSN: 1423-0380
DOI
https://doi.org/10.1007/s13277-014-2445-4

Other articles of this Issue 11/2014

Tumor Biology 11/2014 Go to the issue

Research Article

Overexpression of CPS1 is an independent negative prognosticator in rectal cancers receiving concurrent chemoradiotherapy

Research Article

RETRACTED ARTICLE: Analysis of Tim-3 as a therapeutic target in prostate cancer

Research Article

MEF2 transcription factors promotes EMT and invasiveness of hepatocellular carcinoma through TGF-β1 autoregulation circuitry

Research Article

Relationship between IL-10 expression and prognosis in patients with primary breast cancer

Research Article

Development of a risk assessment tool for projecting individualized probabilities of developing breast cancer for Chinese women

Research Article

Over-expression of TRPM8 is associated with poor prognosis in urothelial carcinoma of bladder
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits