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Functional and clinical evidence for NDRG2 as a candidate suppressor of liver cancer metastasis

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dc.contributor.authorLee, Dong Chul-
dc.contributor.authorKang, Yun Kyung-
dc.contributor.authorKim, Woo Ho-
dc.contributor.authorJang, Ye Jin-
dc.contributor.authorKim, Dong Joon-
dc.contributor.authorPark, In Young-
dc.contributor.authorSohn, Bo Hwa-
dc.contributor.authorSohn, Hyun Ahm-
dc.contributor.authorLee, Hee Gu-
dc.contributor.authorLim, Jong Seok-
dc.contributor.authorKim, Jae Wha-
dc.contributor.authorSong, Eun Young-
dc.contributor.authorKim, Dong Min-
dc.contributor.authorLee, Mi-Ni-
dc.contributor.authorOh, Goo Taeg-
dc.contributor.authorKim, Soo Jung-
dc.contributor.authorPark, Kyung Chan-
dc.contributor.authorYoo, Hyang Sook-
dc.contributor.authorChoi, Jong Young-
dc.contributor.authorYeom, Young Il-
dc.date.accessioned2010-07-06T23:36:42Z-
dc.date.available2010-07-06T23:36:42Z-
dc.date.issued2008-06-04-
dc.identifier.citationCancer Res. 2008;68(11):4210-4220en
dc.identifier.issn1538-7445 (Electronic)-
dc.identifier.urihttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18519680-
dc.identifier.urihttp://cancerres.aacrjournals.org/cgi/reprint/68/11/4210.pdf-
dc.identifier.urihttps://hdl.handle.net/10371/68364-
dc.description.abstractWe searched for potential suppressors of tumor metastasis by identifying the genes that are frequently down-regulated in hepatocellular carcinomas (HCC) while being negatively correlated with clinical parameters relevant to tumor metastasis, and we report here on the identification of N-myc downstream regulated gene 2 (NDRG2) as a promising candidate. NDRG2 expression was significantly reduced in HCC compared with nontumor or normal liver tissues [87.5% (35 of 40) and 62% (62 of 100) at RNA and protein levels, respectively]. Reduction of NDRG2 expression was intimately associated with promoter hypermethylation because its promoter region was found to carry extensively methylated CpG sites in HCC cell lines and primary tumors. Immunohistochemical analysis of NDRG2 protein in 100 HCC patient tissues indicated that NDRG2 expression loss is significantly correlated with aggressive tumor behaviors such as late tumor-node-metastasis (TNM) stage (P = 0.012), differentiation grade (P = 0.024), portal vein thrombi (P = 0.011), infiltrative growth pattern (P = 0.015), nodal/distant metastasis (P = 0.027), and recurrent tumor (P = 0.021), as well as shorter patient survival rates. Ectopically expressed NDRG2 suppressed invasion and migration of a highly invasive cell line, SK-Hep-1, and experimental tumor metastasis in vivo, whereas small interfering RNA-mediated knockdown resulted in increased invasion and migration of a weakly invasive cell line, PLC/PRF/5. In addition, NDRG2 could antagonize transforming growth factor beta1-mediated tumor cell invasion by specifically down-regulating the expression of matrix metalloproteinase 2 and laminin 332 pathway components, with concomitant suppression of Rho GTPase activity. These results suggest that NDRG2 can inhibit extracellular matrix-based, Rho-driven tumor cell invasion and migration and thereby play important roles in suppressing tumor metastasis in HCC.en
dc.description.sponsorshipGrant-in-Aid for the 21C Frontier Human Genome Functional
Analysis Project from the Ministry of Science and Technology of Korea and by Korea
Research Institute of Bioscience and Biotechnology Research Initiative Program.
en
dc.language.isoenen
dc.publisherAmerican Association for Cancer Researchen
dc.subjectBase Sequenceen
dc.subjectCell Line, Tumoren
dc.subjectCpG Islandsen
dc.subjectHumansen
dc.subjectImmunohistochemistryen
dc.subjectLiver Neoplasms/genetics/*pathologyen
dc.subjectNeoplasm Invasivenessen
dc.subjectPromoter Regions, Geneticen
dc.subjectRNA, Small Interferingen
dc.subjectReverse Transcriptase Polymerase Chain Reactionen
dc.subjectTumor Suppressor Proteins/*genetics/physiologyen
dc.subjectGenes, Tumor Suppressor-
dc.subjectNeoplasm Metastasis-
dc.titleFunctional and clinical evidence for NDRG2 as a candidate suppressor of liver cancer metastasisen
dc.typeArticleen
dc.contributor.AlternativeAuthor이동철-
dc.contributor.AlternativeAuthor강윤경-
dc.contributor.AlternativeAuthor김우호-
dc.contributor.AlternativeAuthor장예진-
dc.contributor.AlternativeAuthor김동준-
dc.contributor.AlternativeAuthor박인영-
dc.contributor.AlternativeAuthor손보화-
dc.contributor.AlternativeAuthor손현암-
dc.contributor.AlternativeAuthor임종석-
dc.contributor.AlternativeAuthor김재화-
dc.contributor.AlternativeAuthor송은영-
dc.contributor.AlternativeAuthor김동민-
dc.contributor.AlternativeAuthor이미니-
dc.contributor.AlternativeAuthor오구택-
dc.contributor.AlternativeAuthor김수정-
dc.contributor.AlternativeAuthor박경찬-
dc.contributor.AlternativeAuthor유향숙-
dc.contributor.AlternativeAuthor최종영-
dc.contributor.AlternativeAuthor염영일-
dc.contributor.AlternativeAuthor이희구-
dc.identifier.doi10.1158/0008-5472.CAN-07-5040-
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