TY - JOUR
T1 - Acquired genetic and functional alterations associated with transforming growth factor β type I resistance in Hep3B human hepatocellular carcinoma cell line
AU - Zimonjic, Drazen B.
AU - Zhou, Xiaoling
AU - Lee, Ju Seog
AU - Ullmannova-Benson, Veronika
AU - Tripathi, Veenu
AU - Thorgeirsson, Snorri S.
AU - Popescu, Nicholas C.
PY - 2009/9
Y1 - 2009/9
N2 - During the neoplastic process tumour cells frequently acquire resistance to the antiproliferative signals of transforming growth factor-β (TGF-β). Here we examined a human hepatocellular carcinoma cell line (Hep3B-TS) sensitive to TGF-β signalling, and a derivative line (Hep3B-TR) rendered resistant to TGF-β by stepwise exposure to TGF-β 1. Comprehensive molecular cytogenetic analysis revealed that the acquisition of TGF-β-resistance by Hep3B-TR cells was due to loss of TGF-β receptor 2 (TGFβRII) gene. As demonstrated by spectral karyotyping and array-based comparative genomic hybridization, and in difference to Hep3B-TS cells, which have three rearranged and two normal copies of chromosome 3 that harbour the TGFβRII gene, Hep3B-TR cells have four rearranged and one apparently normal chromosome 3, which nonetheless underwent a critical microdeletion at the site of TGFβRII gene. Gene expression analysis using an oligonucleotide microarray of 21,397 genes showed that Hep3B-TR differentially expressed 307 genes, out of which 197 and 110 were up- and down-regulated, respectively, compared to Hep3B-TS. Six of differentially expressed genes were identified as downstream targets of the tumour necrosis factor (TNF) gene, suggesting that loss of TGFβRII triggered activation of the TNF pathway known to be regulated by TGF-β 1 network. On the functional level, the TGF-β-resistant Hep3B-TR cells displayed significantly enhanced capacity for anchorage independent growth and cell migration in vitro, and also increased tumorigenicity in vivo and in vitro and in vivo tumorigenicity compared with parental sensitive cells. No claim to original US government works Journal compilation
AB - During the neoplastic process tumour cells frequently acquire resistance to the antiproliferative signals of transforming growth factor-β (TGF-β). Here we examined a human hepatocellular carcinoma cell line (Hep3B-TS) sensitive to TGF-β signalling, and a derivative line (Hep3B-TR) rendered resistant to TGF-β by stepwise exposure to TGF-β 1. Comprehensive molecular cytogenetic analysis revealed that the acquisition of TGF-β-resistance by Hep3B-TR cells was due to loss of TGF-β receptor 2 (TGFβRII) gene. As demonstrated by spectral karyotyping and array-based comparative genomic hybridization, and in difference to Hep3B-TS cells, which have three rearranged and two normal copies of chromosome 3 that harbour the TGFβRII gene, Hep3B-TR cells have four rearranged and one apparently normal chromosome 3, which nonetheless underwent a critical microdeletion at the site of TGFβRII gene. Gene expression analysis using an oligonucleotide microarray of 21,397 genes showed that Hep3B-TR differentially expressed 307 genes, out of which 197 and 110 were up- and down-regulated, respectively, compared to Hep3B-TS. Six of differentially expressed genes were identified as downstream targets of the tumour necrosis factor (TNF) gene, suggesting that loss of TGFβRII triggered activation of the TNF pathway known to be regulated by TGF-β 1 network. On the functional level, the TGF-β-resistant Hep3B-TR cells displayed significantly enhanced capacity for anchorage independent growth and cell migration in vitro, and also increased tumorigenicity in vivo and in vitro and in vivo tumorigenicity compared with parental sensitive cells. No claim to original US government works Journal compilation
KW - ACGH profile
KW - Chromosomal rearrangements
KW - Expression profiling
KW - FISH
KW - HCC
KW - Hep3B
KW - Invasion
KW - Microdeletion
KW - Migration
KW - Resistance
KW - SKY karyotype
KW - TGF-β
KW - TGFβRII
KW - Tumorigenicity
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UR - http://www.scopus.com/inward/citedby.url?scp=77449107905&partnerID=8YFLogxK
U2 - 10.1111/j.1582-4934.2009.00769.x
DO - 10.1111/j.1582-4934.2009.00769.x
M3 - Article
C2 - 19426152
AN - SCOPUS:77449107905
SN - 1582-1838
VL - 13
SP - 3985
EP - 3992
JO - Journal of Cellular and Molecular Medicine
JF - Journal of Cellular and Molecular Medicine
IS - 9 B
ER -