Attenuation of transforming growth factor beta-induced growth inhibition in human hepatocellular carcinoma cell lines by cyclin D1 overexpression.
Transforming growth factor-beta1 (TGF-beta1) causes growth inhibition in many cell types. Since its role in the outgrowth of human hepatocellular carcinoma (HCC) is not clearly understood, we investigated the growth inhibitory effects of TGF-beta1, the genetic and molecular integrity of TGF-beta receptors, and the expression levels of cell cycle regulating proteins in 11 human HCC cell lines. Of 11 cell lines, 3 (27%) showed growth inhibition to TGF-beta1, whereas the other 8 cell lines did not. We performed Southern and Northern analysis of TGF-beta type I and II receptors and examined poly-adenine track mutation of the TGF-beta type II receptor, but failed to find any genetic mutation. The transcriptional induction of plasminogen activator inhibitor-1 and p21(WAF1/CIP1) by TGF-beta were detected in all HCC cell lines, implying that the molecular integrity of the TGF-beta receptors might be intact. The amplification and overexpression of cyclin D1 gene was detected in 4 (50%) of 8 HCC cells that showed resistance to TGF-beta1. The suppression of cyclin D1 expression with antisense cyclin D1 facilitated the TGF-beta1-triggered growth inhibition in a TGF-beta1 resistant HCC cell line containing amplified cyclin D1 gene. In conclusion, the overexpression of cyclin D1 may be responsible for the attenuation of TGF-beta1 induced growth inhibition in some HCC cells.
Jong
Hyun-Soon
HS
Cancer Research Institute, Seoul National University College of Medicine, Chongno-gu, Seoul 110-799, Korea.
Lee
Ho Soon
HS
Kim
Tae You
TY
Im
Young-Hyuck
YH
Park
Jae-Won
JW
Kim
Noe Kyeong
NK
Bang
Yung-Jue
YJ
D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle; D002455:Cell Division / Q000187:drug effects; D019938:Cyclin D1 / Q000096:biosynthesis / Q000235:genetics*; D004247:DNA / Q000096:biosynthesis; D016373:DNA, Antisense / Q000494:pharmacology; D005784:Gene Amplification; D006131:Growth Inhibitors / Q000037:antagonists & inhibitors*; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D012334:RNA, Neoplasm / Q000096:biosynthesis; D018125:Receptors, Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics; D015533:Transcriptional Activation; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured
D016373:DNA, Antisense; D006131:Growth Inhibitors; D012334:RNA, Neoplasm; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D019938:Cyclin D1; D004247:DNA