PMID- 8033155
OWN - NLM
STAT- MEDLINE
DCOM- 19940815
LR  - 20071114
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 54
IP  - 15
DP  - 1994 Aug 1
TI  - Inhibition of tumor growth in liver epithelial cells transfected with a 
      transforming growth factor alpha antisense gene.
PG  - 4224-32
AB  - Transforming growth factor alpha (TGF alpha) overexpression is associated with 
      human hepatocellular carcinoma and with transformation of rat liver epithelial 
      cell lines. In transgenic mice TGF alpha overexpression in the liver induces 
      hepatocyte proliferation and leads to the development of tumors. Using a 
      transformed rat liver epithelial cell line which can give rise to hepatocellular 
      carcinomas, we used antisense genes to examine the importance of TGF alpha in 
      tumor growth. Two different rat TGF alpha complementary DNA fragments were cloned 
      in the antisense orientation into a thymidine kinase minigene downstream of a 
      retroviral long terminal repeat. Cell lines that stably expressed the more 
      effective construct, which contained a fragment that spanned the TGF alpha start 
      codon, exhibited a 4-fold reduction in TGF alpha secretion relative to cell lines 
      that expressed the thymidine kinase minigene alone. Following introduction into 
      nude mice of 2 x 10(5) cells the control cell lines grew rapidly to produce 
      large, highly cellular tumors by 5-6 weeks following injection, whereas with the 
      antisense cell lines tumor growth was delayed so that tumors needed an additional 
      5 weeks to reach the same size. A high level of growth inhibition was also 
      evident following injection of 2 x 10(6) cells, although the delay in tumor 
      growth from antisense lines was shortened to about 3 weeks. Furthermore, tumors 
      produced by 3 of the 4 antisense cell lines tested were fibrotic and hypocellular 
      relative to those produced by the control cell lines. Growth of tumors from the 
      antisense cell lines was associated with a decline in antisense RNA expression. 
      In contrast, tumors generated from the control cell lines maintained high levels 
      of expression of the control thymidine kinase minigene. These data demonstrate 
      that tumor growth from highly tumorigenic liver cells can be inhibited by 
      disrupting their ability to produce TGF alpha.
FAU - Laird, A D
AU  - Laird AD
AD  - Department of Pathology and Laboratory Medicine, Brown University School of 
      Medicine, Providence, Rhode Island 02912.
FAU - Brown, P I
AU  - Brown PI
FAU - Fausto, N
AU  - Fausto N
LA  - eng
GR  - CA 23226/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (Oligonucleotides, Antisense)
RN  - 0 (RNA, Messenger)
RN  - 0 (Transforming Growth Factor alpha)
SB  - IM
MH  - Animals
MH  - Base Sequence
MH  - Cell Division/genetics
MH  - Epithelium/metabolism/pathology
MH  - Humans
MH  - Liver/metabolism/*pathology
MH  - Liver Neoplasms/genetics/metabolism/*pathology
MH  - Molecular Sequence Data
MH  - Oligonucleotides, Antisense/*genetics
MH  - Plasmids/*genetics
MH  - RNA, Messenger/analysis
MH  - Rats
MH  - Transfection
MH  - Transforming Growth Factor alpha/*genetics/metabolism
MH  - Tumor Cells, Cultured
EDAT- 1994/08/01 00:00
MHDA- 1994/08/01 00:01
CRDT- 1994/08/01 00:00
PHST- 1994/08/01 00:00 [pubmed]
PHST- 1994/08/01 00:01 [medline]
PHST- 1994/08/01 00:00 [entrez]
PST - ppublish
SO  - Cancer Res. 1994 Aug 1;54(15):4224-32.