Abstract | OBJECTIVE: SUMMARY BACKGROUND DATA:
Transforming growth factor-beta ( TGF-beta) is part of a superfamily of peptide-signaling molecules that play an important role in modulating cell growth. It is secreted as a latent complex and therefore, must be activated to elicit a biological response. Bioactivation of the TGF-beta complex is facilitated by binding to the M6-P/IGF-IIr. Once activated, TGF-beta exerts its effects by binding to specific cell membrane TGF-beta receptors. The loss of responsiveness of hepatocytes to TGF-beta has been implicated in hepatocarcinogenesis and could result from a loss in the expression of either the TGF-beta receptors or the M6-P/IGF-IIr. METHODS: Human hepatocellular carcinomas and surrounding normal tissue were collected from operating room samples and snap-frozen in liquid nitrogen (n = 13). Tissues from two tumors were fixed in Omni-fix for sectioning and immunohistochemistry staining for the M6-P/IGF-IIr and TGF-beta 1. RNA was extracted from both normal and malignant liver tissue and analyzed using an RNase protection assay. SDS-PAGE of purified membrane hybridized with 125I-TGF-beta 1 and 125I-IGF-II was used to determine the TGF-beta type I (TGF-betarI) and type II ( TGF-beta rII) receptors and M6-P/IGF-IIr protein levels, respectively. Gels were quantitated by phosphorimager, and a paired t test was used for statistical analysis. RESULTS: In HCC, a 60% (p < 0.01) and 49% (p < 0.02) reduction in the mRNA levels for T beta rI and T beta rII, respectively, relative to the receptor levels in surrounding normal liver, was shown. A similar decrease in the receptor protein levels also was observed. The M6-P/IGF-IIr mRNA and protein levels were reduced in 7 of 11 hepatocellular carcinomas. Immunohistochemical staining demonstrated an absence of intracellular TGF-beta 1 and reduced M6-P/IGF-IIr in the hepatocellular carcinoma cells. CONCLUSIONS: These results demonstrate that human HCCs have a significantly reduced expression of both the TGF-beta rI- and TGF-beta rII-signaling receptors for TGF-beta. This may provide a selective growth advantage to the HCC by allowing them to escape the mito-inhibitory effects of activated TGF-beta. Furthermore, in the subset of HCC in which the expression of the M6-P/IGF-IIr is downregulated, the bioactivation of TGF-beta also may be impaired.
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Authors | S R Sue, R S Chari, F M Kong, J J Mills, R L Fine, R L Jirtle, W C Meyers |
Journal | Annals of surgery
(Ann Surg)
Vol. 222
Issue 2
Pg. 171-8
(Aug 1995)
ISSN: 0003-4932 [Print] United States |
PMID | 7639583
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)
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Chemical References |
- RNA, Messenger
- Receptor, IGF Type 2
- Receptors, Transforming Growth Factor beta
- Sodium Dodecyl Sulfate
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Topics |
- Adult
- Aged
- Aged, 80 and over
- Carcinoma, Hepatocellular
(genetics, metabolism, pathology)
- Down-Regulation
- Electrophoresis, Polyacrylamide Gel
- Female
- Gene Expression Regulation, Neoplastic
- Humans
- Liver
(metabolism)
- Liver Neoplasms
(genetics, metabolism, pathology)
- Male
- Middle Aged
- RNA, Messenger
(analysis, genetics)
- Receptor, IGF Type 2
(genetics, metabolism)
- Receptors, Transforming Growth Factor beta
(genetics, metabolism)
- Sodium Dodecyl Sulfate
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