Transforming growth factor-beta receptors and mannose 6-phosphate/insulin-like growth factor-II receptor expression in human hepatocellular carcinoma.

The authors examined the expression of transforming growth factor-beta receptor (TGF-beta r) types I and II and the mannose 6-phosphate/insulin-like growth factor-II receptor (M6-P/IGF-IIr) in human hepatocellular carcinoma (HCC).
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.
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.
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.
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.
AuthorsS R Sue, R S Chari, F M Kong, J J Mills, R L Fine, R L Jirtle, W C Meyers
JournalAnnals of surgery (Ann Surg) Vol. 222 Issue 2 Pg. 171-8 (Aug 1995) ISSN: 0003-4932 [Print] UNITED STATES
PMID7639583 (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.)
Chemical References
  • RNA, Messenger
  • Receptor, IGF Type 2
  • Receptors, Transforming Growth Factor beta
  • Sodium Dodecyl Sulfate
  • 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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