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


BACKGROUND
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.
Sue
S R
SR
Department of Surgery, Duke University, Durham, North Carolina, USA.
Chari
R S
RS
Kong
F M
FM
Mills
J J
JJ
Fine
R L
RL
Jirtle
R L
RL
Meyers
W C
WC
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015536:Down-Regulation; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008099:Liver / Q000378:metabolism; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D017527:Receptor, IGF Type 2 / Q000235:genetics* / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism; D012967:Sodium Dodecyl Sulfate
D012333:RNA, Messenger; D017527:Receptor, IGF Type 2; D018125:Receptors, Transforming Growth Factor beta; D012967:Sodium Dodecyl Sulfate