Transforming Growth Factor-Beta Receptors and Mannose 6-Phosphate/Insulin-Like Growth Factor-II Receptor Expression in Human Hepatocellular Carcinoma

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ObjectiveThe authors examined the expression of transforming growth factor-beta receptor (TGF-βr) types I and II and the mannose 6-phosphate/insulin-like growth factor-II receptor (M6-P/IGF-IIr) in human hepatocellular carcinoma (HCC).Summary Background DataTransforming growth factor-beta (TGF-β) 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. Bioactivaton of the TGF-β complex is facilitated by binding to the M6-P/IGF-IIr. Once activated, TGF-β exerts its effects by binding to specific cell membrane TGF-β receptors. The loss of responsiveness of hepatocytes to TGF-β has been implicated in hepatocarcinogenesis and could result from a loss in the expression of either the TGF-β receptors or the M6-P/IGF-IIr.MethodsHuman 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-β1. 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-IGF-β1 and 125I-IGF-II was used to determine the TGF-β type I (TGF-βrl) and type II (TGF-βrll) receptors and M6-P/IGF-IIr protein levels, respectively. Gels were quantitated by phosphorimager, and a paired t test was used for statistical analysis.ResultsIn HCC, a 60% (p < 0.01) and 49% (p < 0.02) reduction in the mRNA levels for Tβrl and Tβrll, 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

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