TRANSFORMING GROWTH-FACTOR-BETA RECEPTORS AND MANNOSE 6-PHOSPHATE INSULIN-LIKE GROWTH FACTOR-II RECEPTOR EXPRESSION IN HUMAN HEPATOCELLULAR-CARCINOMA

被引:87
作者
SUE, SR
CHARI, RS
KONG, FM
MILLS, JJ
FINE, RL
JIRTLE, RL
MEYERS, WC
机构
[1] DUKE UNIV, MED CTR, DEPT SURG, DURHAM, NC 27710 USA
[2] DUKE UNIV, MED CTR, DEPT HEMATOL ONCOL, DURHAM, NC 27710 USA
[3] DUKE UNIV, MED CTR, DEPT RADIAT ONCOL, DURHAM, NC 27710 USA
[4] VET ADM MED CTR, DURHAM, NC USA
关键词
D O I
10.1097/00000658-199508000-00009
中图分类号
R61 [外科手术学];
学科分类号
摘要
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). 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 I-125-TGF-beta(1) and I-125-IGF-II was used to determine the TGF-beta type I (TGF-beta rI) 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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页码:171 / 178
页数:8
相关论文
共 49 条
[1]   TRANSFORMING GROWTH FACTOR-BETA IN THE CONTROL OF EPIDERMAL PROLIFERATION [J].
BARNARD, JA ;
BASCOM, CC ;
LYONS, RM ;
SIPES, NJ ;
MOSES, HL .
AMERICAN JOURNAL OF THE MEDICAL SCIENCES, 1988, 296 (03) :159-163
[2]  
BASSING C, 1994, VITAM HORM, V46, P111
[3]   A TRANSFORMING GROWTH-FACTOR-BETA TYPE-I RECEPTOR THAT SIGNALS TO ACTIVATE GENE-EXPRESSION [J].
BASSING, CH ;
YINGLING, JM ;
HOWE, DJ ;
WANG, TW ;
HE, WW ;
GUSTAFSON, ML ;
SHAH, P ;
DONAHOE, PK ;
WANG, XF .
SCIENCE, 1994, 263 (5143) :87-89
[4]   TRANSFORMING GROWTH FACTOR-BETA-1 IS PRESENT AT SITES OF EXTRACELLULAR-MATRIX GENE-EXPRESSION IN HUMAN PULMONARY FIBROSIS [J].
BROEKELMANN, TJ ;
LIMPER, AH ;
COLBY, TV ;
MCDONALD, JA .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1991, 88 (15) :6642-6646
[5]  
CARR BI, 1986, CANCER RES, V46, P2330
[6]   TRANSFORMING GROWTH FACTOR-BETA-1 AND FACTOR-ALPHA IN CHRONIC LIVER-DISEASE - EFFECTS OF INTERFERON ALFA THERAPY [J].
CASTILLA, A ;
PRIETO, J ;
FAUSTO, N .
NEW ENGLAND JOURNAL OF MEDICINE, 1991, 324 (14) :933-940
[7]  
CHOMCZYNSKI P, 1987, ANAL BIOCHEM, V162, P156, DOI 10.1016/0003-2697(87)90021-2
[8]   CORRELATION OF FIBROSIS AND TRANSFORMING GROWTH FACTOR-BETA TYPE-2 LEVELS IN THE EYE [J].
CONNOR, TB ;
ROBERTS, AB ;
SPORN, MB ;
DANIELPOUR, D ;
DART, LL ;
MICHELS, RG ;
DEBUSTROS, S ;
ENGER, C ;
KATO, H ;
LANSING, M ;
HAYASHI, H ;
GLASER, BM .
JOURNAL OF CLINICAL INVESTIGATION, 1989, 83 (05) :1661-1666
[9]  
DAHMS NM, 1989, J BIOL CHEM, V264, P12115
[10]   CELLULAR ACTIVATION OF LATENT TRANSFORMING GROWTH-FACTOR-BETA REQUIRES BINDING TO THE CATION-INDEPENDENT MANNOSE 6-PHOSPHATE INSULIN-LIKE GROWTH-FACTOR TYPE-II RECEPTOR [J].
DENNIS, PA ;
RIFKIN, DB .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1991, 88 (02) :580-584