Expression, regulation and clinical significance of bone morphogenetic protein 6 in esophageal squamous-cell carcinoma.
Bone morphogenetic proteins (BMPs) are multifunctional cytokines. BMP-6 is involved in early steps of keratinogenesis. Esophageal squamous-cell carcinoma often shows abnormal keratinization. The aim of this study was to examine the expression and regulation of BMP-6 in esophageal carcinoma and to determine the relationship of its expression with tumor characteristics and survival. Avidin-biotin-peroxidase staining was performed using paraffin-wax-embedded tumor specimens collected from 172 patients with esophageal squamous-cell carcinoma, who underwent potentially curative surgery. Expression of BMP-6 and EGF-receptor in the esophageal-squamous-cell-carcinoma cell line COLO-680N and the hypopharyngeal-squamous-cell-carcinoma cell line FaDu was assayed with specific RT-PCR. In standard cell-cultivation conditions, COLO-680N and FaDu cells showed distinct expression of BMP-6, whereas in serum-free conditions BMP-6 expression was hardly detectable. The addition of EGF or EGF-related growth factors could elevate BMP-6 mRNA content. Immunohistochemically, all 172 tumors exhibited cytoplasmic immunoreactivity for BMP-6. The content of BMP-6 protein was inversely correlated with tumor differentiation (p < 0.01). Univariate survival analysis revealed that 74 patients with tumors of low immunoreactivity had higher 2-year and 5-year survival rates (50.0%/27.7%) than 75 patients with tumors of high immunoreactive scores (33.3%/21.6%). (p < 0.05). We conclude that BMP-6 is expressed in esophageal squamous-cell carcinoma. EGF-receptor activation is crucial for regulation of BMP-6 expression. BMP-6 protein content is correlated with the grade of tumor-cell differentiation and may add to indications of poor prognosis.
Raida
M
M
Department of Internal Medicine II, Friedrich-Schiller-Universität Jena, Jena, Germany. raida@polkim.med.uni-jena.de
Sarbia
M
M
Clement
J H
JH
Adam
S
S
Gabbert
H E
HE
Höffken
K
K
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D055418:Bone Morphogenetic Protein 6; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D016895:Culture Media, Serum-Free; D066246:ErbB Receptors / Q000378:metabolism; D004938:Esophageal Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D004947:Esophagus / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007012:Hypopharyngeal Neoplasms / Q000378:metabolism; D007150:Immunohistochemistry; D015603:Keratinocytes / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D013997:Time Factors; D014407:Tumor Cells, Cultured
C525816:BMP6 protein, human; D055418:Bone Morphogenetic Protein 6; D019485:Bone Morphogenetic Proteins; D016895:Culture Media, Serum-Free; D066246:ErbB Receptors