Mechanism of the abnormal vitamin K-dependent gamma-carboxylation process in human hepatocellular carcinomas.

Abstract

BACKGROUND:

An important marker for hepatocellular carcinoma is the presence of des-gamma-carboxy (abnormal) prothrombin. However, the molecular basis for the reduced carboxylation of prothrombin is unknown.

METHODS:

Two groups of patients were defined according to the absence (Group I, n = 7) or presence (Group II, n = 8) of des-gamma-carboxy prothrombin. The enzymatic activity of gamma-carboxylase and the total microsomal prothrombin concentration were determined in all tumors. The kinetic parameters for the synthetic peptide Phe-Leu-Glu-Glu-Leu (FLEEL) were measured in eight tumors. The gamma-carboxylase mRNA expression was evaluated by Northern blot analysis in 12 of 15 tumors. In addition, the total vitamin K content (K1, K1 epoxide, and menaquinones 4-10) in 10 tumors was investigated by high performance liquid chromatography.

RESULTS:

Concentrations of menaquinones 4-10 were normal in the nontumorous part of the liver but significantly decreased (P = 0.02) in all the tumors (Groups I and II). This decrease was more severe in Group II (P = 0.02). The tumors in Group I had normal or increased gamma-carboxylase activity and increased mRNA expression (P < 0.02) as compared with their nontumorous counterparts. The tumors in Group II were heterogeneous. Five tumors displayed low gamma-carboxylase activity, associated with low mRNA expression in two, whereas two others had high gamma-carboxylase activity and mRNA expression. The concentration of FLEEL at half-maximal velocity was normal in all the tumors examined (Groups I and II), and a relation was found between the level of expression of gamma-carboxylase and the maximal velocity for FLEEL carboxylation in the tumors in Group II (r = 0.98; P < 0.01). The microsomal content of normal prothrombin was within normal limits in all tumors (Groups I and II).

CONCLUSIONS:

Tumor vitamin K content has a critical role in the synthesis of des-gamma-carboxy prothrombin. Furthermore, the gamma-carboxylase defect, which is observed in some secreting tumors, is the result of the defective gene expression of a normal enzyme and not the consequence of the presence of a competitive inhibitor. It is possible that a 75% reduction in gamma-carboxylase gene expression could take a part in the secretion of des-gamma-carboxy prothrombin, but this mechanism is not predominant.

• Authors: M G Huisse, M Leclercq, J Belghiti, J F Flejou, J W Suttie, A Bezeaud, D W Stafford, M C Guillin
• Journal: Cancer (Cancer) Vol. 74 Issue 5 Pg. 1533-41 (Sep 01 1994) ISSN: 0008-543X [Print] United States
• PMID: 7520347 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Biomarkers
• Protein Precursors
• RNA, Neoplasm
• alpha-Fetoproteins
• Vitamin K 2
• Vitamin K
• vitamin K1 oxide
• menatetrenone
• acarboxyprothrombin
• RNA
• Vitamin K 1
• Factor V
• Prothrombin
• Ligases
• Carbon-Carbon Ligases
• glutamyl carboxylase

Topics

• Biomarkers
• Carbon-Carbon Ligases
• Carcinoma, Hepatocellular (blood, genetics, metabolism, pathology)
• Factor V (analysis)
• Gene Expression Regulation, Neoplastic
• Humans
• Ligases (analysis, genetics, metabolism)
• Liver (enzymology, metabolism)
• Liver Neoplasms (blood, genetics, metabolism, pathology)
• Microsomes, Liver (enzymology)
• Protein Precursors (analysis, genetics, metabolism)
• Prothrombin (analysis, genetics, metabolism)
• RNA (analysis, genetics)
• RNA, Neoplasm (analysis, genetics)
• Vitamin K (analogs & derivatives, analysis, metabolism)
• Vitamin K 1 (analogs & derivatives, analysis)
• Vitamin K 2 (analogs & derivatives)
• alpha-Fetoproteins (analysis)