Levels of vitamin K, immunoreactive prothrombin, des‐γ‐carboxy prothrombin and γ‐glutamyl carboxylase activity in hepatocellular carcinoma tissue

Abstract

To clarify the mechanism of production of des-gamma-carboxy (abnormal) prothrombin (DCP) by hepatocellular carcinoma (HCC), we measured the levels of vitamin K, DCP, immunoreactive prothrombin and the activity of gamma-glutamyl carboxylase in liver tissues from HCC patients and in the medium of cultured human hepatoma cells. There was no significant difference in vitamin K (K1, MK-4) contents between HCC and non-HCC cirrhotic liver tissues. The activity of gamma-glutamyl carboxylase per unit amount of endogenous microsomal prothrombin precursor was decreased in HCC tissue compared with non-HCC liver tissue (positive plasma DCP: 335 +/- 72 vs 372 +/- 67, negative plasma DCP: 370 +/- 84 vs 393 +/- 56 nmol/min per mg prothrombin precursor, P > 0.05), although the total incorporation of 14COOH into microsomal precursor protein was higher in the former. By contrast, levels of DCP and immunoreactive prothrombin in HCC tissue were greater (P < 0.05) than those in non-HCC cirrhotic liver tissue. Furthermore, production of large amounts of immunoreactive prothrombin was observed in human hepatoma cells huH-1 and huH-2, which produced large amounts of DCP. These results suggest that there was excessive synthesis of prothrombin precursors by human HCC tissue and hepatoma cell lines huH-1 and huH-2. Thus, excessive synthesis of prothrombin precursors seems to be the main mechanism of DCP production by HCC.

PIVKA-II Is the Best Prognostic Predictor in Patients with Hepatocellular Carcinoma after Radiofrequency Ablation Therapy

“…Therefore, a deficiency of vitamin K or a decrease in g-glutamyl carboxylase activity results in the secretion into the blood of immature prothrombin that lacks g-carboxyglutamic acid residues, PIVKA-II. It has been reported that the vitamin K levels in HCC tissue are significantly lower than in the surrounding tissue, although this remains controversial [27, 28]. Several authors reported a role for vitamin K in controlling cell growth, and vitamin K analogues cause cell growth inhibition in hepatoma cell lines [29, 30].…”

Serum levels of des-?-carboxy prothrombin measured using the revised enzyme immunoassay kit with increased sensitivity in relation to clinicopathologic features of solitary hepatocellular carcinoma

“…21,29 The production of DCP is specific to HCC, 9,21 and DCP has been established as a useful tumor marker for HCC with very high specificity.…”

Vitamin K Contents in Liver Tissue of Hepatocellular Carcinoma Patients

“…20,21) But details of the mechanism are not known. Huisse et al, 17) Ono et al, 18) and Yamagata et al 19) reported vitamin K contents in hepatocellular carcinoma. Huisse et al measured PK and MK contents (sum of MK-4-MK-10) in the cancerous and the noncancerous tissues of 10 patients with hepatocellular carcinoma and in the normal liver tissues of 10 patients with metastatic carcinoma of the liver, and reported that MK contents in the cancerous tissues of hepatocellular carcinoma patients are significantly more decreased than in the noncancerous tissues of hepatocellular carcinoma patients or the normal liver tissues of metastatic liver carcinoma patients.…”

“…The mechanism causing the elevation of serum PIVKA-II levels in hepatocellular carcinoma patients is proposed to be as follows; (1) vitamin K deficiency in local cancerous tissue due to an abnormal vitamin K uptake of hepatic cancer cells [17][18][19] ; (2) excessive production of a prothrombin precursor (PIVKA) in hepatic cancer cells [18][19][20] ; (3) decline of γ-glutamylcarboxylase activity in hepatic cancer cells 20) ; (4) decline of the ability to use vitamin K due to oxidation-reduction cycle abnormality in hepatic cancer cells; or (5) prothrombin gene abnormality in hepatic cancer cells. 20,21) But details of the mechanism are not known.…”