Des-γ-carboxy Prothrombin Is a Potential Autologous Growth Factor for Hepatocellular Carcinoma

Suzuki, Mayumi; Shiraha, Hidenori; Fujikawa, Tatsuya; Takaoka, Nobuyuki; Ueda, Naonori; Nakanishi, Yoshinobu; Koike, Kazuko; Takaki, Akinobu; Shiratori, Yasushi

doi:10.1074/jbc.m406714200

Cited by 107 publications

(115 citation statements)

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“…Among various types of malignancy, antitumor activity of vitamin K on HCC has intensively been investigated, because lack of vitamin K2 induces elevation of serum levels of des-γ-carboxy prothrombin (DCP), a serum protein that increases at a notably high level in patients with HCC, and DCP was shown to have a mitogenic effect on human HCC cell lines (38). Nishiguchi and colleagues have reported that vitamin K2 had a preventive effect on the development of HCC in women with viral liver cirrhosis (39).…”

Section: Discussionmentioning

confidence: 99%

Vitamins K2, K3 and K5 exert antitumor effects on established colorectal cancer in mice by inducing apoptotic death of tumor cells

Ogawa¹,

Nakai²,

Deguchi³

et al. 2007

Int J Oncol

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Abstract. Although a number of studies have shown that vitamin K possesses antitumor activities on various neoplastic cell lines, there are few reports demonstrating in vivo antitumor effects of vitamin K, and the antitumor effect on colorectal cancer (CRC) remains to be examined. Therefore, antitumor effects of vitamin K on CRC were examined both in vitro and in vivo. Vitamins K2, K3 and K5 suppressed the proliferation of colon 26 cells in a dose-dependent manner, while vitamin K1 did not. On flow cytometry, induction of apoptosis by vitamins K2, K3 and K5 was suggested by population in sub-G1 phase of the cell cycle. Hoechst 33342 staining and a twocolor flow cytometric assay using fluorescein isothiocyanateconjugated annexin V and propidium iodide confirmed that vitamins K2, K3 and K5 induced apoptotic death of colon 26 cells. Enzymatic activity of caspase-3 in colon 26 cells was significantly up-regulated by vitamins K2, K3 and K5. The pan-caspase inhibitor, benzyloxycarbonyl-Val-Ala-Aspfluoromethyl ketone, substantially prevented vitamin Kmediated apoptosis. In vivo study using syngeneic mice with subcutaneously established colon 26 tumors demonstrated that intravenous administration of vitamins K2, K3 and K5 significantly suppressed the tumor growth. The number of apoptotic tumor cells was significantly larger in the vitamin K-treated groups than in the control group. These results suggest that vitamins K2, K3 and K5 exerted effective antitumor effects on CRC in vitro and in vivo by inducing caspasedependent apoptotic death of tumor cells, suggesting that these K vitamins may be promising agents for the treatment of patients with CRC. IntroductionWorldwide, colorectal cancer (CRC) ranks third in cancer incidence after lung and breast, and is a major cause of cancer mortality (1). In 2000, there were 943,000 new cases diagnosed and 510,000 deaths worldwide, corresponding figures for Europe were 363,000 cases and 199,000 deaths (2). Although surgery alone is the standard approach in localized malignancy, approximately 50% of early-stage patients present disease relapse (3). Furthermore, approximately 30% of CRC is diagnosed when it is already at an advanced stage. There are also a considerable number of patients who cannot undergo surgery even at an early stage of the disease due to severe complications, such as chronic heart failure, chronic renal failure and chronic obstructive pulmonary diseases. Fluoropyrimidine-based chemotherapy is now considered the standard treatment for patients with inoperable CRC, but approximately 90% of patients do not respond to chemotherapy based on 5-fluorouracil (5-FU)/folinic acid (4). Thus, the development of new treatment modalities is necessary to improve the overall survival rate of patients with CRC.Vitamin K is an essential vitamin that was discovered as a fat-soluble anti-hemorrhagic agent. Vitamin K is also known as an obligatory cofactor in the post-translational γ-carboxylation of glutamic acid residues (5-8). Vitamin K-dependent proteins include prothrombin (fact...

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Section: Discussionmentioning

confidence: 99%

Vitamins K2, K3 and K5 exert antitumor effects on established colorectal cancer in mice by inducing apoptotic death of tumor cells

Ogawa¹,

Nakai²,

Deguchi³

et al. 2007

Int J Oncol

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“…Since the major physiological function of K vitamins is to act as a cofactor for carboxylation of prothrombin (factor II) and other K vitamin dependent coagulation factors (VII, IX and X) as well as proteins C and S, we considered the possibility that prothrombin itself might have growth regulatory activity. In addition, it was recently shown that DCP has some mild growth stimulatory activity for hepatoma cells in vitro (Suzuki et al, 2005), and therefore we wished to examine whether the fully carboxylated form of prothrombin might also have growth regulatory effects.…”

Section: Discussionmentioning

confidence: 99%

“…As a result, the underlying normal liver produces mature prothrombin, but HCCs within that liver produce under-carboxylated or immature prothrombin, DCP, one of the more useful HCC serum markers (Weitz et al, 1993;Huisse et al, 1994;Liebman et al, 1984;Nakao et al, 1991;Liebman et al, 1989;Li et al, 2002). The biological significance of this has never been clear, but it has recently been suggested that immature prothrombin or DCP has HCC growth promoting properties (Suzuki et al, 2005). This led us to consider that mature prothrombin, a major vitamin K-dependent blood coagulation factor, might also have growth regulatory properties, since K vitamins have previously been shown to have growth inhibitory activities (Yoshida etal., 2003;Otsuka et al, 2004;Lamson and Plaza, 2003;Wang et al, 1995;Nishikawa et al, 1995;Hitomi et al, 2005;Bouzahzah et al, 1995) in addition to their well-described physiological effects as cofactors for several blood coagulation proteins (such as prothrombin and factors VII, IX and X).…”

Section: Introductionmentioning

confidence: 99%

Growth inhibitory actions of prothrombin on normal hepatocytes: Influence of matrix

Carr

Kar

Wang

et al. 2007

Cell Biology International

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Most hepatomas have a defect in prothrombin carboxylation, and can secrete under-carboxylated prothrombin or des-γ-carboxy-prothrombin (DCP), the function of which is unknown. We considered that prothrombin-DCP axis might also be involved in growth control. Hepatocytes and hepatoma cells were treated with prothrombin, and DNA synthesis and cytoskeleton were studied. Prothrombin inhibited DNA synthesis in hepatocytes on fibronectin, but not collagen matrix. Hepatoma cell lines were not inhibited. We found that hepatoma cell matrix conferred resistance to hepatocytes. Prothrombin decreased fibronectin but not collagen amounts, but only in the presence of hepatocytes and not hepatoma cells, indicating that it has a differential action on matrix proteins. It also caused changes in cell shape and actin depolymerization. In vivo, there was a decrease in plasma prothrombin activity after a partial hepatectomy (PH) concomitant with a peak of DNA synthesis by the hepatocyte at 24 h after PH. Injection of warfarin at the time of PH, further inhibited PT activity and enhanced this 24 h peak of DNA synthesis. Furthermore, repeated injection of prothrombin lowered the peak DNA synthesis after PH. The data support the hypothesis that prothrombin can act as a hepatocyte growth inhibitor, likely at the level of fibronectin loss and result in cytoskeletal changes. Hepatomas resist this action, possibly due to their different matrix proteins. This represents a novel mechanism for growth regulation and provides a possible biological significance for the tumor marker DCP.

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“…Suzuki et al [38] reported that DCP exerts a mitogenic effect on hepatocellular carcinoma cells via a Met-Janus kinase 1-STAT3 signaling pathway. On the other hand, it has been demonstrated that the antiproliferative effect of vitamin K on hepatic carcinoma is not due to a depressed production of DCP, but rather caused by protein kinase A [39] .…”

Section: Discussionmentioning

confidence: 99%

Des-gamma-carboxy prothrombin as an important prognostic indicator in patients with small hepatocellular carcinoma

Hakamada

Kimura²,

Miura³

et al. 2008

WJG

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tumor recurrence. Because many patients with a high preoperative DCP level develop extrahepatic recurrence, it is necessary to screen the whole body. INTRODUCTIONDes-gamma-carboxy prothrombin (DCP) is a tumor marker specific for hepatocellular carcinoma [1] . It is believed that the elevation of the serum DCP level correlates with the presence of vascular invasion or intrahepatic metastases [2][3][4][5][6][7][8] . Furthermore, DCP has been reported to be an independent prognostic factor for recurrence and survival after hepatic resection [4,[9][10][11][12][13] , liver transplantation [6,14] , ablation treatment [15][16][17] , and transarterial chemoembolization (TAE) treatment [18] . However, the rate of detectable serum DCP levels in patients with small hepatocellular carcinoma is low [19][20][21][22][23][24] . Although methods have been improved [25,26] , sensitivity is still at about 50% for most small cell carcinoma [27][28][29][30] . Thus, almost all reports on the biological nature of DCP and its prognostic value are based on analyses of patients with larger or more advanced tumors with various degrees of hepatic functional reserve. Reports on the relevance of preoperative DCP level as a prognostic marker in small hepatocellular carcinoma patients are rare.This study thus aimed analysing the predictive value of preoperative serum DCP level on tumor recurrence and prognosis, particularly in hepatocellular carcinoma patients who had undergone liver resection and who met the criteria for small hepatocellular carcinoma [31] , i.e. a single Abstract AIM: To clarify the effect of a high des-gamma-carboxy prothrombin (DCP) level on the invasiveness and prognosis of small hepatocellular carcinoma. METHODS:Among 142 consecutive patients with known DCP levels, who underwent hepatectomy because of hepatocellular carcinoma, 85 patients met the criteria for small hepatocellular carcinoma, i.e. one ≤ 5 cm sized single tumor or no more than three ≤ 3 cm sized tumors. RESULTS:The overall survival rate of the 142 patients was 92.1% for 1 year, 69.6% for 3 years, and 56.9% for 5 years. Multivariate analysis showed that microscopic vascular invasion (P = 0.03) and serum DCP ≥ 400 mAU/mL (P = 0.02) were independent prognostic factors. In the group of patients who met the criteria for small hepatocellular carcinoma, DCP ≥ 400 mAU/mL was found to be an independent prognostic factor for recurrence-free (P = 0.02) and overall survival (P = 0.0005). In patients who did not meet the criteria, the presence of vascular invasion was an independent factor for recurrence-free (P = 0.02) and overall survivals (P = 0.01). In 75% of patients with small hepatocellular carcinoma and high DCP levels, recurrence occurred extrahepatically. CONCLUSION:For small hepatocellular carcinoma, a high preoperative DCP level appears indicative for

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Des-γ-carboxy Prothrombin Is a Potential Autologous Growth Factor for Hepatocellular Carcinoma

Abstract: Des-␥-carboxyl prothrombin (DCP) is

Cited by 107 publications

References 62 publications

Vitamins K2, K3 and K5 exert antitumor effects on established colorectal cancer in mice by inducing apoptotic death of tumor cells

Vitamins K2, K3 and K5 exert antitumor effects on established colorectal cancer in mice by inducing apoptotic death of tumor cells

Growth inhibitory actions of prothrombin on normal hepatocytes: Influence of matrix

Des-gamma-carboxy prothrombin as an important prognostic indicator in patients with small hepatocellular carcinoma

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