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Expression of group II phospholipase A2 in malignant and nonmalignant human hepatocytes
International Congress Series 1255 (2003) 367 – 373
Expression of group II phospholipase A2 in malignant and nonmalignant human hepatocytes S. Ohshima a, H. Egami a,*, H. Ohmachi a, R. Yao a, T. Kurizaki a, H. Kiyohara a, K. Sakamoto a, Y. Ishimaru b, M. Ogawa a a
Department of Surgery II, Kumamoto University Medical School, Honjo 1-1-1, Kumamoto 860-8556, Japan b Department of Surgical Pathology, Kumamoto University Medical School, Kumamoto, Japan
Abstract Using a monoclonal antibody (MoAb) against human group II PLA2, we investigated the expression of human group II PLA2 in hepatocytes from adults, and hepatocellular carcinoma (HCC) and hepatoblastoma cells. The immunoreactivity of group II PLA2 was found only in a limited number of hepatocytes from adults. In HCC, however, immunoreactivity was found in 15 of 25 cases (60.0%) and 14 of 16 moderately differentiated HCC expressed group II PLA2. In contrast, immunoreactivity was observed in only one of eight poorly differentiated HCC, and no immunoreactivity was detected in one undifferentiated HCC and six hepatoblastomas. The incidence of the expression of this enzyme was significantly higher in trabecular-type HCC than in compacttype HCC. Moreover, expression of group II PLA2 was higher in the infiltrative tumor than in an expansive tumor. A high incidence was found in the tumor with larger amounts of interstitial tissue and 2/2 scirrhous-type HCC expressed this enzyme. Our observations suggest that hepatocytes in the adult liver have the potential to produce group II PLA2, and that expression of this enzyme is positively related to differentiation of the hepatocyte. The possibility was discussed that the expression of this enzyme may be involved in the differentiation, cancer cell invasion and proliferation of interstitial tissue of the HCC. D 2003 Elsevier B.V. All rights reserved. Keywords: Group II PLA2; Liver; HCC; Immunohistochemistry
1. Introduction The viperid/crotalid-type PLA2 (group II PLA2) is present in the cytosol and membrane-associated fraction and is recognized as membrane associated [1]. Though * Corresponding author. Tel.: +81-96-373-5212; fax: +81-96-371-4378. E-mail address: [email protected] (H. Egami). 0531-5131/03 D 2003 Elsevier B.V. All rights reserved. doi:10.1016/S0531-5131(03)00915-4
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group II PLA2 is thought to play an important regulatory role in several metabolic pathways, the biological function of the secretory type is not clear. An RIA for human group II PLA2 using a murine monoclonal antibody (MoAb) has been developed, and it has been found that the serum immunoreactivity of this enzyme was elevated in patients with surgical trauma [2]. The kinetics of serum immunoreactivity in these patients was similar to the hepatic acute phase reactants [2]. These findings prompt us to clarify whether nonmalignant and malignant hepatocytes express group II PLA2. To clarify the biological significance and function of group II PLA2, the immunohistochemical expression of group II PLA2 in hepatocytes from adults and the fetus, and hepatocellular carcinoma (HCC) and hepatoblastoma cells was examined.
2. Materials and methods 2.1. Tissues Tissues of normal adult liver were obtained at the time of surgical biopsy and liver tissues were obtained from 23- to 25-week-old fetuses from necropsy specimens. Uninvolved liver tissues in the specimens resected for malignant liver tumors were also studied. A total of 25 tissues of HCC and six of hepatoblastoma were obtained from surgical biopsy. There were 19 male and 6 female patients with HCC and ages ranged from 16 to 78 years (average age: 59.6 years). 2.2. Immunohistochemistry The immunohistochemistry was performed by the ABC method using the monoclonal antihuman group II PLA2 antibody (IgG) raised in mice for first antibody. The sections were counter-stained with Mayer’s hematoxylin. The negative control was prepared as follows: (1) sections were processed without primary antibody, and (2) nonspecific mouse IgG were used instead of first antibody. 2.3. Histological findings of HCC The histological type, the type of structure and the growth pattern of the tumor were determined based on the general rules for the clinical and pathological study of primary liver cancer by the Liver Cancer Study Group of Japan. The histological types of HCC can vary within the same tumor. Usually, one tumor contains multiple sites with different differentiation. Therefore, the histological type of the tumor was defined according to the predominant histological finding in each case. Among 25 HCC examined in this study, 16 were moderately differentiated, 8 poorly differentiated and 1 undifferentiated carcinoma. Six cases of hepatoblastoma were also studied. The type of structure was categorized into four groups as follows: (1) trabecular: tumor cells grow in cords of variable thickness separated by prominent sinusoids lined with flat endothelial cells; (2) pseudoglandular: tumors have a variety of gland-like structures; (3) compact: this is basically a trabecular pattern but the tumor cells grow
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in apparently solid masses, and sinusoids are rendered inconspicuous by compression; and (4) scirrhous: tumors have areas with abundant fibrous stroma separating cords of tumor cells. The growth pattern of the tumor was classified into two groups as
Fig. 1. (A) Immunohistochemical expression of group II PLA2 in normal hepatocytes. A limited number of hepatocytes in the area adjacent to the central vein expressed group II PLA2 in a cytoplasmic granular pattern ( 25). (B) Strong expression of group II PLA2 in normal hepatocytes adjacent to HCC. HCC also expressed group II PLA2 ( 16).
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follows: (1) expansive: tumor shows expansive growth, and (2) infiltrative: tumor shows infiltrative growth. The amount of interstitial tissue in the tumor was classified into two group as follows: (1) medullary: tumor with scant stroma, and (2) fibrous: tumor with rich fibrous stroma. 2.4. Statistical analysis Statistical comparison was made using the v2 test; a p < 0.05 value was considered to be statistically significant.
3. Results 3.1. Immunohistochemical expression of group II PLA2 3.1.1. Normal liver In the adult liver, immunohistochemical expression of group II PLA2 was observed in a limited number of hepatocytes and Kupffer cells adjacent to the central vein. The pattern of the staining was a cytoplasmic granular one (Fig. 1A). Kupffer cells were also immunoreactive in a cytoplasmic glanular pattern. In most cases, the strong expression of group II PLA2 was detected in hepatocytes in the area adjacent to the cancer, in particular, adjacent to the fibrous capsule of the tumor (Fig. 1B). On the other hand, immunoreactivity of group II PLA2 in the liver of the fetus was absent. These results suggest that the potential to produce this enzyme may be related to the maturation of hepatocytes. 3.1.2. Hepatocellular carcinomas and hepatoblastomas The expression of group II PLA2 was observed in 15 out of 25 cases of HCC (60.0%). The relationship between the expression of group II PLA2 and histologic types of liver cancers is shown in Table 1. The expression of this enzyme was found in 14 out of 16 (87.5%) cases of moderately differentiated carcinoma (Fig. 2A). The immunoreactivity was observed in only one of eight (12.5%) cases of poorly differentiated carcinoma. No Table 1 Relationship between group II PLA2 expression and histological type of hepatocellular carcinoma and hepatoblastoma Group II PLA2 expression ( Hepatocellular carcinoma Differentiation Moderately differentiated Poorly differentiated Undifferentiated Hepatoblastoma * p < 0.05.
2 7 1 6
)
(+)
Incidence (%)
p value
14 1 0 0
14/16 1/8 0/1 0/6
* *
(87.5) (12.5) (0.0) (0.0)
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Fig. 2. (A) Immunohistochemical expression of group II PLA2 in a moderately differentiated HCC. Expression was found in a cytoplasmic granular pattern ( 50). (B) Immunohistochemical expression of group II PLA2 in a scirrhous-type HCC ( 50).
immunoreactivity was found in one case of undifferentiated carcinoma and in six cases of hepatoblastoma. Table 2 shows the relationship between the expression and other histological findings of HCC. The immunohistochemical expression was observed in 10 out of 14 (71.4%) trabecullar-type HCCs, one (100%) pseudoglandular-type HCC and two
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Table 2 Relationship between group II PLA2 expression and histological findings in hepatocellular carcinoma Group II PLA2 expression (
(+)
Incidence (%)
p value
4 0 6
10 1 2
10/14 (71.4) 1/1 (100.0) 2/8 (25.0)
*
Growth pattern Expansive Infiltrative
5 5
3 12
3/8 (37.5) 12/17 (70.6)
** **
Amount of interstitial tissue Medullary Fibrous
6 4
5 10
5/11 (45.5) 10/14 (71.4)
** **
Structure Trabecular Pseudoglandular Compact Scirrhous
)
*
* p < 0.05. ** N.S.
out of two (100%) scirrhous-type HCCs (Fig. 2B). In contrast, the expression was found in only two out of eight (25.0%) compact-type carcinomas. The incidence of expression was higher in infiltrative HCC than in expansive HCC. The expression of this enzyme was also higher in the tumor with a larger amount of interstitial tissue.
4. Discussion We previously reported that group II PLA2 was widely distributed in human digestive organs [3]. In the present study, we found that group II PLA2 was expressed in hepatocytes and Kupffer cells in the liver of adults. In contrast, there was no expression in the fetal liver. These results suggest that the potential to produce this enzyme may be related to the maturation of hepatocytes. Even in the adult liver, expression of this enzyme was found only in a limited number of hepatocytes in normal tissues. In separate investigations, we noted that elevation of serum immunoreactive group II PLA2 was seen after elective surgery for various sites, and that the peak serum group II PLA2 after surgery significantly correlated with the peak serum IL-6 [4], which is known to play the principle role in the induction of hepatic acute phase reactants [4]. Moreover, the induction of group II PLA2 expression in hepatoma cells (HepG2) was demonstrated by IL-6 and other cytokines [5]. From these observations, group II PLA2 is thought to be a hepatic acute phase reactant. In relation to this, we revealed strong expression of group II PLA2 in hepatocytes in the area adjacent to the cancer. Since many cancer cell lines produce cytokines such as IL-6, this expression in hepatocytes is suggested to be a result of stimulations such as cytokines produced by cancer cells [6]. The present study also revealed the higher incidence of group II PLA2 expression in infiltrative-type HCC and in the tumors with larger amounts of interstitial tissue. In
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addition, all scirrhous types of cancer expressed group II PLA2. Recently, we reported similar observation of the expression of group II PLA2 in human pancreatic cancer, the expression of group II PLA2 being significantly increased in relation to the amount of interstitial tissue of the tumor [7]. Originally, PLA2 was thought to be a rate-limiting enzyme in the biosynthesis of prostaglandins [8] and some types of fibroblast proliferate in response to prostaglandins [9,10]. Therefore, the observations in this study suggest that prostaglandin induced by group II PLA2 activation may stimulate the growth of interstitial tissue. Moreover, we previously found that human group II PLA2 also stimulated DNA synthesis of murine fibroblast [11]. Although the biological function of group II PLA2 is unknown, group II PLA2 may be involved in the proliferation of interstitial tissues of HCC by its own function or through the PGS production, since the present results indicate a possibility that group II PLA2 possess of the function(s) which is previously unrecognized. The observations in this study suggest that hepatocytes in the adult liver have the potential to produce group II PLA2, and that expression of this enzyme is positively related to differentiation of the hepatocyte. The expression of this enzyme might be involved in the differentiation, cancer cell invasion and proliferation of interstitial tissue of the HCC.
References [1] M. Ogawa, S. Yamashita, K. Sakamoto, S. Ikei, Elevation of group II phospholipase A2 in patients with cancers of digestive organs, Res. Commun. Chem. Pathol. Pharmacol. 74 (1991) 241 – 244. [2] M. Ogawa, H. Arakawa, S. Yamashita, K. Sakamoto, S. Ikei, Postoperative elevation of serum interleukin 6 and group II phospholipase A2: group II phospholipase A2 in serum is an acute phase reactant, Res. Commun. Chem. Pathol. Pharmacol. 75 (1992) 109 – 115. [3] H. Kiyohara, H. Egami, Y. Shibata, K. Murata, S. Ohshima, M. Ogawa, Light microscopic immunohistochemical analysis of the distribution of group II phospholipase A2 in human digestive organs, J. Histochem. Cytochem. 40 (1992) 1659 – 1664. [4] J. Gauldie, C. Richards, D. Harnish, Interferon 2/B-cell stimulatory factor type 2 shares identity with monocyte-derived hepatocyte-stimulating factor and regulates the major acute phase protein response in liver cells, Proc. Natl. Acad. Sci. U. S. A. 84 (1987) 7251 – 7255. [5] R.M. Crowl, T.J. Stoller, R.R. Cmonroy, Induction of phospholipase A2 gene expression in human hepatoma cells by mediators of the acute phase response, J. Biol. Chem. 266 (1991) 2647 – 2651. [6] M. Ogawa, H. Arakawa, S. Yamashita, K. Sakamoto, S. Ikei, Postoperative elevation of serum interleukin 6 and group II phospholipase A2: group II phospholipase A2 in serum is an acute phase reactant, Res. Commun. Chem. Pathol. Pharmacol. 75 (1992) 109 – 115. [7] H. Kiyohara, H. Egami, H. Kako, Y. Shibata, K. Murata, S. Ohshima, K. Sei, S. Suko, R. Kurano, M. Ogawa, Immunohistochemical localization of group II phospholipase A2 in human pancreatic carcinomas, Int. J. Pancreatol. 13 (1993) 49 – 57. [8] H. Van den Bosch, Intracellular phospholipase A2, Biochim. Biophys. Acta 604 (1980) 191 – 246. [9] E. Rozengurt, K.L.M. Collins, M. Keehan, Mitogenic effect of prostaglandin E1 in Swiss 3T3 cells: role of cyclic AMP, J. Cell. Physiol. 116 (1983) 379 – 384. [10] D.R. Nolan, M.R. Danilowicz, E.T. Eling, Role of arachidonic acid metabolism in the mitogenic response of BALB/c 3T3 fibroblasts to epidermal growth factor, Mol. Pharmacol. 33 (1988) 650 – 656. [11] T. Kurizaki, H. Egami, K. Murata, H. Kiyohara, N. Yoshida, M. Ogawa, Membrane-associated phospholipase A2 stimulates DNA synthesis in two murine fibroblasts, Res. Commun. Chem. Pathol. Pharmacol. 78 (1992) 39 – 45.
Expression of group II phospholipase A2 in malignant and nonmalignant human hepatocytes S. Ohshima a, H. Egami a,*, H. Ohmachi a, R. Yao a, T. Kurizaki a, H. Kiyohara a, K. Sakamoto a, Y. Ishimaru b, M. Ogawa a a
Department of Surgery II, Kumamoto University Medical School, Honjo 1-1-1, Kumamoto 860-8556, Japan b Department of Surgical Pathology, Kumamoto University Medical School, Kumamoto, Japan
Abstract Using a monoclonal antibody (MoAb) against human group II PLA2, we investigated the expression of human group II PLA2 in hepatocytes from adults, and hepatocellular carcinoma (HCC) and hepatoblastoma cells. The immunoreactivity of group II PLA2 was found only in a limited number of hepatocytes from adults. In HCC, however, immunoreactivity was found in 15 of 25 cases (60.0%) and 14 of 16 moderately differentiated HCC expressed group II PLA2. In contrast, immunoreactivity was observed in only one of eight poorly differentiated HCC, and no immunoreactivity was detected in one undifferentiated HCC and six hepatoblastomas. The incidence of the expression of this enzyme was significantly higher in trabecular-type HCC than in compacttype HCC. Moreover, expression of group II PLA2 was higher in the infiltrative tumor than in an expansive tumor. A high incidence was found in the tumor with larger amounts of interstitial tissue and 2/2 scirrhous-type HCC expressed this enzyme. Our observations suggest that hepatocytes in the adult liver have the potential to produce group II PLA2, and that expression of this enzyme is positively related to differentiation of the hepatocyte. The possibility was discussed that the expression of this enzyme may be involved in the differentiation, cancer cell invasion and proliferation of interstitial tissue of the HCC. D 2003 Elsevier B.V. All rights reserved. Keywords: Group II PLA2; Liver; HCC; Immunohistochemistry
1. Introduction The viperid/crotalid-type PLA2 (group II PLA2) is present in the cytosol and membrane-associated fraction and is recognized as membrane associated [1]. Though * Corresponding author. Tel.: +81-96-373-5212; fax: +81-96-371-4378. E-mail address: [email protected] (H. Egami). 0531-5131/03 D 2003 Elsevier B.V. All rights reserved. doi:10.1016/S0531-5131(03)00915-4
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group II PLA2 is thought to play an important regulatory role in several metabolic pathways, the biological function of the secretory type is not clear. An RIA for human group II PLA2 using a murine monoclonal antibody (MoAb) has been developed, and it has been found that the serum immunoreactivity of this enzyme was elevated in patients with surgical trauma [2]. The kinetics of serum immunoreactivity in these patients was similar to the hepatic acute phase reactants [2]. These findings prompt us to clarify whether nonmalignant and malignant hepatocytes express group II PLA2. To clarify the biological significance and function of group II PLA2, the immunohistochemical expression of group II PLA2 in hepatocytes from adults and the fetus, and hepatocellular carcinoma (HCC) and hepatoblastoma cells was examined.
2. Materials and methods 2.1. Tissues Tissues of normal adult liver were obtained at the time of surgical biopsy and liver tissues were obtained from 23- to 25-week-old fetuses from necropsy specimens. Uninvolved liver tissues in the specimens resected for malignant liver tumors were also studied. A total of 25 tissues of HCC and six of hepatoblastoma were obtained from surgical biopsy. There were 19 male and 6 female patients with HCC and ages ranged from 16 to 78 years (average age: 59.6 years). 2.2. Immunohistochemistry The immunohistochemistry was performed by the ABC method using the monoclonal antihuman group II PLA2 antibody (IgG) raised in mice for first antibody. The sections were counter-stained with Mayer’s hematoxylin. The negative control was prepared as follows: (1) sections were processed without primary antibody, and (2) nonspecific mouse IgG were used instead of first antibody. 2.3. Histological findings of HCC The histological type, the type of structure and the growth pattern of the tumor were determined based on the general rules for the clinical and pathological study of primary liver cancer by the Liver Cancer Study Group of Japan. The histological types of HCC can vary within the same tumor. Usually, one tumor contains multiple sites with different differentiation. Therefore, the histological type of the tumor was defined according to the predominant histological finding in each case. Among 25 HCC examined in this study, 16 were moderately differentiated, 8 poorly differentiated and 1 undifferentiated carcinoma. Six cases of hepatoblastoma were also studied. The type of structure was categorized into four groups as follows: (1) trabecular: tumor cells grow in cords of variable thickness separated by prominent sinusoids lined with flat endothelial cells; (2) pseudoglandular: tumors have a variety of gland-like structures; (3) compact: this is basically a trabecular pattern but the tumor cells grow
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in apparently solid masses, and sinusoids are rendered inconspicuous by compression; and (4) scirrhous: tumors have areas with abundant fibrous stroma separating cords of tumor cells. The growth pattern of the tumor was classified into two groups as
Fig. 1. (A) Immunohistochemical expression of group II PLA2 in normal hepatocytes. A limited number of hepatocytes in the area adjacent to the central vein expressed group II PLA2 in a cytoplasmic granular pattern ( 25). (B) Strong expression of group II PLA2 in normal hepatocytes adjacent to HCC. HCC also expressed group II PLA2 ( 16).
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follows: (1) expansive: tumor shows expansive growth, and (2) infiltrative: tumor shows infiltrative growth. The amount of interstitial tissue in the tumor was classified into two group as follows: (1) medullary: tumor with scant stroma, and (2) fibrous: tumor with rich fibrous stroma. 2.4. Statistical analysis Statistical comparison was made using the v2 test; a p < 0.05 value was considered to be statistically significant.
3. Results 3.1. Immunohistochemical expression of group II PLA2 3.1.1. Normal liver In the adult liver, immunohistochemical expression of group II PLA2 was observed in a limited number of hepatocytes and Kupffer cells adjacent to the central vein. The pattern of the staining was a cytoplasmic granular one (Fig. 1A). Kupffer cells were also immunoreactive in a cytoplasmic glanular pattern. In most cases, the strong expression of group II PLA2 was detected in hepatocytes in the area adjacent to the cancer, in particular, adjacent to the fibrous capsule of the tumor (Fig. 1B). On the other hand, immunoreactivity of group II PLA2 in the liver of the fetus was absent. These results suggest that the potential to produce this enzyme may be related to the maturation of hepatocytes. 3.1.2. Hepatocellular carcinomas and hepatoblastomas The expression of group II PLA2 was observed in 15 out of 25 cases of HCC (60.0%). The relationship between the expression of group II PLA2 and histologic types of liver cancers is shown in Table 1. The expression of this enzyme was found in 14 out of 16 (87.5%) cases of moderately differentiated carcinoma (Fig. 2A). The immunoreactivity was observed in only one of eight (12.5%) cases of poorly differentiated carcinoma. No Table 1 Relationship between group II PLA2 expression and histological type of hepatocellular carcinoma and hepatoblastoma Group II PLA2 expression ( Hepatocellular carcinoma Differentiation Moderately differentiated Poorly differentiated Undifferentiated Hepatoblastoma * p < 0.05.
2 7 1 6
)
(+)
Incidence (%)
p value
14 1 0 0
14/16 1/8 0/1 0/6
* *
(87.5) (12.5) (0.0) (0.0)
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Fig. 2. (A) Immunohistochemical expression of group II PLA2 in a moderately differentiated HCC. Expression was found in a cytoplasmic granular pattern ( 50). (B) Immunohistochemical expression of group II PLA2 in a scirrhous-type HCC ( 50).
immunoreactivity was found in one case of undifferentiated carcinoma and in six cases of hepatoblastoma. Table 2 shows the relationship between the expression and other histological findings of HCC. The immunohistochemical expression was observed in 10 out of 14 (71.4%) trabecullar-type HCCs, one (100%) pseudoglandular-type HCC and two
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Table 2 Relationship between group II PLA2 expression and histological findings in hepatocellular carcinoma Group II PLA2 expression (
(+)
Incidence (%)
p value
4 0 6
10 1 2
10/14 (71.4) 1/1 (100.0) 2/8 (25.0)
*
Growth pattern Expansive Infiltrative
5 5
3 12
3/8 (37.5) 12/17 (70.6)
** **
Amount of interstitial tissue Medullary Fibrous
6 4
5 10
5/11 (45.5) 10/14 (71.4)
** **
Structure Trabecular Pseudoglandular Compact Scirrhous
)
*
* p < 0.05. ** N.S.
out of two (100%) scirrhous-type HCCs (Fig. 2B). In contrast, the expression was found in only two out of eight (25.0%) compact-type carcinomas. The incidence of expression was higher in infiltrative HCC than in expansive HCC. The expression of this enzyme was also higher in the tumor with a larger amount of interstitial tissue.
4. Discussion We previously reported that group II PLA2 was widely distributed in human digestive organs [3]. In the present study, we found that group II PLA2 was expressed in hepatocytes and Kupffer cells in the liver of adults. In contrast, there was no expression in the fetal liver. These results suggest that the potential to produce this enzyme may be related to the maturation of hepatocytes. Even in the adult liver, expression of this enzyme was found only in a limited number of hepatocytes in normal tissues. In separate investigations, we noted that elevation of serum immunoreactive group II PLA2 was seen after elective surgery for various sites, and that the peak serum group II PLA2 after surgery significantly correlated with the peak serum IL-6 [4], which is known to play the principle role in the induction of hepatic acute phase reactants [4]. Moreover, the induction of group II PLA2 expression in hepatoma cells (HepG2) was demonstrated by IL-6 and other cytokines [5]. From these observations, group II PLA2 is thought to be a hepatic acute phase reactant. In relation to this, we revealed strong expression of group II PLA2 in hepatocytes in the area adjacent to the cancer. Since many cancer cell lines produce cytokines such as IL-6, this expression in hepatocytes is suggested to be a result of stimulations such as cytokines produced by cancer cells [6]. The present study also revealed the higher incidence of group II PLA2 expression in infiltrative-type HCC and in the tumors with larger amounts of interstitial tissue. In
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addition, all scirrhous types of cancer expressed group II PLA2. Recently, we reported similar observation of the expression of group II PLA2 in human pancreatic cancer, the expression of group II PLA2 being significantly increased in relation to the amount of interstitial tissue of the tumor [7]. Originally, PLA2 was thought to be a rate-limiting enzyme in the biosynthesis of prostaglandins [8] and some types of fibroblast proliferate in response to prostaglandins [9,10]. Therefore, the observations in this study suggest that prostaglandin induced by group II PLA2 activation may stimulate the growth of interstitial tissue. Moreover, we previously found that human group II PLA2 also stimulated DNA synthesis of murine fibroblast [11]. Although the biological function of group II PLA2 is unknown, group II PLA2 may be involved in the proliferation of interstitial tissues of HCC by its own function or through the PGS production, since the present results indicate a possibility that group II PLA2 possess of the function(s) which is previously unrecognized. The observations in this study suggest that hepatocytes in the adult liver have the potential to produce group II PLA2, and that expression of this enzyme is positively related to differentiation of the hepatocyte. The expression of this enzyme might be involved in the differentiation, cancer cell invasion and proliferation of interstitial tissue of the HCC.
References [1] M. Ogawa, S. Yamashita, K. Sakamoto, S. Ikei, Elevation of group II phospholipase A2 in patients with cancers of digestive organs, Res. Commun. Chem. Pathol. Pharmacol. 74 (1991) 241 – 244. [2] M. Ogawa, H. Arakawa, S. Yamashita, K. Sakamoto, S. Ikei, Postoperative elevation of serum interleukin 6 and group II phospholipase A2: group II phospholipase A2 in serum is an acute phase reactant, Res. Commun. Chem. Pathol. Pharmacol. 75 (1992) 109 – 115. [3] H. Kiyohara, H. Egami, Y. Shibata, K. Murata, S. Ohshima, M. Ogawa, Light microscopic immunohistochemical analysis of the distribution of group II phospholipase A2 in human digestive organs, J. Histochem. Cytochem. 40 (1992) 1659 – 1664. [4] J. Gauldie, C. Richards, D. Harnish, Interferon 2/B-cell stimulatory factor type 2 shares identity with monocyte-derived hepatocyte-stimulating factor and regulates the major acute phase protein response in liver cells, Proc. Natl. Acad. Sci. U. S. A. 84 (1987) 7251 – 7255. [5] R.M. Crowl, T.J. Stoller, R.R. Cmonroy, Induction of phospholipase A2 gene expression in human hepatoma cells by mediators of the acute phase response, J. Biol. Chem. 266 (1991) 2647 – 2651. [6] M. Ogawa, H. Arakawa, S. Yamashita, K. Sakamoto, S. Ikei, Postoperative elevation of serum interleukin 6 and group II phospholipase A2: group II phospholipase A2 in serum is an acute phase reactant, Res. Commun. Chem. Pathol. Pharmacol. 75 (1992) 109 – 115. [7] H. Kiyohara, H. Egami, H. Kako, Y. Shibata, K. Murata, S. Ohshima, K. Sei, S. Suko, R. Kurano, M. Ogawa, Immunohistochemical localization of group II phospholipase A2 in human pancreatic carcinomas, Int. J. Pancreatol. 13 (1993) 49 – 57. [8] H. Van den Bosch, Intracellular phospholipase A2, Biochim. Biophys. Acta 604 (1980) 191 – 246. [9] E. Rozengurt, K.L.M. Collins, M. Keehan, Mitogenic effect of prostaglandin E1 in Swiss 3T3 cells: role of cyclic AMP, J. Cell. Physiol. 116 (1983) 379 – 384. [10] D.R. Nolan, M.R. Danilowicz, E.T. Eling, Role of arachidonic acid metabolism in the mitogenic response of BALB/c 3T3 fibroblasts to epidermal growth factor, Mol. Pharmacol. 33 (1988) 650 – 656. [11] T. Kurizaki, H. Egami, K. Murata, H. Kiyohara, N. Yoshida, M. Ogawa, Membrane-associated phospholipase A2 stimulates DNA synthesis in two murine fibroblasts, Res. Commun. Chem. Pathol. Pharmacol. 78 (1992) 39 – 45.