[Show abstract][Hide abstract] ABSTRACT: Polycomb-group proteins Bmi1 and EZH2 are involved in the malignant transformation and biological aggressiveness of several human carcinomas. We herein examined the significance of the Bmi1 and EZH2 expression in hepatocellular carcinoma (HCC) and its preneoplastic lesions, dysplastic nodules. The expression of Bmi1 and EZH2 were examined immunohistochemically in HCC (n=27) and dysplastic nodules (n=14), and combined hepatocellular and cholangiocarcinoma (HC-CC) (n=14). The effect of Bmi1 and EZH2 knockdown was examined in cultured HCC cells (HuH7 and HepG2) using siRNA. It was determined that Bmi1 was constantly expressed in cholangiocytes, but not in hepatocytes, and EZH2 was detected in neither cholangiocytes nor hepatocytes. Bmi1 and EZH2 were overexpressed in HCC and more extensively in HC-CC (P<0.01). Interestingly, Bmi1 and EZH2 were not overexpressed in the dysplastic nodules. The expression of Bmi1 and EZH2 was heterogeneous and associated with vascular infiltration, the histological grades, and the cell proliferation activity in HCC and HC-CC. In cultured carcinoma cells overexpressing Bmi1 and EZH2, knockdown of Bmi1 and EZH2 resulted in decreased cell proliferation activities. Therefore, the overexpression of polycomb-group proteins Bmi1 and EZH2 is associated with the malignant progression of HCC, thereby reflecting the aggressive biological behavior in HCC and HC-CC.
[Show abstract][Hide abstract] ABSTRACT: Aim: In cases of idiopathic portal hypertension (IPH), the deposition of elastic fibers in the major portal vein branches and peripheral portal tracts is a common and characteristic histological finding, which may be related to the disease's pathogenesis. This study aimed to clarify the mechanism of this portal fibroelastosis.
Methods: The expression of fibulin-5 and fibrillin-1, proteins essential for elastogenesis, was examined in IPH livers (n = 15) using immunohistochemistry. Liver specimens obtained from patients with chronic viral hepatitis (CVH)/liver cirrhosis (LC) (n = 12) and normal/subnormal livers (n = 10) were used as controls.
Results: In IPH livers, immunohistochemical labeling of fibulin-5 was observed in the major portal vein branches in eight cases (53%), and the distribution corresponded to that of elastic fibers in the vessel walls, while the peripheral portaltracts totally lacked fibulin-5 in spite of the presence of dense elastic fibers. In CVH/LC and normal livers, fibulin-5 expression was absent or faint throughout the sections. Fibrillin-1 was detected in the connective tissue of the hilar region and peripheral portal tracts in IPH, CVH/LC and normal livers, with the expression varying greatly among cases.
Conclusions: These results suggest that fibulin-5, rather than fibrillin-1, expressed in the major portal vein branches of IPH livers is related to phlebosclerosis, leading to an increase in presinusoidal vascular resistance and portal hypertension. In addition, the mechanism of fibroelastosis may differ between the major portal vein branches and peripheral portal tracts of IPH livers.
Hepatology Research 03/2008; 38(2):166-73. DOI:10.1111/j.1872-034X.2007.00253.x · 2.74 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Xanthogranulomatous cholecystitis (XGC) is characterized by the infiltration of numerous foamy macrophages. Bacterial infection is thought to be involved in the pathogenesis of XGC. Using XGC and cultured murine biliary epithelial cells (BEC), the participation of E. coli and the role of the scavenger receptor class A (SCARA), as well as chemokine(C-X-C motif) ligand 16 (CXCL16) and its receptor chemokine(C-X-C motif) receptor 6 (CXCR6), were examined in the pathogenesis of XGC. E. coli components and genes were detected in XGC on immunohistochemistry and polymerase chain reaction (PCR), respectively. SCARA-recognizing E. coli was found in foamy macrophages aggregated in xanthogranulomatous lesions. CXCL16, which functions as a membrane-bound molecule and soluble chemokine to induce adhesion and migration of CXCR6(+) cells, was detected on gallbladder epithelia, and CXCR6(+)/CD8(+) T cells and CXCR6(+)/CD68(+) macrophages were also accumulated. In cultured BEC, CXCL16 mRNA and secreted soluble CXCL16 were constantly detected and upregulated by treatment with E. coli and lipopolysaccharide through Toll-like receptor 4. These suggest that SCARA in macrophages is involved in the phagocytosis of E. coli followed by foamy changes and that bacterial infection causes the upregulation of CXCL16 in gallbladder epithelia, leading to the chemoattraction of macrophages via CXCL16-CXCR6 interaction and formation of the characteristic histology of XGC.
Pathology International 11/2007; 57(10):652-63. DOI:10.1111/j.1440-1827.2007.02154.x · 1.69 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Primary biliary cirrhosis (PBC) is an autoimmune liver disease targeting the intrahepatic small bile ducts showing chronic non-suppurative destructive cholangitis (CNSDC). Recent studies suggest that naturally-occurring CD4+CD25high regulatory T cells (Tregs) expressing Forkhead box P3 (Foxp3) play an active role in immunological self-tolerance.
To investigate whether Foxp3+Tregs are involved in the pathogenesis of PBC.
Foxp3+Tregs was detected immunohistochemically in livers from patients with PBC (n = 27), chronic viral hepatitis (CVH) (n = 15), and normal subjects (n = 10). The distribution of Tregs in portal tracts was semi-quantitatively evaluated in each groups. Levels of Foxp3, IL-10, TGFbeta, IFNgamma and TNFalpha mRNA was evaluated in PBC (n = 15) and control livers (n = 21) using semi-quantitative reverse transcriptase-PCR.
In PBC and CVH livers, the amounts of infiltrating Foxp3+Tregs in portal tracts were in parallel with the degree of portal inflammation irrespective of disease. The infiltration of Foxp3+Tregs into portal tracts with CNSDC in PBC was foremost in comparison with inflamed portal tracts in CVH or those without CNSDC in PBC (p<0.05). Focally, Tregs infiltrated into the biliary epithelial layer at the site of CNSDC. The level of Foxp3, IL-10 and TGFbeta mRNA expression was high in PBC compared with normal livers (p<0.05). IFNgamma and TNFalpha mRNA was high in early PBC and CVH livers.
Results of this evaluation of Foxp3+Tregs do not suggest that the reduced regulatory function accounts for the development of CNSDC in PBC.
[Show abstract][Hide abstract] ABSTRACT: The histogenesis and biological behaviour of peripheral intrahepatic cholangiocarcinoma (peripheral CC) remain unclarified. The aim of this study was to examine the growth pattern of peripheral CC (24 cases) in comparison with hepatocellular carcinoma (HCC, 27 cases) and metastatic colorectal adenocarcinoma (MCA, 24 cases).
Tumour/surrounding liver borders were classified as: (i) fibrous encapsulation, (ii) compressive growth, and (iii) infiltrating replacement. Nineteen of 24 peripheral CCs showed (iii), whereas 23 of 27 HCCs showed (i) and 17 of 24 MCAs showed (ii). In (iii), carcinoma cells infiltrated the surrounding liver without compression, and hepatic supporting vascular structures such as portal tracts were secondarily incorporated into the tumour. In (i) and (ii), the surrounding liver was compressed and no or few portal tracts were incorporated within the tumour. Fifteen of 24 peripheral CCs were composed of carcinoma cells resembling reactive bile ductules and these cells were positive for neural cell adhesion molecule (NCAM), a marker of proliferating bile ductules. The remaining nine peripheral CCs were composed of ordinary adenocarcinoma and negative for NCAM.
A subgroup of peripheral CCs with an infiltrating replacement growth pattern resembles reactive bile ductules and expresses NCAM. 'Bile ductular carcinoma' may be a better term for this subgroup.
[Show abstract][Hide abstract] ABSTRACT: Idiopathic portal hypertension (IPH) is characterized by noncirrhotic portal hypertension due mainly to increased intrahepatic, presinusoidal resistance to portal blood flow. Marked splenomegaly is always seen in IPH. To clarify the pathogenetic significance of splenomegaly, immunohistochemical expression of inducible nitric oxide synthese (iNOS), endothelial NOS (eNOS), and endothelin-1 (ET-1) in spleens from patients with IPH was examined. Sinus lining cells of IPH spleens showed diffuse and strong expression of iNOS and eNOS. Sinus lining cells of spleens from patients with liver cirrhosis (LC) also showed positive signals for iNOS and eNOS, but the staining intensity was significantly weak. ET-1 was detectable in only a few mononuclear leukocytes in the red pulp of both IPH and LC spleens. These results suggest that NO liberated in spleen, rather than ET-1, is responsible for the dilatation of splenic sinuses, leading to splenomegaly, and thereby contributes to portal hypertension in IPH.
[Show abstract][Hide abstract] ABSTRACT: Idiopathic portal hypertension (IPH) is thought to be benign if bleeding gastroesophageal varices can be controlled or prevented. A recent autopsy of a woman with IPH who died of hemorrhagic intestinal infarction related to mesenteric thrombosis prompted the authors to examine the terminal antemortem features and causes of death of IPH.
Autopsy cases registered as IPH from 1986 to 1997 were surveyed in the records of the Annuals of Pathological Autopsy Cases in Japan, with permission from the Japanese Society of Pathology. The records of 65 of these cases were collected and examined pathologically.
It was found that the most frequent cause of death in these cases was (i) bacterial infection (20 cases). The next three causes of death were directly or indirectly related to hepatic disease or its altered portal hemodynamics as follows: (ii) progressive hepatic failure (16 cases); (iii) massive hemorrhage from ruptured gastroesophageal varices (11 cases); and (iv) hemorrhagic intestinal infarction due to mesenteric venous thrombosis (5 cases). Although portal venous thrombosis was closely associated with (iv), (ii) and (iii) seemed not to be associated with portal venous thrombosis. In addition, intracranial hemorrhage and other heterogeneous factors were identified as the cause of death in five cases and eight cases, respectively.
These results suggest that progressive hepatic failure and intestinal hemorrhagic infarction should be considered in addition to rupture of gastroesophageal varices when monitoring patients with IPH. Clinicians should be also aware of severe bacterial infection and intracranial hemorrhage as a fatal complication of IPH.
Journal of Gastroenterology and Hepatology 03/2007; 22(2):204-9. DOI:10.1111/j.1440-1746.2006.04492.x · 3.50 Impact Factor