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Papers - KANAI Yae

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The E-cadherin gene is silenced by CpG methylation in human hepatocellular carcinomas.

Kanai Y, Ushijima S, Hui AM, Ochiai A, Tsuda H, Sakamoto M, Hirohashi S.

Int J Cancer (International Journal of Cancer) 71 ( 3 ) 355 - 359 1997

Accepted, ISSN 00207136

Our study was designed to clarify the significance of silencing the E- cadherin gene, which is located on 16q22.1, due to CpG methylation during hepatocarcinogenesis. The CpG methylation status of primary hepatocellular carcinomas (HCCs) and corresponding liver tissues showing chronic hepatitis or cirrhosis, which are widely considered to be precancerous conditions, were assessed by digesting DNA with methylation-sensitive and non-sensitive restriction enzymes. CpG methylation around the promoter region of the E- cadherin gene was detected in 46% of liver tissues showing chronic hepatitis or cirrhosis and 67% of HCCs examined. Immunohistochemical examination revealed reduced E-cadherin expression in 59% of HCCs examined. CpG methylation around the promoter region correlated significantly with reduced E-cadherin expression in HCCs (p < 0.05). CpG methylation around the promoter region, which increases during the progression from a precancerous condition to HCC, may participate in hepatocarcinogenesis through reduction of E- cadherin expression, resulting in loss of intercellular adhesiveness and destruction of tissue morphology.

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Histological prognostic parameters for adenocarcinoma of the pancreatic head. Proposal for scoring system for prediction of outcome.

Nakatsura T, Hasebe T, Tsubono Y, Ryu M, Kinoshita T, Kawano N, Konishi M, Kosuge T, Kanai Y, Mukai, K.

J Hep Bil Pancr Surg, 4 441 - 448 1997

Accepted

Insulin-dependent diabetic mastopathy: a case report.

Kuno T, Fukutomi T, Akashi-Tanaka S, Nanasawa T, Kanai Y, Tsuda H. I

Breast Cancer (Breast Cancer) 4 ( 3 ) 175 - 177 1997

Accepted, ISSN 13406868

We report a case of insulin-dependent diabetic fibrous mastopathy, which clinically simulated breast cancer. The patient is a 55-year-old woman with stony-hard breast lumps, who had been treated with insulin for diabetes mellitus. Mammmography revealed a highly-dense mass shadow in the left breast and ultrasonography detected hypoechoic lesions with acoustic shadows in both breasts, suggestive of malignancy. Excisional biopsy was performed for the left breast lump. On histopathological examination, this was fibrosis with dense lymphocytic infiltration around lobules, which is a characteristic feature of diabetic fibrous mastopathy.

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Intraductal papillary tumors and mucinous cystic tumors of the pancreas: clinicopathologic study of 38 cases.

Fukushima N, Mukai K, Kanai Y, Hasebe T, Shimada K, Ozaki H, Kinoshita T, Kosuge T.

Hum Pathol (Human Pathology) 28 ( 9 ) 1010 - 1017 1997

Accepted, ISSN 00468177

Clinicopathological features of 28 patients with intraductal papillary tumor (IDPT) and 10 patients with mucinous cystic tumor (MCT) of the pancreas were studied. Both IDPT and MCT showed papillary projections of the epithelium with abundant mucus secretion in the ectatic ducts or cystic spaces. The patients with IDPT comprised 19 men and 9 women with a mean age of 64.9 years. Three fourths of the IDPTs were located in the pancreatic head, and the mean tumor size was 9.5 cm. Local recurrence was observed in one patient, but none died of IDPT. In contrasts all patients with MCT were women, with a mean age of 49.4 years. None of the MCTs arose in the head, and the mean tumor size was 7.1 cm. One patient died of MCT, but all of the others survived without recurrence. Eight IDPTs and three MCTs showed invasion into the surrounding pancreatic tissue. Muconodular infiltration was mainly observed in five IDPTs and one MCTs and tubular infiltration in three IDPTs and two MCTs. A characteristic histological finding associated with the muconodular infiltration in IDPT was subepithelial 'mucin droplets' that appeared to represent a change in polarity of mucus secretion. The formation of such subepithelial 'mucin droplets' may he the initial step of muconodular infiltration in IDPT. Muconodular infiltration in IDPT appears different morphologically and biologically from the mucinous carcinoma subtype of conventional invasive ductal carcinorma.

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Metastatic renal cell carcinoma to the gallbladder: color Doppler sonography and CT findings.

Furukawa H, Mizuguchi Y, Kanai Y, Mukai K.

AJR Am J Roentgenol 169 1466 - 1467 1997

Accepted

Arteriovenous hemangioma of the gallbladder: CT and pathologic findings.

Furukawa H, Kanai Y, Mukai K, Yamasaki S.

AJR Am J Roentgenol 168 1383 1997

Accepted

Involvement of the anterior urethra in male patients with transitional cell-carcinoma of the bladder undergoing radical cystectomy with simultaneous urethrectomy.

Tobisu K, Kanai Y, Sakamoto M, Fujimoto H, Doi N, Horie S, Kakizoe T.

Jpn J Clin Oncol (Japanese Journal of Clinical Oncology) 27 ( 6 ) 406 - 409 1997

Accepted, ISSN 03682811

Histological tumor extension into the prostate, urethra and urethra was examined in 52 specimens obtained by cystourethrectomy for transitional cell carcinoma of the bladder with one or more risk factors for urethral involvement. In four (21.1%) of 19 patients with diffuse carcinoma in situ in the bladder extending to the internal urethral orifice and prostatic urethra, the anterior urethra was affected by transitional cell carcinoma, including one specimen with invasion into the corpus spongiosum. However, none of 33 patients without these findings had synchronous anterior urethral transitional cell carcinoma involvement. It is recommended that patients with diffuse carcinoma in situ extending into the prostatic urethra undergo careful preoperative assessment of the anterior urethra before cystectomy. In other cases, the anterior urethra can be preserved and used for orthotopic neobladder replacement.

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Differentiating agent, hexamethylene bisacetamide, inhibits neointimal formation after vascular injury.

Ishikawa S, Hori S, Kusuhara M, Kanai Y, Handa S, Yamaguchi K, Hosoda Y, Ogawa, S.

Coron Artery Dis (Coronary Artery Disease) 8 ( 1 ) 28 - 32 1997

Accepted, ISSN 09546928

Background: Hexamethylene bisacetamide (HMBA), a potent differentiating agent of transformed cell lines, has been reported to affect phenotypic modulation and suppress proliferation of vascular smooth muscle cells (VSMCs). The effects of HMBA on the growth of VSMCs were studied in the rat carotid injury model. Methods: HMBA was added to culture medium of VSMCs explanted from aorta of Sprague Dawley rats and the cell number was counted after 5 days of incubation. The carotid artery of Sprague Dawley rats was denuded with a balloon embolectomy catheter. The rats were treated with continuous infusion of HMBA (1 g/day) or saline for 7 days after injury. Results: HMBA inhibited VSMC proliferation in a dose-dependent manner (at a HMBA concentration of 1-5 mM). Plasma concentration of HMBA during continuous infusion was in the range 0.8-1.0 mM. Immunohistochemistry of proliferating cell nuclear antigan showed that HMBA inhibited VSMC proliferation after vascular injury. Cell number in the intima and neointimal thickening were significantly reduced in HMBA-treated rats at 14 days after injury. Conclusions: Systemic administration of HMBA inhibited VSMC proliferation in the rat carotid injury model.

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Temporal alterations of endothelial-vasodilator functions in lung injury induced by monocrotaline.

Yamaguchi K, Kanai Y, Asano K, Takasugi T, Tanaka T, Yasuoka M, Hosoda Y.

Respir Physiol (Respiration Physiology) 107 ( 1 ) 47 - 58 1997

Accepted, ISSN 00345687

To assess the time course of alterations in pulmonary endothelial vasodilator functions during pathological development of pulmonary hypertension (PH) and right ventricular hypertrophy (RVH), we examined changes in serotonin (5-HT) removal rates and the production of prostacyclin (PGI2) and nitric oxide (NO) in isolated rat lungs harvested at various times after single exposure to monocrotaline (MCT). We assessed the generation of vasodilator substances under conditions of both the absence and the presence of 5-HT in lungs perfused with blood-free solution. Major findings included: (i) remodeling of the pulmonary vasculature associated with RVH evident 14 days after MCT injection; (ii) the capacity for 5-HT removal was suppressed at day 1 and 7 but had been restored by day 14 after MCT exposure; (iii) basal PGI2 production in the absence of 5-HT was augmented at day 1 but had returned to control levels in lungs harvested 7 or 14 days postinjection of MCT; (iv) PGI2 production evoked by 5-HT was suppressed in MCT lungs obtained at all time points examined; (v) basal NO production was suppressed at day 1 but enhanced at day 7 and 14 in MCT lungs; (vi) NO production elicited by 5-HT stimulation in 1-day-MCT lungs was obviously suppressed while that in 7- and 14-day-MCT lungs had been restored to the control level. These findings suggest that transitional changes in endothelial functions including 5-HT removal and production of vasodilators in MCT lungs do not follow the same time course.

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Reduced p21(WAF1/CIP1) expression and p53 mutation in hepatocellular carcinomas.

Hui AM, Kanai Y, Sakamoto M, Tsuda H, Hirohashi S.

Hepatology (Hepatology) 25 ( 3 ) 575 - 579 1997

Accepted, ISSN 02709139

p21(WAF1/CIP1) is a universal cyclin-dependent kinase (cdk) inhibitor, the expression of which is regulated by p53-dependent and p53-independent pathways. We examined p21(WAF1/CIP1) expression in and p53 status of 21 primary hepatocellular carcinomas (HCCs) by reverse-transcriptase polymerase chain reaction (RT-PCR) and by PCR single-strand conformation polymorphism (PCR-SSCP) analysis. p21(WAF1/CIP1) messenger RNA expression was reduced markedly in 8 of 21 HCCs (38.1%) and 5 of these 8 HCCs bore p53 mutations. The relative p21(WAF1/CIP1) messenger RNA expression value of HCCs with p53 mutations (.73 ± .13 U, n = 6) was significantly lower than that of HCCs with wild-type p53 (1.00 ± 0.21 U, n = 14; P < .01). The p21(WAF1/CIP1) expression levels in cancerous tissues (.73 ± .13 U) were significantly reduced in comparison with those in noncancerous tissues (.97 ± .13 U) (P < .01) in the 6 cases with p53 mutations. These data indicate that p21(WAF1/CIP1) expression in HCCs is predominantly regulated by dependence on p53 and that reduced p21(WAF1/CIP1) expression may participate in hepatocarcinogenesis.

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Increased DNA methyltransferase expression is associated with an early stage of human hepatocarcinogenesis.

Sun L, Hui AM, Kanai Y, Sakamoto M, Hirohashi S.

Jpn J Cancer Res (Japanese Journal of Cancer Research) 88 ( 12 ) 1165 - 1170 1997

Accepted, ISSN 09105050

The present study was designed to determine whether changes in DNA methyltransferase (DNA MTase) expression are involved in hepatocarcinogenesis. We examined DNA MTase expression in normal liver tissue (with no remarkable histological findings), liver tissue showing chronic hepatitis or cirrhosis, which are generally thought to be precancerous conditions, and hepatocellular carcinomas (HCCs) using the reverse-transcriptase polymerase chain reaction assay. DNA MTase mRNA levels were significantly higher in liver tissue showing chronic hepatitis and cirrhosis (DNA MTase mRNA/β-actin mRNA ratio = 0.30 ± 0.22, n = 24, P < 0.01) than in normal liver tissue either from patients with liver metastatic lesions of colonic cancer (0.14 ± 0.05, n = 6) or from patients with HCCs (0.16 ± 0.07, n = 3). DNA MTase mRNA levels were even higher in HCC tissue (0.34 ± 0.18, n = 29). These results suggest that increased DNA MTase expression may be an early event during hepatocarcinogenesis. DNA MTase is a potential target for HCC preventive therapy.

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DNA hypermethylation at the D17S5 locus in non-small cell lung cancers: its association with smoking history.

Eguchi K, Kanai Y, Kobayashi K, Hirohashi S.

Cancer Res (Cancer Research) 57 ( 21 ) :4913 - 4915 1997

Accepted, ISSN 00085472

The aim of this study was to examine the association between DNA hypermethylation and clinicopathological features of non-small cell lung cancers (NSCLCs). The DNA methylation status at the D17S5 loci, at which a candidate tumor suppressor gene, HIC-1 (hypermethylated in cancer), was identified, of 51 paired tumor and nontumorous lung tissue specimens from NSCLC patients were examined by Southern blot analysis, using a methylation- sensitive restriction enzyme. DNA hypermethylation at this locus was found in 17 (33%) tumors and 16 (31%) nontumorous lung tissues. DNA in hypermethylation at this locus occurred more frequently in poorly than in well-differentiated tumors, especially in adenocarcinomas, and correlated significantly with the differentiation grade (P = 0.01). DNA hypermethylation at the D17S5 locus correlated significantly with the loss of heterozygosity at this locus in tumors (P = 0.01). The incidence of DNA hypermethylation was significantly higher in smokers than those who had never smoked in both tumors and nontumorous lung tissues (P = 0.03 and P = 0.01, respectively). These results suggest that DNA hypermethylation at the D17S5 locus may play a role in the development of NSCLCs in cigarette smokers.

Histological prognostic parameters for adenocarcinoma of the pancreatic head. Proposal for a scoring system for prediction of outcome

Kanai Y.

Journal of Hepato-Biliary-Pancreatic Surgery (Journal of Hepato-Biliary-Pancreatic Surgery) 4 ( 4 ) 441 - 448 1997

ISSN 09441166

To find new histopathological prognostic parameters for adenocarcinoma of the pancreatic head, 27 of these carcinomas, at stage IV according to the Japan Pancreas Society, which had been curatively resected, were histologically examined. In addition to previously recognized histological prognostic parameters, sections were examined for the following factors: fibrotic focus (FF), direct invasion of the tumor into the lymph node (DILN), and tumor necrosis (TN). Frequency of tumor recurrence or death was higher in patients with any one of the three new factors than in those without any of these factors. To develop an accurate system for predicting the outcome, the presence or absence of each factor and lymphatic permeation was given a score of 1 (present) or 0 (absent), and the total score was than calculated for each patient. All patients with a score of 0 were alive without tumor recurrence, at a mean follow-up of 20 months, whereas all seven patients with a score of 4 had experienced tumor recurrence, and six died subsequently. The results of this study demonstrated that FF, DILN, and TN are good histological parameters of ductal adenocarcinoma of the pancreatic head, and that the scoring system proposed in this paper is useful for prediction of the outcome of the disease. © Springer-Verlag 1997.

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Inactivation of p16(INK4) in hepatocellular carcinoma

Hui A., Sakamoto M., Kanai Y., Ino Y., Gotoh M., Yokota J., Hirohashi S.

Hepatology (Hepatology) 24 ( 3 ) 575 - 579 1996.09

ISSN 02709139

We analyzed the p16(INK4) status of 6 hepatocellular carcinoma (HCC) cell lines and 32 primary HCC tumors, including 9 early-stage tumors, to determine whether p16(INK4) tumor-suppressor gene inactivation participates in hepatocarcinogenesis. p16(INK4) was studied at its protein level through Western blotting, at its messenger RNA (mRNA) level through reverse- transcriptase polymerase chain reaction analysis (RT-PCR) and Northern blotting, and at its genomic level through Southern blotting and PCR-single- strand conformation polymorphism analysis. The p16 protein was absent from 3 of 6 cell lines (50%) and 11 of 32 primary tumors (34%), but present in noncancerous tissues, indicating that p16(INK4) is involved in hepatocarcinogenesis. Furthermore, we suggest that the p16 protein loss may contribute to the following: (1) early-stage hepatocarcinogenesis, because it was observed in 22% of early stage tumors; and (2) tumor progression, because it occurred approximately twice as often in advanced rather than in early stage tumors (40%). It was striking that neither p16(INK4) homozygous deletion and mutation nor loss of p16(INK4) mRNA expression were observed in HCC cell lines and primary tumors, including those specimens from which the p16 protein was absent except the Li7HM cell line, in which p16(INK4) mRNA was not detected. These results suggest that p16(INK4) in HCC is inactivated predominantly by posttranscriptional regulation rather than by genomic aberrations and lack of transcription.

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Aberrant DNA methylation on chromosome 16 is an early event in hepatocarcinogenesis.

Kanai Y, Ushijima S, Tsuda H, Sakamoto M, Sugimura T, Hirohashi S.

Jpn J Cancer Res 87: 1210-1217, 1996. (Japanese Journal of Cancer Research) 87 ( 12 ) 1210 - 1217 1996

Accepted, ISSN 09105050

In order to clarify the significance of DNA methylation in both earlier and later stages of hepatocarcinogenesis, the DNA methylation state on chromosome 16, on which loss of heterozygosity (LOH) has frequently been detected in human hepatocellular carcinomas (HCCs), was examined. DNA from primary HCCs and tissues showing chronic hepatitis and liver cirrhosis, which are considered to be precancerous conditions, was analyzed by digestion with methylation-sensitive and non-sensitive restriction enzymes. DNA hypermethylation at the D16S32, tyrosine aminotransferase (TAT) and D16S7 loci and hypomethylation at the D16S4 locus were detected in 18%, 58%, 20% and 48% of examined HCCs, respectively. Aberrant DNA methylation occurred more frequently in advanced HCCs than in early HCCs. Moreover, DNA hypermethylation at the D16S32, TAT and D16S7 loci was frequently observed in chronic hepatitis and liver cirrhosis. The incidence of DNA hypermethylation was higher than that of LOH (42% at the TAT locus). These data suggest that DNA hypermethylation might predispose the locus to allelic loss. Aberrant DNA methylation is a significant change which may participate in the early developmental stages of HCCs.

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Formation of focal adhesion and spreading of polarized human colon cancer cells in association with tyrosine phosphorylation of paxillin in response to phorbol ester.

Sakamoto M, Ino Y, Ochiai A, Kanai Y, Akimoto S, Hirohashi S.

Lab Invest (Laboratory Investigation) 74 ( 1 ) 199 - 208 1996

ISSN 00236837

Regulation of cell adhesion systems is involved in both normal development and the invasive behavior of carcinomas. We examined alterations of cell morphology and adhesion molecules in response to phorbol ester treatment of the SW1116 colon cancer cell line, which forms well-organized dome-like tubular structures in culture. 12-O-Tetradecanoylphorbol-13 acetate (TPA) induced rapid spreading of cancer-cell colonies through formation of focal adhesion and disappearance of adherens junctions. Immunologic analyses demonstrated that tyrosine-phosphorylated proteins were concentrated at focal adhesions, and that tyrosine phosphorylation of two proteins, paxillin and an unidentified 130-kd protein, was significantly increased. Tyrosine phosphorylation of paxillin was detectable within 15 min after TPA treatment, when only lamellipodia had extended from the colony, and in cells treated with blocking antibodies against integrins β1 and β5, which strongly inhibited spreading and disorganization while preserving adherens junctions. The level of paxillin phosphorylation correlated well with the degree of morphologic change induced by low-dose TPA, and the dephosphorylation occurred before reversion of morphology upon removal of TPA. These findings suggest that the TPA signal was transduced to the tyrosine phosphorylation of paxillin strongly associated with formation of focal adhesion, and that this in turn induced dysfunction of the cadherin system and caused spreading and disorganization of the tubular structure. The mechanism responsible for disruption of the cadherin system at adherens junctions was not clear, but the transition of β-catenin into nuclei corresponded to the disappearance of its signal along areas of cell-cell contact. This SW1116 model provides a good system for studying the molecules involved in transient regulation and crosstalk between the cell-cell and cell-substratum adhesion systems, which may explain the mechanism of invasion of well-differentiated human carcinomas.

Serous cystadenoma of the pancreas communicating with a pancreatic duct.

Furukawa H, Takayasu K, Mukai K, Kanai Y, Kosuge T, Mizuguchi Y, Ushio K.

Int J Pancreatol (International Journal of Pancreatology) 19 ( 2 ) 141 - 144 1996

Accepted, ISSN 01694197

Conclusion: To differentiate serous cystadenoma from other cystic lesions communicating with the pancreatic duct, careful radiological examination is necessary. Background: Communication between the cystic cavity and the pancreatic duct in an ordinary serous cystadenoma is uncommon, although it is not uncommon in other cystic lesions, such as pseudocyst, mucinous cystadenoma/adenocarcinoma, and intraductal papillary tumor. Methods: A serous cystadenoma of the pancreas communicating with main pancreatic duct in a 76-yr-old male is reported. Results: The communication was preoperatively demonstrated by endoscopic retrograde cholangiopancreatography and confirmed by histopathological examination of the resected specimen.

Late contrast-enhanced CT for small pancreatic carcinoma: delayed enhanced area on CT with histopathological correlation.

Furukawa H, Takayasu K, Mukai K, Kanai Y, Inoue K, Kosuge T, Ushio, K.

Hepatogastroenterology (Hepato-Gastroenterology) 43 ( 11 ) 1230 - 1237 1996

Accepted, ISSN 01726390

Purpose: To determine the appearance of pancreatic adenocarcinoma on delayed contrast enhanced computed tomography (CT) and verify the diagnostic significance. Patients and Methods: Twenty-two surgically resected lesions of pancreatic adenocarcinoma were studied with dynamic CT and findings were compared with those on histopathology. Results: Ten 45% of 22 pancreatic adenocarcinoma demonstrated masses on unenhanced CT, while 21 (95%) demonstrated on early contrast-enhanced CT (early CT), and 15 (68%) demonstrated masses on delayed contrast-enhanced CT (late CT). Pancreatic mass was demonstrated as a low-density area on unenhanced and early CT, but mass density varied on late CT. Delayed enhancement of the mass was predominantly observed in small lesions; 3 (75%) of 4 lesions 2 cm or smaller were detected as high-density areas. Histologically, delayed enhanced lesions showed severe or moderate degrees of fibrosis. Conclusion: Late CT is useful for the detection of pancreatic adenocarcinoma with fibrosis as a high-density area, especially in small lesions.

E-cadherin gene mutations in signet ring cell carcinoma of the stomach.

Muta H, Noguchi M, Kanai Y, Ochiai A, Nawata H, Hirohashi S.

Jpn J Cancer Res (Japanese Journal of Cancer Research) 87 ( 8 ) 843 - 848 1996

Accepted, ISSN 09105050

To clarify the significance of E-cadherin gene alterations in the development of diffuse-type adenocarcinoma of the stomach, we analyzed mutations of the E-cadherin gene using the polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP) method followed by direct sequencing. Twenty-two signet ring cell carcinomas of the stomach (10 intramucosal and 12 advanced cancers) were examined. Genomic DNA was extracted separately from cancerous and non-cancerous tissues and PCR-SSCP analysis was performed on exons 5 to 9 and the adjacent 30- to 40 base pair intron sequences of the E-cadherin gene. Mobility shifts were found in 2 of the 10 intramucosal cancers. In 2 of the 12 advanced cancers, abnormalities of the E-cadherin gene were observed in intramucosal lesions as well as in deeply invaded areas. These results indicated that E-cadherin gene mutations are an early event in the development of signet ring cell carcinoma of the stomach. Direct sequencing revealed that the locations of mutations of the E-cadherin gene included the branch point sequence in the intron which is responsible for RNA splicing. Reverse transcriptase-PCR demonstrated aberrant RNA splicing in a case with a branch point mutation, suggesting that branch point mutations play an important role in functional modifications of E-cadherin in signet ring cell carcinoma of the stomach.

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Inactivation of p16INK4 in hepatocellular carcinoma.

Hui AM, Sakamoto M, Kanai Y, Ino Y, Gotoh M, Yokota J, Hirohashi S.

Hepatology 24 575 - 579 1996

Accepted

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