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Papers - KANAI Yae

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Genome-wide DNA methylation profiles in urothelial carcinomas and urothelia at the precancerous stage

Nishiyama, Naotaka, Arai, Eri, Chihara, Yoshitomo, Fujimoto, Hiroyuki, Hosoda, Fumie, Shibata, Tatsuhiro, Kondo, Tadashi, Tsukamoto, Taiji, Yokoi, Sana, Imoto, Issei, Inazawa, Johji, Hirohashi, Setsuo, Kanai, Yae

CANCER SCIENCE (WILEY-BLACKWELL PUBLISHING, INC) 101 ( 1 ) 231 - 240 2010.01

Research paper (scientific journal), ISSN 1347-9032

To clarify genome-wide DNA methylation profiles during multistage urothelial carcinogenesis, bacterial artificial chromosome (BAC) array-based methylated CpG island amplification (BAMCA) was performed in 18 normal urothelia obtained from patients without urothelial carcinomas (UCs) (C), 17 noncancerous urothelia obtained from patients with UCs (N), and 40 UCs. DNA hypo- and hypermethylation on multiple BAC clones was observed even in N compared to C. Principal component analysis revealed progressive DNA methylation alterations from C to N, and to UCs. DNA methylation profiles in N obtained from patients with invasive UCs were inherited by the invasive UCs themselves, that is DNA methylation alterations in N were correlated with the development of more malignant UCs. The combination of DNA methylation status on 83 BAC clones selected by Wilcoxon test was able to completely discriminate N from C, and diagnose N as having a high risk of carcinogenesis, with 100% sensitivity and specificity. The combination of DNA methylation status on 20 BAC clones selected by Wilcoxon test was able to completely discriminate patients who suffered from recurrence after surgery from patients who did not. The combination of DNA methylation status for 11 BAC clones selected by Wilcoxon test was able to completely discriminate patients with UCs of the renal pelvis or ureter who suffered from intravesical metachronous UC development from patients who did not. Genome-wide alterations of DNA methylation may participate in urothelial carcinogenesis from the precancerous stage to UC, and DNA methylation profiling may provide optimal indicators for carcinogenetic risk estimation and prognostication. (Cancer Sci 2009).

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Fibroblast growth factor receptor 3 mutation in voided urine is a useful diagnostic marker and significant indicator of tumor recurrence in non-muscle invasive bladder cancer

Miyake, Makito, Sugano, Kokichi, Sugino, Hitomi, Imai, Kazuho, Matsumoto, Eri, Maeda, Koshi, Fukuzono, Shinich, Ichikawa, Hiroki, Kawashima, Kiyotaka, Hirabayashi, Kaoru, Kodama, Tetsuro, Fujimoto, Hiroyuki, Kakizoe, Tadao, Kanai, Yae, Fujimoto, Kiyohide, Hirao, Yoshihiko

CANCER SCIENCE (WILEY-BLACKWELL PUBLISHING, INC) 101 ( 1 ) 250 - 258 2010.01

Research paper (scientific journal), ISSN 1347-9032

The fibroblast growth factor receptor (FGFR)-3 gene encodes a receptor tyrosine kinase that is frequently mutated in non-muscle invasive bladder cancer (NMIBC). A sensitive and quantitative assay using peptide nucleic acid-mediated real-time PCR was developed for detecting FGFR3 mutations in the urine samples and evaluated as a molecular marker for detecting intravesical recurrence of NMIBC in patients undergoing transurethral resection of bladder tumor. FGFR3 mutation was examined in tumor tissues and serially taken pre- and postoperative urine sediments in 45 NMIBC patients with a median follow up of 32 months. FGFR3 mutations were detected in 53.3% (24/45) of primary tumor tissues, among which intravesical recurrence developed in 37.5% (9/24) of cases. FGFR3 mutation in the primary tumor was not a significant prognostic indicator for recurrence, while the proportion of FGFR3 mutation (i.e. tumor cellularity was >= 11%) in the preoperative urine sediments was a significant indicator for recurrence in patients with FGFR3 mutations in the primary tumors. FGFR3 mutations were detected in 78% (7/9) of postoperative urine samples from recurrent cases with FGFR3 mutations in the tumor, while no mutations were detected in the urine of 15 non-recurrent cases. Urine cytology was negative in all cases with FGFR3 mutations in the primary tumors, while the sensitivity of cytological examination was as high as 56% (5/9) in cases showing wild-type FGFR3 in the primary tumors. Urine FGFR3 mutation assay and cytological examination may be available in the future as complementary diagnostic modalities in postoperative management of NMIBC. (Cancer Sci 2009).

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Genome-wide DNA methylation profiles in precancerous conditions and cancers.

Kanai Y.

Cancer Sci (WILEY-BLACKWELL PUBLISHING, INC) 101 ( 1 ) 36 - 45 2010

Accepted, ISSN 13479032

Alterations of DNA methylation, which result in chromosomal instability and silencing of tumor-related genes, are among the most consistent epigenetic changes observed in human cancers. Analysis of tissue specimens has revealed that DNA methylation alterations participate in multistage carcinogenesis, even from the early and precancerous stages, especially in association with chronic inflammation and/or persistent viral infection, such as chronic hepatitis or liver cirrhosis resulting from infection with hepatitis B or C virus. DNA methylation alterations can account for the histological heterogeneity and clinicopathological diversity of human cancers. Overexpression of DNA methyltransferase 1 is not a secondary result of increased cell proliferative activity, but is significantly correlated with accumulation of DNA hypermethylation in CpG islands of tumor-related genes. Alteration of DNA methyltransferase 3b splicing may result in chromosomal instability through DNA hypomethylation in pericentromeric satellite regions. Genome-wide analysis of DNA methylation status has revealed that the DNA methylation profile at the precancerous stage is basically inherited by the corresponding cancers developing in individual patients. DNA methylation status is not simply altered at the precancerous stage; rather, DNA methylation alterations at the precancerous stage may confer vulnerability to further genetic and epigenetic alterations, generate more malignant cancers, and thus determine patient outcome. Therefore, genome-wide DNA methylation profiling may provide optimal indicators for carcinogenetic risk estimation and prognostication, and thus provide an avenue for cancer prevention and therapy on an individual basis. (Cancer Sci 2009).

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Tumour necrosis is a postoperative prognostic marker for pancreatic cancer patients with a high interobserver reproducibility in histological evaluation.

Hiraoka N, Ino Y, Sekine S, Tsuda H, Shimada K, Kosuge T, Zavada J, Yoshida M, Yamada K, Koyama T, Kanai Y.

Br J Cancer (NATURE PUBLISHING GROUP) 103 ( 7 ) 1057 - 1065 2010

Accepted, ISSN 00070920

BACKGROUND: Tumour necrosis reflects the presence of hypoxia, which can be indicative of an aggressive tumour phenotype. The aim of this study was to investigate whether histological necrosis is a useful predictor of outcome in patients with pancreatic ductal carcinoma (PDC).
METHODS: We reviewed histopathological findings in 348 cases of PDC in comparison with clinicopathological information. We counted small necrotic foci (micronecrosis) as necrosis, in addition to massive necrosis that had been only defined as necrosis in previous studies. The reproducibility of identifying histological parameters was tested by asking five independent observers to blindly review 51 examples of PDC.
RESULTS: Both micronecrosis and massive necrosis corresponded to hypoxic foci expressing carbonic anhydrase IX detected by immunohistochemistry. Multivariate survival analysis showed that histological necrosis was an independent predictor of poor outcome in terms of both disease-free survival (DFS) and disease-specific survival (DSS) of PDC patients. In addition, metastatic status, and lymphatic, venous, and intrapancreatic neural invasion were independent prognostic factors for shorter DFS and metastatic status, margin status, lymphatic invasion, and intrapancreatic neural invasion were independent prognostic factors for DSS. The interobserver reproducibility of necrosis identification among the five independent observers was 'almost perfect' (kappa-value of 0.87).
CONCLUSION: Histological necrosis is a simple, accurate, and reproducible predictor of postoperative outcome in PDC patients. British Journal of Cancer (2010) 103, 1057-1065. doi:10.1038/sj.bjc.6605854 www.bjcancer.com Published online 24 August 2010 (C) 2010 Cancer Research UK

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Genome-wide DNA methylation profiles in liver tissue at the precancerous stage and in hepatocellular carcinoma

Arai, Eri, Ushijima, Saori, Gotoh, Masahiro, Ojima, Hidenori, Kosuge, Tomoo, Hosoda, Fumie, Shibata, Tatsuhiro, Kondo, Tadashi, Yokoi, Sana, Imoto, Issei, Inazawa, Johji, Hirohashi, Setsuo, Kanai, Yae

INTERNATIONAL JOURNAL OF CANCER (WILEY-LISS) 125 ( 12 ) 2854 - 2862 2009.12

Research paper (scientific journal), ISSN 0020-7136

To clarify genome-wide DNA methylation profiles during hepatocarcinogenesis, bacterial artificial chromosome (BAC) array-based methylated CpG island amplification was performed on 126 tissue samples. The average numbers of BAC clones showing DNA hypo- or hypermethylation increased from noncancerous liver tissue obtained from patients with hepatocellular carcinomas (HCCs) (N) to HCCs. N appeared to be at the precancerous stage, showing DNA methylation alterations that were correlated with the future development of HCC. Using Wilcoxon test, 25 BAC clones, whose DNA methylation status was inherited by HCCs from N and were able to discriminate 15 N samples from 10 samples of normal liver tissue obtained from patients without HCCs (C) with 100% sensitivity and specificity, were identified. The criteria using the 25 BAC clones were able to discriminate 24 additional N samples from 26 C samples in the validation set with 95.8% sensitivity and 96.2% specificity. Using Wilcoxon test, 41 BAC clones, whose DNA methylation status was able to discriminate patients who survived more than 4 years after hepatectomy from patients who suffered recurrence within 6 months and died within a year after hepatectomy, were identified. The DNA methylation status of the 41 BAC clones was correlated with the cancer-free and overall survival rates of patients with HCC. Multivariate analysis revealed that satisfying the criteria using the 41 BAC clones was an independent predictor of overall outcome. Genome-wide alterations of DNA methylation may participate in hepatocarcinogenesis from the precancerous stage, and DNA methylation profiling may provide optimal indicators for carcinogenetic risk estimation and prognostication. (C) 2009 UICC

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Dicer is required for proper liver zonation

Sekine, Shigeki, Ogawa, Reiko, Mcmanus, Michael T., Kanai, Yae, Hebrok, Matthias

JOURNAL OF PATHOLOGY (JOHN WILEY & SONS LTD) 219 ( 3 ) 365 - 372 2009.11

Research paper (scientific journal), ISSN 0022-3417

A number of genes and their protein products are expressed within the liver lobules in a region-specific manner and confer heterogeneous metabolic properties to hepatocytes; this phenomenon is known as 'metabolic zonation'. To elucidate the roles of Dicer, an endoribonuclease III type enzyme required for microRNA biogenesis, in the establishment of liver zonation, we examined the distribution of proteins exhibiting pericentral or periportal localization in hepatocyte-specific Dicer1 knockout mouse livers. Immunohistochemistry showed that the localization of pericentral proteins was mostly preserved in Dicer1-deficient livers. However, glutamine synthetase, whose expression is normally confined to a few layers of hepatocytes surrounding the central veins, was expressed in broader pericentral areas. Even more striking was the observation that all the periportal proteins that were examined, including phosphoenolpyruvate carboxykinase, E-cadherin, arginase 1, and carbamoyl phosphate synthetase-I, lost their localized expression patterns and were diffusely expressed throughout the entire lobule. Thus, with regard to periportal protein expression, the consequences of Dicer loss were similar to those caused by the disruption of beta-catenin. An analysis of livers deficient in beta-catenin did not identify the down-regulation of Dicer1 or any microRNAs, indicating that they are not directly activated by beta-catenin. Thus, the present study illustrates that Dicer plays a pivotal role in the establishment of liver zonation. Dicer is essential for the suppression of periportal proteins by Wnt/beta-catenin/TCF signalling, albeit it likely acts in an indirect manner. Copyright (C) 2009 Pathological Society of Great Britain and Ireland. Published by lolin Wiley & Sons, Ltd.

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Characteristics of prostate cancers found in specimens removed by radical cystoprostatectomy for bladder cancer and their relationship with serum prostate-specific antigen level

Nakagawa, Tohru, Kanai, Yae, Komiyama, Motokiyo, Fujimoto, Hiroyuki, Kakizoe, Tadao

CANCER SCIENCE (WILEY-BLACKWELL PUBLISHING, INC) 100 ( 10 ) 1880 - 1884 2009.10

Research paper (scientific journal), ISSN 1347-9032

Prostate cancer mass screening using serum prostate-specific antigen (PSA) has been conducted widely in the world. However, little is known about the true prevalence of prostate cancer in the 'normal' PSA range (4.0 ng/mL or less). The aim of the present study was to elucidate the clinicopathological features of prostate cancer occurring in men with a wide range of PSA levels. The study comprised 349 male patients who underwent radical cystoprostatectomy for bladder cancer. Patients who had had treatment for known prostate cancer were excluded. Tissue specimens were reviewed microscopically. Ninety-one patients (26.1%) were found to have prostate cancer, and 68 (74.7%) of these 91 cancers were considered to be clinically significant. Both increasing patient age and PSA level were significantly correlated with an increased incidence of both all and significant prostate cancers. Sixty-five (21.9%) among 297 patients with PSA < 4.0 ng/mL had prostate cancer, and 45 (69.2%) of the 65 cancers were significant cancers. Eighteen patients had prostate cancers 0.5 mL or more in volume. Among the 18 patients, the PSA level was 4 ng/mL or more in 11, and 3 ng/mL or more in 15. Our study shows that prostate cancer is a common finding in radical cystoprostatectomy specimens excised because of bladder cancers, and a significant proportion of these cancers are clinically significant. PSA still appears to be a useful screening tool for detecting prostate cancers with significant volume. (Cancer Sci 2009; 100: 1880-1884).

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Quantitative proteomics using formalin-fixed paraffin-embedded tissues of oral squamous cell carcinoma

Negishi, Ayako, Masuda, Mari, Ono, Masaya, Honda, Kazufumi, Shitashige, Miki, Satow, Reiko, Sakuma, Tomohiro, Kuwabara, Hideya, Nakanishi, Yukihiro, Kanai, Yae, Omura, Ken, Hirohashi, Setsuo, Yamada, Tesshi

CANCER SCIENCE (WILEY-BLACKWELL PUBLISHING, INC) 100 ( 9 ) 1605 - 1611 2009.09

Research paper (scientific journal), ISSN 1347-9032

Clinical proteomics using a large archive of formalin-fixed paraffin-embedded (FFPE) tissue blocks has long been a challenge. Recently, a method for extracting proteins from FFPE tissue in the form of tryptic peptides was developed. Here we report the application of a highly sensitive mass spectrometry (MS)-based quantitative proteome method to a small amount of samples obtained by laser microdissection from FFPE tissues. Cancerous and adjacent normal epithelia were microdissected from FFPE tissue blocks of 10 squamous cell carcinomas of the tongue. Proteins were extracted in the form of tryptic peptides and analyzed by 2-dimensional image-converted analysis of liquid chromatography and mass spectrometry (2DICAL), a label-free quantitative proteomics method developed in our laboratory. From a total of 25 018 peaks we selected 72 mass peaks whose expression differed significantly between cancer and normal tissues (P < 0.001, paired t-test). The expression of transglutaminase 3 (TGM3) was significantly down-regulated in cancer and correlated with loss of histological differentiation. Hypermethylation of TGM3 gene CpG islands was observed in 12 oral squamous cell carcinoma (OSCC) cell lines with reduced TGM3 expression. These results suggest that epigenetic silencing of TGM3 plays certain roles in the process of oral carcinogenesis. The method for quantitative proteomic analysis of FFPE tissue described here offers new opportunities to identify disease-specific biomarkers and therapeutic targets using widely available archival samples with corresponding detailed pathological and clinical records. (Cancer Sci 2009; 100: 1605-1611).

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Prognostic Significance of CXCL12 Expression in Patients With Colorectal Carcinoma

Akishima-Fukasawa, Yuri, Nakanishi, Yukihiro, Ino, Yoshinori, Moriya, Yoshihiro, Kanai, Yae, Hirohashi, Setsuo

AMERICAN JOURNAL OF CLINICAL PATHOLOGY (AMER SOC CLINICAL PATHOLOGY) 132 ( 2 ) 202 - 210 2009.08

Research paper (scientific journal), ISSN 0002-9173

The present study investigated the protein expression level of CXCL12 in colorectal cancer and aimed to elucidate its association with prognosis. CXCL 12 positivity in 50% or more of tumor cells was defined as high expression and that in less than 50% of the tumor cells as low expression. CXCL12+ tumor budding at the invasive from was divided into 2 grades: high with 10 or more budding foci per x 200 field of view and low grade with fewer than 10 budding foci. Patients with high expression (72.7%) and high grade CXCL12+ tumor budding (43.0%) had significantly shorter survival than patients with low expression (P = .014) and low grade (P = .003), respectively. Patients with a combination of high expression and high grade had the worst outcome (P < .001). Our study demonstrated that CXCL12 expression in colorectal cancer cells and at sites of budding were significant prognostic factors. Furthermore, together with lymph node metastasis, a combination of both expression patterns was a more powerful independent prognostic factor.

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Disruption of Dicer1 Induces Dysregulated Fetal Gene Expression and Promotes Hepatocarcinogenesis

Sekine, Shigeki, Ogawa, Reiko, Ito, Rie, Hiraoka, Nobuyoshi, McManus, Michael T., Kanai, Yae, Hebrok, Matthias

GASTROENTEROLOGY (W B SAUNDERS CO-ELSEVIER INC) 136 ( 7 ) 2304 - 2315 2009.06

Research paper (scientific journal), ISSN 0016-5085

Background & Aims: Growing evidence suggests that microRNAs coordinate various biological processes in the liver. We describe experiments to address the physiologic roles of these new regulators of gene expression in the liver that are as of yet largely undefined. Methods: We disrupted Dicer, an enzyme essential for the processing of microRNAs, in hepatocytes using a conditional knockout mouse model to elucidate the consequences of loss of microRNAs. Results: The conditional knockout mouse livers showed the efficient disruption of Dicer1 at 3 weeks after birth. This resulted in prominent steatosis and the depletion of glycogen storage. Dicer1-deficient liver exhibited increased growth-promoting gene expression and the robust expression of fetal stage-specific genes. The consequence of Dicer elimination included both increased hepatocyte proliferation and overwhelming apoptosis. Over time, Dicer1-expressing wild-type hepatocytes that had escaped Cre-mediated recombination progressively repopulated the entire liver. Unexpectedly, however, two thirds of the mutant mice spontaneously developed hepatocellular carcinomas derived from residual Dicer1-deficient hepatocytes at 1 year of age. Conclusions: Dicer and microRNAs have critical roles in hepatocyte survival, metabolism, developmental gene regulation, and tumor suppression in the liver. Loss of Dicer primarily impairs hepatocyte survival but can promote hepatocarcinogenesis in cooperation with additional oncogenic stimuli.

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Esophageal melanomas harbor frequent NRAS mutations unlike melanomas of other mucosal sites

Sekine, Shigeki, Nakanishi, Yukihiro, Ogawa, Reiko, Kouda, Satoko, Kanai, Yae

VIRCHOWS ARCHIV (SPRINGER) 454 ( 5 ) 513 - 517 2009.05

Research paper (scientific journal), ISSN 0945-6317

Mucosal melanomas have genetic alterations distinct from those in cutaneous melanomas. For example, NRAS- and BRAF-activating mutations occur frequently in cutaneous melanomas, but not in mucosal melanomas. We examined 16 esophageal melanomas for genetic alterations in NRAS, BRAF, and KIT to determine whether they exhibit genetic features common to melanomas arising from other mucosal sites. A sequencing analysis identified NRAS mutations in six cases; notably, four of these mutations were located in exon 1, an uncommon mutation site in cutaneous and other mucosal melanomas. BRAF and KIT mutations were found in one case each. Immunohistochemistry showed KIT expression in four cases, including the tumor with a KIT mutation and two other intramucosal tumors. The low frequency of BRAF mutations and the presence of a KIT mutation-positive case are findings similar to those of mucosal melanomas of other sites, but the prevalence of NRAS mutations was even higher than that of cutaneous melanomas. The present study implies that esophageal melanomas have genetic alterations unique from those observed in other mucosal melanomas.

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Genome-wide DNA methylation profiles in both precancerous conditions and clear cell renal cell carcinomas are correlated with malignant potential and patient outcome

Arai, Eri, Ushijima, Saori, Fujimoto, Hiroyuki, Hosoda, Fumie, Shibata, Tatsuhiro, Kondo, Tadashi, Yokoi, Sana, Imoto, Issei, Inazawa, Johji, Hirohashi, Setsuo, Kanai, Yae

CARCINOGENESIS (OXFORD UNIV PRESS) 30 ( 2 ) 214 - 221 2009.02

Research paper (scientific journal), ISSN 0143-3334

To clarify genome-wide DNA methylation profiles during multistage renal carcinogenesis, bacterial artificial chromosome array-based methylated CpG island amplification (BAMCA) was performed. Non-cancerous renal cortex tissue obtained from patients with clear cell renal cell carcinomas (RCCs) (N) was at the precancerous stage where DNA hypomethylation and DNA hypermethylation on multiple bacterial artificial chromosome (BAC) clones were observed. By unsupervised hierarchical clustering analysis based on BAMCA data for their N, 51 patients with clear cell RCCs were clustered into two subclasses, Clusters A(N) (n = 46) and B-N (n = 5). Clinicopathologically aggressive clear cell RCCs were accumulated in Cluster B-N, and the overall survival rate of patients in Cluster B-N was significantly lower than that of patients in Cluster A(N). By unsupervised hierarchical clustering analysis based on BAMCA data for their RCCs, 51 patients were clustered into two subclasses, Clusters A(T) (n = 43) and B-T (n = 8). Clinicopathologically aggressive clear cell RCCs were accumulated in Cluster B-T, and the overall survival rate of patients in Cluster B-T was significantly lower than that of patients in Cluster A(T). Multivariate analysis revealed that belonging to Cluster B-T was an independent predictor of recurrence. Cluster B-N was completely included in Cluster B-T, and the majority of the BAC clones that significantly discriminated Cluster B-N from Cluster A(N) also discriminated Cluster B-T from Cluster A(T). In individual patients, DNA methylation status in N was basically inherited by the corresponding clear cell RCC. DNA methylation alterations in the precancerous stage may generate more malignant clear cell RCCs and determine patient outcome.

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Mucus Rupture (Extrusion) and Duct Expansion/Expansive Growth are not Diagnostic of Minimal Invasion When Seen With Intraductal Papillary Mucinous Neoplasms Reply

Nara, Satoshi, Shimada, Kazuaki, Kosuge, Tomoo, Kanai, Yae, Hiraoka, Nobuyoshi

AMERICAN JOURNAL OF SURGICAL PATHOLOGY (LIPPINCOTT WILLIAMS & WILKINS) 33 ( 2 ) 321 - 322 2009.02

Research paper (scientific journal), ISSN 0147-5185

Intraductal carcinoma component as a favorable prognostic factor in biliary tract carcinoma

Ojima, Hidenori, Kanai, Yae, Iwasaki, Motoki, Hiraoka, Nobuyoshi, Shimada, Kazuaki, Sano, Tsuyoshi, Sakamoto, Yoshihiro, Esaki, Minoru, Kosuge, Tomoo, Sakamoto, Michiie, Hirohashi, Setsuo

CANCER SCIENCE 100 ( 1 ) 62 - 70 2009.01

Research paper (scientific journal), Accepted, ISSN 1347-9032

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Chromatin remodeling at Alu repeats by epigenetic treatment activates silenced microRNA-512-5p with downregulation of Mcl-1 in human gastric cancer cells.

Saito Y, Suzuki H, Tsugawa H, Nakagawa I, Matsuzaki J, Kanai Y, Hibi T.

Oncogene (NATURE PUBLISHING GROUP) 28 ( 30 ) 2738 - 2744 2009

Accepted, ISSN 09509232

Epigenetic therapy using DNA methylation inhibitors and histone deacetylase (HDAC) inhibitors has clinical promise for the treatment of human malignancies. To investigate roles of microRNAs (miRNAs) on epigenetic therapy of gastric cancer, the miRNA expression profile was analysed in human gastric cancer cells treated with 5-aza-2'-deoxycytidine (5-Aza-CdR) and 4-phenylbutyric acid (PBA). miRNA microarray analysis shows that most of miRNAs activated by 5-Aza-CdR and PBA in gastric cancer cells are located at Alu repeats on chromosome 19. Analyses of chromatin modification show that DNA demethylation and HDAC inhibition at Alu repeats activates silenced miR-512-5p by RNA polymerase II. In addition, activation of miR-512-5p by epigenetic treatment induces suppression of Mcl-1, resulting in apoptosis of gastric cancer cells. These results suggest that chromatin remodeling at Alu repeats plays critical roles in the regulation of miRNA expression and that epigenetic activation of silenced Alu-associated miRNAs could be a novel therapeutic approach for gastric cancer. Oncogene (2009) 28, 2738-2744; doi:10.1038/onc.2009.140; published online 8 June 2009

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MicroRNA-500 as a potential diagnostic marker for hepatocellular carcinoma

Yamamoto, Yusuke, Kosaka, Nobuyoshi, Tanaka, Minoru, Koizumi, Fumiaki, Kanai, Yae, Mizutani, Takayuki, Murakami, Yoshiki, Kuroda, Masahiko, Miyajima, Atsushi, Kato, Takashi, Ochiya, Takahiro

BIOMARKERS (TAYLOR & FRANCIS LTD) 14 ( 7 ) 529 - 538 2009

Research paper (scientific journal), ISSN 1354-750X

We identified that microRNA expression changed dynamically during liver development and found that miR-500 is an oncofetal miRNA in liver cancer. miR-500 was abundantly expressed in several human liver cancer cell lines and 45% of human hepatocellular carcinoma (HCC) tissue. Most importantly, an increased amount of miR-500 was found in the sera of the HCC patients. In fact, miR-500 levels in sera of the HCC patients returned to normal after the surgical treatment in three HCC patients. Our findings reveal that diverse changes of miRNAs occur during liver development and, one of these, miR-500 is an oncofetal miRNA relevant to the diagnosis of human HCC.

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Podoplanin Expression Identified in Stromal Fibroblasts as a Favorable Prognostic Marker in Patients with Colorectal Carcinoma

Yamanashi, Takahiro, Nakanishi, Yukihiro, Fujii, Gen, Akishima-Fukasawa, Yuri, Moriya, Yoshihiro, Kanai, Yae, Watanabe, Masahiko, Hirohashi, Setsuo

ONCOLOGY (KARGER) 77 ( 1 ) 53 - 62 2009

Research paper (scientific journal), ISSN 0030-2414

Objective: The microenvironment of cancer plays a critical role in its progression. However, the molecular features of cancer-associated fibroblasts (CAFs) are less well understood than those of cancer cells. We investigated the clinicopathological significance of podoplanin expression in stromal fibroblasts in patients with colorectal cancer (CRC). Methods: We selected podoplanin as an upregulated marker in CAF from a DNA microarray experiment. Consequently, podoplanin was identified as an upregulated gene. Immunohistochemical podoplanin expression was investigated at the National Cancer Center Hospital, Tokyo, Japan, in 120 patients with advanced CRC, and its clinicopathological significance was examined. The biological function of podoplanin expression was also assessed by a coculture invasion assay with CRC cell lines such as HCT116 and HCT15. Results: Podoplanin expression was exclusively confined to stromal fibroblasts and absent in tumor cells. Podoplanin is absent in normal stroma except for lymphatic vessels. Staining was considered positive when over 30% of the cancer stroma was stained. Positive podoplanin expression was significantly correlated with a more distal tumor localization (p = 0.013) and a shallower depth of tumor invasion (p = 0.011). Univariate analysis revealed that negative podoplanin expression in stromal fibroblasts was significantly associated with reduced disease-specific survival (p = 0.0017) and disease-free survival (p < 0.0001). Multivariate analysis revealed that negative podoplanin expression (p = 0.016) and lymph node metastasis (p = 0.027) were significantly associated with disease-free survival. CRC cell invasion was augmented by coculture with CAFs that were treated with siRNA for podoplanin. Conclusions: Our results suggest that a positive podoplanin expression in stromal fibroblasts could have a protective role against CRC cell invasion and is a significant indicator of a good prognosis in patients with advanced CRC, supported by biological analysis showing that podoplanin expression in CAFs is associated with decreased CRC cell invasion. Copyright (C) 2009 S. Karger AG, Basel

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OP-459 2002年TNM分類におけるpT3腎細胞癌の亜分類の再考(腎腫瘍/診断・マーカー,一般演題口演,第97回日本泌尿器科学会総会)

中川徹, 新井恵吏, 熊谷伸, 堀淳一, 根岸孝仁, 中西弘之, 込山元清, 金井弥栄, 藤元博行

日本泌尿器科学会雑誌 (一般社団法人日本泌尿器科学会) 100 ( 2 ) 303 - 303 2009

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Alterations of DNA methylation and clinicopathological diversity of human cancers

Kanai, Yae

PATHOLOGY INTERNATIONAL (WILEY-BLACKWELL) 58 ( 9 ) 544 - 558 2008.09

Research paper (scientific journal), ISSN 1320-5463

Alterations of DNA methylation can account for the histological heterogeneity, reflected in the stepwise progression and complex biological characteristics of human cancers, that genetic alterations alone cannot explain. Analysis of DNA methylation status in tissue samples can be an aid to understanding the molecular mechanisms of multistage carcinogenesis. Human cancer cells show a drastic change in DNA methylation status, that is, overall DNA hypomethylation and regional DNA hypermethylation, which results in chromosomal instability and silencing of tumor-suppressor genes. Overexpression of DNA methyltransferase (DNMT) 1 is not a secondary result of increased cell proliferative activity but may underline the CpG island methylator phenotype of cancers. Splicing alteration of DNMT3B may result in chromosomal instability through DNA hypomethylation of pericentromeric satellite regions. Alterations of DNA methylation are observed even in the precancerous stage frequently associated with chronic inflammation and/or persistent viral infection or with cigarette smoking. Precancerous conditions showing alterations of DNA methylation may generate more malignant cancers. Aberrant DNA methylation is significantly associated with aggressiveness of cancers and poorer outcome of cancer patients. Genome-wide analysis of DNA methylation status based on array-based technology may identify DNA methylation profiles that can be used as appropriate indicators for carcinogenetic risk estimation and prognostication.

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Genetic clustering of clear cell renal cell carcinoma based on array-comparative genomic hybridization: Its association with DNA methylation alteration and patient outcome

Arai, Ed, Ushijima, Saori, Tsuda, Hitoshi, Fujimoto, Hiroyuki, Hosoda, Fumie, Shibata, Tatsuhiro, Kondo, Tadashi, Imoto, Issei, Inazawa, Johji, Hirohashi, Setsuo, Kanai, Yae

CLINICAL CANCER RESEARCH (AMER ASSOC CANCER RESEARCH) 14 ( 17 ) 5531 - 5539 2008.09

Research paper (scientific journal), ISSN 1078-0432

Purpose:The aim of this study was to clarify genetic and epigenetic alterations occurring during renal carcinogenesis.
Experimental Design: Copy number alterations were examined by array-based comparative genomic hybridization analysis using an array harboring 4,361 bacterial artificial chromosome clones, and DNA methylation alterations on CpG islands of the p16 human MutL homologue I von Hippel-Lindau, and thrombospondin 1 genes and the methylated in tumor (MINT-11, MINT-2, MINT-112, MINT-25, and MINT-31) clones were examined in 51 clear cell renal cell carcinomas (RCC).
Results: By unsupervised hierarchical clustering analysis based on copy number alterations, clear cell RCCs were clustered into the two subclasses, clusters A (n = 34) and B (n = 17). Copy number alterations were accumulated in cluster B. Loss of chromosome 3p and gain of 5q and 7 were frequent in both clusters A and B, whereas loss of 1p, 4, 9,13q, and 14q was frequent only in cluster B. The average number of methylated CpG islands in cluster B was significantly higher than those in clusterA. Clear cell RCCs showing higher histologic grades, vascular involvement, renal vein tumor thrombi, and higher pathologic stages were accumulated in cluster B. The recurrence-free and overall survival rates of patients in cluster B were significantly lower than those of patients in cluster A. Multivariate analysis revealed that genetic clustering was a predictor of recurrence-free survival and was independent of histologic grade and pathologic stage.
Conclusions: This genetic clustering of clear cell RCC is significantly associated with regional DNA hypermethylation and may become a prognostic indicator for patients with RCC.

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