研究者詳細 - 鈴木　拓

論文 - 鈴木　拓

分割表示 344 件中 221 - 240 件目／全件表示 >>

Emerging links between epigenetic alterations and dysregulation of noncoding RNAs in cancer

Reo Maruyama, Hiromu Suzuki, Eiichiro Yamamoto, Kohzoh Imai, Yasuhisa Shinomura

TUMOR BIOLOGY ( SPRINGER ) 33 ( 2 ) 277 - 285 2012年04月 [査読有り]

Epigenetic changes, including DNA methylation and histone modification, play key roles in the dysregulation of tumor-related genes, thereby affecting numerous cellular processes, including cell proliferation, cell adhesion, apoptosis, and metastasis. In recent years, numerous studies have shown that noncoding RNAs (ncRNAs) are key players in the initiation and progression of cancer and epigenetic mechanisms are deeply involved in their dysregulation. Indeed, the growing list of microRNA (miRNA) genes aberrantly methylated in cancer suggests that a large number of miRNAs exert tumor-suppressive or oncogenic effects. In addition, it now appears that long ncRNAs may be causally related to epigenetic dysregulation of critical genes in cancer. Dissection of the relationships between ncRNAs and epigenetic alterations may lead to the development of novel approaches to the diagnosis and treatment of cancer.

DOI PubMed

p53により発現抑制される分泌性増殖因子HDGFの同定とがん組織における発現解析

佐々木泰史, 根岸秀明, 小山良太, 井戸川雅史, 鈴木拓, 今井浩三, 篠村恭久, 時野隆至

日本臨床分子医学会学術総会プログラム・抄録集 ( 日本臨床分子医学会 ) 49回 133 - 133 2012年04月

DNA methylation biomarker candidates for early detection of colon cancer

Joo Mi Yi, Mashaal Dhir, Angela A. Guzzetta, Christine A. Iacobuzio-Donahue, Kyu Heo, Kwang Mo Yang, Hiromu Suzuki, Minoru Toyota, Hwan-Mook Kim, Nita Ahuja

TUMOR BIOLOGY ( SPRINGER ) 33 ( 2 ) 363 - 372 2012年04月 [査読有り]

Promoter CpG island hypermethylation of tumor suppressor genes is a common hallmark of all human cancers. Many researchers have been looking for potential epigenetic therapeutic targets in cancer using gene expression profiling with DNA microarray approaches. Our recent genome-wide platform of CpG island hypermethylation and gene expression in colorectal cancer (CRC) cell lines revealed that FBN2 and TCERG1L gene silencing is associated with DNA hypermethylation of a CpG island in the promoter region. In this study, promoter DNA hypermethylation of FBN2 and TCERG1L in CRC occurs as an early and cancer-specific event in colorectal cancer. Both genes showed high frequency of methylation in colon cancer cell lines (> 80% for both of genes), adenomas (77% for FBN2, 90% for TCERG1L, n = 39), and carcinomas (86% for FBN2, 99% for TCERG1L, n = 124). Bisulfite sequencing confirmed cancer-specific methylation of FBN2 and TCERG1L of promoters in colon cancer cell line and cancers but not in normal colon. Methylation of FBN2 and TCERG1L is accompanied by downregulation in cell lines and in primary tumors as described in the Oncomine (TM) website. Together, our results suggest that gene silencing of FBN2 and TCERG1L is associated with promoter DNA hypermethylation in CRC tumors and may be excellent biomarkers for the early detection of CRC.

DOI PubMed

Aberrant DNA methylation associated with aggressiveness of gastrointestinal stromal tumour

Yasuyuki Okamoto, Akira Sawaki, Seiji Ito, Toshirou Nishida, Tsuyoshi Takahashi, Minoru Toyota, Hiromu Suzuki, Yasuhisa Shinomura, Ichiro Takeuchi, Keiko Shinjo, Byonggu An, Hidemi Ito, Kenji Yamao, Makiko Fujii, Hideki Murakami, Hirotaka Osada, Hiromi Kataoka, Takashi Joh, Yoshitaka Sekido, Yutaka Kondo

GUT ( B M J PUBLISHING GROUP ) 61 ( 3 ) 392 - 401 2012年03月 [査読有り]

Background and aims The majority of gastrointestinal stromal tumors (GISTs) have KIT mutations; however, epigenetic abnormalities that could conceivably potentiate the aggressiveness of GISTs are largely unidentified. Our aim was to establish epigenetic profiles associated with the malignant transformation of GISTs. Methods Methylation of four tumor suppressor genes, RASSF1A, p16, CDH1, and MGMT was analyzed in GISTs. Additionally, genome-wide DNA methylation profiles were compared between small, malignant-prone, and malignant GISTs using methylated GpG island amplification microarrays (MCAM) in a training set (n=40). Relationships between the methylation status of genes identified by MCAM and clinical features of the disease were tested in a validation set (n=75). Results Methylation of RASSF1A progressively increased from small to malignant GISTs. p16 was specifically methylated in malignant-prone and malignant GISTs. MCAM analysis showed that more genes were methylated in advanced than in small GISTs (average of 473 genes vs 360 genes, respectively, P=0.012). Interestingly, the methylation profile of malignant GISTs was prominently affected by their location. Two genes, REC8 and PAX3, which were newly-identified via MCAM analysis, were differentially methylated in small and malignant GISTs in the training and validation sets. Patients with methylation of at least REC8, PAX3, or p16 had a significantly poorer prognosis (P=0.034). Conclusion Our results suggest that GIST is not, in epigenetic terms, a uniform disease and that DNA methylation in a set of genes is associated with aggressive clinical behavior and unfavorable prognosis. The genes identified may potentially serve as biomarkers for predicting aggressive GISTs with poor survivability.

DOI PubMed

A Novel Pit Pattern Identifies the Precursor of Colorectal Cancer Derived From Sessile Serrated Adenoma

Tomoaki Kimura, Eiichiro Yamamoto, Hiro-o Yamano, Hiromu Suzuki, Seiko Kamimae, Masanori Nojima, Takeshi Sawada, Masami Ashida, Kenjiro Yoshikawa, Ryo Takagi, Ryusuke Kato, Taku Harada, Ryo Suzuki, Reo Maruyama, Masahiro Kai, Kohzoh Imai, Yasuhisa Shinomura, Tamotsu Sugai, Minoru Toyota

AMERICAN JOURNAL OF GASTROENTEROLOGY ( NATURE PUBLISHING GROUP ) 107 ( 3 ) 460 - 469 2012年03月 [査読有り]

OBJECTIVES: Sessile serrated adenomas (SSAs) are known to be precursors of sporadic colorectal cancers (CRCs) with microsatellite instability (MSI), and to be tightly associated with BRAF mutation and the CpG island methylator phenotype (CIMP). Consequently, colonoscopic identification of SSAs has important implications for preventing CRCs, but accurate endoscopic to clarify which endoscopic findings are specific to SSAs. METHODS: The morphological, histological and molecular features of 261 specimens from 226 colorectal tumors were analyzed. Surface microstructures were analyzed using magnifying endoscopy. Mutation in BRAF and KRAS was examined by pyrosequencing. Methylation of p16, IGFBP7, MLH1 and MINT1, -2, -12 and -31 was analyzed using bisulfite pyrosequencing. RESULTS: Through retrospective analysis of a training set (n=145), we identified a novel surface microstructure, the Type II open-shape pit pattern (Type II-O), which was specific to SSAs with BRAF mutation and CIMP. Subsequent prospective analysis of an independent validation set (n=116) confirmed that the Type II-O pattern is highly predictive of SSAs (sensitivity, 65.5%; specificity, 97.3%). BRAF mutation and CIMP occurred with significant frequency in Type II-O-positive serrated lesions. Progression of SSAs to more advanced lesions was associated with further accumulation of aberrant DNA methylation and additional morphological changes, including the Type III, IV and V pit patterns. CONCLUSIONS: Our results suggest the Type II-O pit pattern is a useful hallmark of the premalignant stage of CRCs with MSI and CIMP, which could serve to improve the efficacy of colonoscopic surveillance.

DOI PubMed

Upregulation of miR-196a and HOTAIR Drive Malignant Character in Gastrointestinal Stromal Tumors

Takeshi Niinuma, Hiromu Suzuki, Masanori Nojima, Katsuhiko Nosho, Hiroyuki Yamamoto, Hiroyuki Takamaru, Eiichiro Yamamoto, Reo Maruyama, Takayuki Nobuoka, Yasuaki Miyazaki, Toshirou Nishida, Takeo Bamba, Tatsuo Kanda, Yoichi Ajioka, Takahiro Taguchi, Satoshi Okahara, Hiroaki Takahashi, Yasunori Nishida, Masao Hosokawa, Tadashi Hasegawa, Takashi Tokino, Koichi Hirata, Kohzoh Imai, Minoru Toyota, Yasuhisa Shinomura

CANCER RESEARCH ( AMER ASSOC CANCER RESEARCH ) 72 ( 5 ) 1126 - 1136 2012年03月 [査読有り]

Large intergenic noncoding RNAs (lincRNA) have been less studied than miRNAs in cancer, although both offer considerable theranostic potential. In this study, we identified frequent upregulation of miR-196a and lincRNA HOTAIR in high-risk gastrointestinal stromal tumors (GIST). Overexpression of miR-196a was associated with high-risk grade, metastasis and poor survival among GIST specimens. miR-196a genes are located within the HOX gene clusters and microarray expression analysis revealed that the HOXCand HOTAIR gene were also coordinately upregulated in GISTs which overexpress miR-196a. In like manner, overexpression of HOTAIR was also strongly associated with high-risk grade and metastasis among GIST specimens. RNA interference-mediated knockdown of HOTAIR altered the expression of reported HOTAIR target genes and suppressed GIST cell invasiveness. These findings reveal concurrent overexpression of HOX genes with noncoding RNAs in human cancer in this setting, revealing miR-196a and HOTAIR as potentially useful biomarkers and therapeutic targets in malignant GISTs. Cancer Res; 72(5); 1126-36. (C) 2012 AACR.

DOI PubMed

【消化器癌治療における新しい分子標的】GIST治療抵抗例からみた新たな分子標的治療の可能性を探る

新沼猛, 鈴木拓, 篠村恭久

分子消化器病 ( (株)先端医学社 ) 9 ( 1 ) 27 - 32 2012年03月

消化管間質腫瘍(GIST)に対する薬物治療としてはイマチニブメシル酸塩(イマチニブ)、スニチニブリンゴ酸塩(スニチニブ)が用いられているが、これらの薬剤に耐性をもつ症例も出現してきている。イマチニブ耐性にはもとから効果が低いと考えられる一次耐性、新たな遺伝子変異の獲得による二次耐性がある。スニチニブ耐性の機序については完全には解明されてはいないが、活性化ループ(activation loop)の変異によるKITの自律活性化やプロモーター領域のメチル化によるPTENの発現低下とAkt経路の活性化などの報告がある。イマチニブ、スニチニブ耐性例に対しては新規のチロシンキナーゼ阻害薬であるニロチニブ塩酸塩や、mTORなどの細胞内シグナル伝達経路の阻害薬、チロシンキナーゼと細胞内シグナル伝達分子の両者を標的とするソラフェニブトシル酸塩などのマルチターゲットチロシンキナーゼなどの治療が考えられている。また熱ショック蛋白(Hsp)90などの腫瘍形成に関与する分子を標的とする薬剤などが治療標的として考えられており、臨床試験も進んでいるところである。(著者抄録)

Insulin-like growth factor receptor expression is associated with aggressive phenotypes and has therapeutic activity in biliary tract cancers

Hirokazu Ohashi, Yasushi Adachi, Hiroyuki Yamamoto, Hiroaki Taniguchi, Katsuhiko Nosho, Hiromu Suzuki, Yoshiaki Arimura, Kohzoh Imai, David P. Carbone, Yasuhisa Shinomura

Cancer Science 103 ( 2 ) 252 - 261 2012年02月 [査読有り]

Insulin-like growth factor (IGF)-I receptor (IGF-IR) signaling is required for carcinogenicity and progression of several cancers but the function of this pathway and its utility as a therapeutic target have not been studied comprehensively in biliary tract carcinomas (BTC). We investigated the immunohistochemical expression of elements of the IGF axis, matrilysin, overexpression of p53 and the methylation status of the IGFBP-3 promoter in 80 surgically resected BTC. We also assessed the effect of IGF-IR blockade on signal transduction, proliferation and survival in three BTC cell lines using a new tyrosine kinase inhibitor, BMS-536924, and dominant negative IGF-IR (IGF-IR/dn). The effects of IGF-IR blockade was also studied in nude mouse xenograft models. IGF-I was expressed in 60% and IGF-II in 50% of tumors. High expression was associated with tumor size. IGF-IR was expressed in 69% of the cases and was associated with advanced stage and matrilysin expression. Hypermethylation of the IGFBP-3 promoter was detected in 41% of BTC and was inversely correlated with p53 expression. BMS-536924 blocked autophosphorylation of IGF-IR and both Akt and ERK activation by both IGF-I and insulin. BMS-536924 suppressed proliferation and tumorigenicity in vitro in a dose-dependent fashion. This inhibitor upregulated chemotherapy-induced apoptosis in a dose-dependent fashion. Moreover, IGF-IR blockade was effective against tumors in mice. IGF-IR might identify a subset of BTC with a particularly aggressive phenotype and is a candidate therapeutic target in this disease. BMS-536924 might have significant therapeutic utility. © 2011 Japanese Cancer Association.

DOI PubMed

Insulin-like growth factor receptor expression is associated with aggressive phenotypes and has therapeutic activity in biliary tract cancers

Hirokazu Ohashi, Yasushi Adachi, Hiroyuki Yamamoto, Hiroaki Taniguchi, Katsuhiko Nosho, Hiromu Suzuki, Yoshiaki Arimura, Kohzoh Imai, David P. Carbone, Yasuhisa Shinomura

CANCER SCIENCE ( WILEY ) 103 ( 2 ) 252 - 261 2012年02月 [査読有り]

DOI

Aberrant DNA methylation associated with aggressiveness of gastrointestinal stromal tumour.

Okamoto Yasuyuki, Sawaki Akira, Ito Seiji, Nishida Toshirou, Takahashi Tsuyoshi, Toyota Minoru, Suzuki Hiromu, Shinomura Yasuhisa, Takeuchi Ichiro, Shinjo Keiko, An Byonggu, Ito Hidemi, Yamao Kenji, Fujii Makiko, Murakami Hideki, Osada Hirotaka, Kataoka Hiromi, Joh Takashi, Sekido Yoshitaka, Kondo Yutaka

Gut 61 ( 3 ) 2012年

BACKGROUND AND AIMS:The majority of gastrointestinal stromal tumors (GISTs) have KIT mutations; however, epigenetic abnormalities that could conceivably potentiate the aggressiveness of GISTs are largely unidentified. Our aim was to establish epigenetic profiles associated with the malignant transformation of GISTs.;METHODS:Methylation of four tumor suppressor genes, RASSF1A, p16, CDH1, and MGMT was analyzed in GISTs. Additionally, genome-wide DNA methylation profiles were compared between small, malignant-prone, and malignant GISTs using methylated GpG island amplification microarrays (MCAM) in a training set (n=40). Relationships between the methylation status of genes identified by MCAM and clinical features of the disease were tested in a validation set (n=75).;RESULTS:Methylation of RASSF1A progressively increased from small to malignant GISTs. p16 was specifically methylated in malignant-prone and malignant GISTs. MCAM analysis showed that more genes were methylated in advanced than in small GISTs (average of 473 genes vs 360 genes, respectively, P=0.012). Interestingly, the methylation profile of malignant GISTs was prominently affected by their location. Two genes, REC8 and

DOI

【大腸癌研究の新たな展開と治療戦略】大腸発癌進展におけるCa感受性受容体のエピジェネティックな不活化と治療戦略

山本博幸, 能正勝彦, 須河恭敬, 國本浩明, 五十嵐央祥, 中澤眞由美, 新沼猛, 志谷真啓, 山本英一郎, 鈴木拓, 佐々木茂, 足立靖, 篠村恭久

消化器内科 ( (有)科学評論社 ) 53 ( 6 ) 639 - 645 2011年12月

p53 Negatively Regulates the Hepatoma Growth Factor HDGF

Yasushi Sasaki, Hideaki Negishi, Masashi Idogawa, Ikuko Yokota, Ryota Koyama, Masanobu Kusano, Hiromu Suzuki, Masahiro Fujita, Reo Maruyama, Minoru Toyota, Tsuyoshi Saito, Takashi Tokino

CANCER RESEARCH ( AMER ASSOC CANCER RESEARCH ) 71 ( 22 ) 7038 - 7047 2011年11月 [査読有り]

Hepatoma-derived growth factor (HDGF) is a secreted heparin-binding growth factor that has been implicated in cancer development and progression. Here, we report that HDGF is a critical target for transcriptional repression by the tumor suppressor p53. Endogenous HDGF expression was decreased in cancer cells with introduction of wild-type p53, which also downregulated HDGF expression after DNA damage. In support of the likelihood that HDGF is a critical driver of cancer cell growth, addition of neutralizing HDGF antibodies to culture media was sufficient to block cell growth, migration, and invasion. Similarly, these effects were elicited by conditioned culture medium from p53-expressing cells, and they could be reversed by the addition of recombinant human HDGF. Interestingly, we found that HDGF was overexpressed also in primary gastric, breast, and lung cancer tissues harboring mutant p53 genes. Mechanistic investigations revealed that p53 repressed HDGF transcription by altering HDAC-dependent chromatin remodeling. Taken together, our results reveal a new pathway in which loss of p53 function contributes to the aggressive pathobiological potential of human cancers by elevating HDGF expression. Cancer Res; 71(22); 7038-47. (C)2011 AACR.

DOI PubMed

形質細胞異常症における血清遊離軽鎖定量法の臨床的有用性の検討

安井寛, 池田博, 青木由佳, 丸山玲緒, 野島正寛, 鈴木拓, 林敏昭, 石田禎夫, 今井浩三, 篠村恭久

生物物理化学 ( 日本電気泳動学会 ) 55 ( Suppl. ) 18 - 18 2011年11月

Genome-wide Profiling of Chromatin Signatures Reveals Epigenetic Regulation of MicroRNA Genes in Colorectal Cancer

Hiromu Suzuki, Shintaro Takatsuka, Hirofumi Akashi, Eiichiro Yamamoto, Masanori Nojima, Reo Maruyama, Masahiro Kai, Hiro-o Yamano, Yasushi Sasaki, Takashi Tokino, Yasuhisa Shinomura, Kohzoh Imai, Minoru Toyota

CANCER RESEARCH ( AMER ASSOC CANCER RESEARCH ) 71 ( 17 ) 5646 - 5658 2011年09月 [査読有り]

Altered expression of microRNAs (miRNA) occurs commonly in human cancer, but the mechanisms are generally poorly understood. In this study, we examined the contribution of epigenetic mechanisms to miRNA dysregulation in colorectal cancer by carrying out high-resolution ChIP-seq. Specifically, we conducted genome-wide profiling of trimethylated histone H3 lysine 4 (H3K4me3), trimethylated histone H3 lysine 27 (H3K27me3), and dimethylated histone H3 lysine 79 (H3K79me2) in colorectal cancer cell lines. Combining miRNA expression profiles with chromatin signatures enabled us to predict the active promoters of 233 miRNAs encoded in 174 putative primary transcription units. By then comparing miRNA expression and histone modification before and after DNA demethylation, we identified 47 miRNAs encoded in 37 primary transcription units as potential targets of epigenetic silencing. The promoters of 22 transcription units were associated with CpG islands (CGI), all of which were hypermethylated in colorectal cancer cells. DNA demethylation led to increased H3K4me3 marking at silenced miRNA genes, whereas no restoration of H3K79me2 was detected in CGI-methylated miRNA genes. DNA demethylation also led to upregulation of H3K4me3 and H3K27me3 in a number of CGI-methylated miRNA genes. Among the miRNAs we found to be dysregulated, many of which are implicated in human cancer, miR-1-1 was methylated frequently in early and advanced colorectal cancer in which it may act as a tumor suppressor. Our findings offer insight into the association between chromatin signatures and miRNA dysregulation in cancer, and they also suggest that miRNA reexpression may contribute to the effects of epigenetic therapy. Cancer Res; 71(17); 5646-58. (C)2011 AACR.

DOI PubMed

Co-expression of laminin β3 and γ2 chains and epigenetic inactivation of laminin α3 chain in gastric cancer.

Ii M, Yamamoto H, Taniguchi H, Adachi Y, Nakazawa M, Ohashi H, Tanuma T, Sukawa Y, Suzuki H, Sasaki S, Imai K, Shinomura Y

International journal of oncology ( SPANDIDOS PUBL LTD ) 39 ( 3 ) 593 - 599 2011年09月 [査読有り]

Laminin-332 (LM-332, formerly termed laminin-5) is a heterotrimeric glycoprotein that regulates cell adhesion and migration. Molecular alterations of LM-332 are involved in cancer progression. The aim of this study was to clarify alterations of LM-332 in gastric carcinoma. The expression of LM-332 subunits in 10 gastric carcinoma cell lines was investigated by RT-PCR, Western blotting, and immunocytochemical/immunofluorescent analyses. The promoter methylation status of LM-332-encoding genes (LAMA3, LAMB3 and LAMC2) was analyzed by methylation-specific PCR (MSP). The relationship between cell migration and LM-332 expression was assessed by the scratch assay. The expression of LM-332 was analyzed immunohistochemically in 90 gastric cancer tissues. Co-expression of laminin beta 3 and gamma 2 chains was often observed in gastric carcinoma cell lines at mRNA and protein levels. In contrast, there was no expression of laminin alpha 3 at either the mRNA or protein levels. Extracellular secretion of laminin beta 3 and gamma 2 chains was found in 2 of the 10 cell lines. The LAMA3 gene was transcriptionally silenced by methylation of the promoter CpG islands in all of the cell lines, while the LAMB3 and LAMC2 genes were silenced in several cell lines. Treatment with a demethylating agent, 5-aza-2'-deoxycytidine (5-aza-dC), restored expression of the LM-332-encoding genes. Methylation frequency of LAMA3 was higher than those of the LAMB2 and LAMC2 genes in gastric cancer tissues. Migration distances were significantly correlated with cytoplasmic laminin gamma 2 chain expression. Immunohistochemistry showed frequent co-expression of laminin beta 3 and gamma 2 chains in gastric carcinoma cells, which was significantly correlated with depth of invasion and advanced tumor stage. The results suggest that the laminin beta 3 and gamma 2 chains accumulate intracellularly and play a role in gastric cancer progression, while epigenetic silencing of the laminin alpha 3 chain may lead to inability to synthesize the basement membrane and may affect cancer cell invasion. Cancer cell motility appears to be associated with the cytoplasmic laminin gamma 2 chain in vitro.

DOI PubMed

p53により発現抑制される分泌性増殖因子HDGFの同定とがんの浸潤・遊走への関与(Negative regulation of hepatoma-derived growth factor by p53)

佐々木泰史, 根岸秀明, 横田育子, 鹿島理沙, 井戸川雅史, 丸山玲緒, 鈴木拓, 豊田実, 今井浩三, 篠村恭久, 時野隆至

日本癌学会総会記事 ( (一社)日本癌学会 ) 70回 153 - 153 2011年09月

多発性骨髄腫におけるDNAメチロームと染色体異常メチル化DNA結合蛋白を利用した次世代シーケンシングによる検討(DNA methylome and chromosomal aberrations in multiple myeloma: an integrated analysis based on MBD-sequencing)

野島正寛, 青木由佳, 安井寛, 丸山玲緒, 鈴木拓, 石田禎夫, 時野隆至, 篠村恭久, 豊田実

日本癌学会総会記事 ( (一社)日本癌学会 ) 70回 47 - 47 2011年09月

多発性骨髄腫におけるDNA繰り返し配列の低メチル化と染色体異常の関連(The relationship between DNA hypomethylation of repetitive elements and chromosomal aberrations in multiple myeloma)

青木由佳, 野島正寛, 安井寛, 丸山玲緒, 鈴木拓, 石田禎夫, 麻奥英毅, 時野隆至, 豊田実, 篠村恭久

日本癌学会総会記事 ( (一社)日本癌学会 ) 70回 137 - 137 2011年09月

Clinicopathological and Molecular Features of Colorectal Serrated Neoplasias With Different Mucosal Crypt Patterns

Yuichiro Yano, Kazuo Konishi, Toshiko Yamochi, Atsushi Katagiri, Hisako Nozawa, Hiromu Suzuki, Minoru Toyota, Yutaro Kubota, Takashi Muramoto, Yoshiya Kobayashi, Masayuki Tojo, Kenichi Konda, Reiko Makino, Kazuhiro Kaneko, Nozomi Yoshikawa, Hidekazu Ota, Michio Imawari

AMERICAN JOURNAL OF GASTROENTEROLOGY ( NATURE PUBLISHING GROUP ) 106 ( 7 ) 1351 - 1358 2011年07月 [査読有り]

OBJECTIVES: Endoscopic examination shows that serrated neoplasias (SNs), such as serrated adenomas and sessile serrated adenomas, exhibit different mucosal crypt patterns. However, it remains unclear whether advanced serrated polyps with different mucosal crypt patterns have different clinicopathological or molecular features. METHODS: We classified the mucosal crypt patterns of 86 SNs into three types (hyperplastic, adenomatous, and mixed pattern) and evaluated their clinicopathological and molecular features. RESULTS: We found significant differences in the proliferative activity status between SNs with mixed/adenomatous patterns and those with the hyperplastic patterns. SNs with the hyperplastic pattern were frequently located in the proximal colon and had a macroscopically superficial appearance, whereas SNs with the adenomatous pattern were often located in the distal colon and had a protruding appearance. Furthermore, a significant difference was observed in the frequency of the CpG island methylator phenotype (CIMP), involving the methylation of two or more CIMP-related genes (MINT1, MINT2, MINT31, p16, and MLH1), between SNs with the hyperplastic pattern and those with the mixed/adenomatous patterns (18/32 (56%) vs. 8/28 (29%) or 7/26 (27%); P = 0.0309 or P = 0.0249, respectively). Moreover, the prevalence of KRAS mutations was significantly higher in SNs with the adenomatous pattern than in those with the hyperplastic pattern (7/26 (27%) vs. 1/32 (3%); P = 0.0173). In comparison with other patterns, the mixed pattern was detected more frequently in mixed serrated polyps (MSPs), which contain separate histological components. Some MSPs exhibited concordant molecular alterations among the different histological components. CONCLUSIONS: The clinicopathological and molecular features of SNs correlated strongly with their mucosal crypt patterns, which were observed using chromoendoscopy.

DOI PubMed

Epigenetic inactivation of calcium-sensing receptor in colorectal carcinogenesis

Keiichi Hizaki, Hiroyuki Yamamoto, Hiroaki Taniguchi, Yasushi Adachi, Mayumi Nakazawa, Tokuma Tanuma, Norihiro Kato, Yasutaka Sukawa, Jose V. Sanchez, Hiromu Suzuki, Shigeru Sasaki, Kohzoh Imai, Yasuhisa Shinomura

MODERN PATHOLOGY ( NATURE PUBLISHING GROUP ) 24 ( 6 ) 876 - 884 2011年06月 [査読有り]

Ca(2+) is a chemopreventive agent for colon cancer. Ion transport systems are often altered in human cancer. The aim of this study was to clarify the alterations of calcium-sensing receptor (CASR), a member of the G protein-coupled receptor family, in colorectal carcinogenesis. We analyzed the expression of CASR in colorectal cancer cell lines and in cancer and adenoma tissues by RT-PCR and immunostaining. In addition, we analyzed methylation of the CASR promoter by using bisulfite sequence analysis and methylation-specific PCR. CASR mRNA and protein expression was significantly downregulated in most of the cancer cell lines. CpG islands were densely methylated in cancer cell lines with reduced CASR mRNA expression. Treatment with a demethylating agent, 5-aza-2 '-deoxycytidine, and/or a histone deacetylase inhibitor, trichostatin A, restored CASR expression in the cancer cell lines. Disruption of CASR expression in CASR-unmethylated HCT-8 cells blocked the enhancing effect of Ca(2+) on the cytotoxic response to 5-fluorouracil. CASR expression was observed in normal colonic epithelial cells and was retained in most adenoma tissues. CASR mRNA and protein expression was significantly downregulated in cancer tissues. There was an inverse relationship between CASR expression and degree of differentiation. Immunohistochemical CASR staining was reduced more predominantly in less-differentiated cancer tissues and/or in cancer cells at the invasive front, where nuclear/cytoplasmic beta-catenin was often localized. CASR methylation was detected in 69% of colorectal cancer tissues and 90% of lymph node metastatic tissues and was significantly correlated with reduced CASR expression. CASR methylation was also detected in 32% of advanced adenoma tissues but was detected in only 9% of adenoma tissues and was not detected in hyperplastic polyp tissues. CASR methylation seems to occur at an early stage and progress in colorectal carcinogenesis. The results suggest that epigenetic inactivation of CASR has an important role in colorectal carcinogenesis. Modern Pathology (2011) 24, 876-884; doi:10.1038/modpathol.2011.10; published online 11 February 2011

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