論文 - 坂元　亨宇

Overexpression of a splice variant of DNA methyltransferase 3b, DNMT3b4, associated with DNA hypomethylation on pericentromeric satellite regions during human hepatocarcinogenesis

Saito, Y., Kanai, Y., Sakamoto, M., Saito, H., Ishii, H. and Hirohashi, S.

Proc Natl Acad Sci U S A 99 （ 15 ） 10060 - 5 2002年07月

ISSN  0027-8424

　概要を見る

DNA hypomethylation on pericentromeric satellite regions is an early and frequent event associated with heterochromatin instability during human hepatocarcinogenesis. A DNA methyltransferase, DNMT3b, is required for methylation on pericentromeric satellite regions during mouse development. To clarify the molecular mechanism underlying DNA hypomethylation on pericentromeric satellite regions during human hepatocarcinogenesis, we examined mutations of the DNMT3b gene and mRNA expression levels of splice variants of DNMT3b in noncancerous liver tissues showing chronic hepatitis and cirrhosis, which are considered to be precancerous conditions, and in hepatocellular carcinomas (HCCs). Mutation of the DNMT3b gene was not found in HCCs. Overexpression of DNMT3b4, a splice variant of DNMT3b lacking conserved methyltransferase motifs IX and X, significantly correlated with DNA hypomethylation on pericentromeric satellite regions in precancerous conditions and HCCs (P = 0.0001). In particular, the ratio of expression of DNMT3b4 to that of DNMT3b3, which is the major splice variant in normal liver tissues and retains conserved methyltransferase motifs I, IV, VI, IX, and X, showed significant correlation with DNA hypomethylation (P = 0.009). Transfection of human epithelial 293 cells with DNMT3b4 cDNA induced DNA demethylation on satellite 2 in pericentromeric heterochromatin DNA. These results suggest that overexpression of DNMT3b4, which may lack DNA methyltransferase activity and compete with DNMT3b3 for targeting to pericentromeric satellite regions, results in DNA hypomethylation on these regions, even in precancerous stages, and plays a critical role in human hepatocarcinogenesis by inducing chromosomal instability.

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Hepatic nodules with early enchancement during computed tomography portography:Report of six cases

Takayasu Kenichi, Muramatsu Yukio, Wakao Fumihiko, Mizuguchi Yasunori, Iwata Ryoko, Maeda Tetsuo, Moriyama Noriyuki, Sakamoto Michiie

Journal of gastroenterology and hepatology 17 （ 7 ） 779-784 2002年07月

研究論文（学術雑誌）, 共著

Correlation between laminin-5γ2 chain expression and epidermal growth factor receptor expression and its clinicopathologic significance in squamous cell carcinoma of the tongue

Katoh Kazuhide, Nakanishi Yukihiro, Akimoto Shingo, Yoshimura Kimio, Takagi Minoru, Sakamoto Michiie, Hirohashi Setsuo

Oncology 62 （ 4 ） 318-326 2002年07月

研究論文（学術雑誌）, 共著

Overexpression of a splice variant of DNA methyltransferase 3b,DNMT3b4,associated with DNA hypomethylation on pericentromeric satellite regions during human hepatocarcinogenesis

Saito Yoshimasa, Kanai Yae, Sakamoto Michiie, Saito Hidetsugu, Ishii Hiromasa, Hirohashi Setsuo

Proceedings of the National Academy of Science of the United States of America 99 （ 15 ） 10060-10065 2002年07月

研究論文（学術雑誌）, 共著

Overexpression of a splice variant of DNA methyltransferase 3b, DNMT3b4, associated with DNA hypomethylation on pericentromeric satellite regions during human hepatocarcinogenesis

Saito Yoshimasa, Kanai Yae, Sakamoto Michiie, Saito Hidetsugu, Ishii Hiromasa, Hirohashi Setsuo

Proceedings of the National Academy of Sciences of the United States of America 99 （ 15 ） 10060-10065 2002年07月

研究論文（学術雑誌）, 共著

Phosphogyceride crystal deposition disease presenting as multiple paragastric masses

Yachida Shinichi, Fukushima Noriyoshi, Nakanishi Yukihiro, Nimura S, Sato M, Shimada K, Miura K, Sakamoto Michiie

Digestive diseases and sciences 47 （ 6 ） 1413-1418 2002年06月

研究論文（学術雑誌）, 共著

Mixed mucinous-type and non-mucinous-type adenocarcinoma of the lung: immunohistochemical examination and K-ras gene mutation

Maeshima Aratumi, Sakamoto Michiie, Hirohashi Setsuo

Virchows Archiv 440 （ 6 ） 598-603 2002年06月

研究論文（学術雑誌）, 共著

Critical involvement of the phosphatidylinositol 3-kinase/Akt pathway in anchorage-independent growth and hematogeneous intrahepatic metastasis of liver cancer

Nakanishi, K., Sakamoto, M., Yasuda, J., Takamura, M., Fujita, N., Tsuruo, T., Todo, S. and Hirohashi, S.

Cancer Res 62 （ 10 ） 2971 - 5 2002年05月

ISSN  0008-5472

　概要を見る

In the multistep process of metastasis, "anchorage-independent growth," where cancer cells need to survive without cell-substratum interaction, is supposed to be important. In this study, we found that anchorage-independent growth analyzed using the soft agar colony formation assay correlated with hematogeneous intrahepatic metastasis of liver cancer cell lines and also Akt activation status. Two highly metastatic liver cancer cell lines showed high Akt activity and formed many colonies in soft agar, whereas three nonmetastatic cell lines showed less Akt activity and formed fewer colonies. Inhibition of Akt activation in the highly metastatic cell line Li7 by transfection with kinase-dead Akt or the phosphatidylinositol 3-kinase inhibitor, LY294002, resulted in formation of fewer colonies in soft agar than was the case with control cells. Moreover, in orthotopic implantation model, this inhibition resulted in a reduced rate of hematogeneous intrahepatic metastasis. These findings indicated that anchorage-independent growth regulated by phosphatidylinositol 3-kinase/Akt pathway plays a critical role in metastasis, and that this could be a potential therapeutic target to combat metastasis.

Critical involvement of the phosphatidylinositol 3-kinase/Akt pathway in anchorage-independent growth and hematogeneous intrahepatic metastasis of liver cancer

Nakanishi Kazuaki, Sakamoto Michiie, Yasuda Jun, Takamura Masaaki, Fujita Naoya, Tsuruo Takashi, Todo Satoru, Hirohashi Setsuo

Cancer research 62 （ 10 ） 2971-2975 2002年05月

研究論文（学術雑誌）, 共著

Implications of peritoneal washing cytology in patients with potentially resectable pancreatic cancer

Yachida Shinchi, Fukushima Noriyoshi, Sakamoto Michiie, Matsuno Y, Kosuge T, Hirohashi Setsuo

British journal of surgery 89 （ 5 ） 573-578 2002年05月

研究論文（学術雑誌）, 共著

Detection of genes expressed in primary colon cancers by in situ hybridization: overexpression of RACK 1

Saito A, Fujii G, Sato Y, Gotoh M, Sakamoto Michiie, Toda G, Hirohashi Setsuo

Molecular pathology 55 （ 1 ） 34-39 2002年02月

研究論文（学術雑誌）, 共著

Overexpression of KIT in chromophobe renal cell carcinoma

Yamazaki Ken, Sakamoto Michiie, Ohta Tsutomu, Kanai Yae, Ohki Misaro, Hirohashi Setsuo

Oncogene 22 （ 6 ） 847-852 2002年02月

研究論文（学術雑誌）, 共著

Overexpression of osteopontin in hepatocellular carcinoma

Gotoh, M., Sakamoto, M., Kanetaka, K., Chuuma, M. and Hirohashi, S.

Pathology International 52 （ 1 ） 19 - 24 2002年01月

ISSN  1320-5463

　概要を見る

Human hepatocellular carcinoma (HCC) is one of the most common and aggressive malignancies. In order to identify genes involved in HCC progression, we conducted a differential display analysis and found osteopontin (OPN) to be overexpressed in HCC. OPN is known to be a secreted adhesive glycoprotein, associated with tumorigenesis and metastasis in several cancers. Quantitative polymerase chain reaction analysis of 30 HCC cases revealed the average ratio of OPN to glyceraldehyde-3-phosphate dehydrogenase in tumors to be significantly higher than that in the surrounding non-cancerous liver (4.7 +/- 1.6 vs 0.18 +/- 0.04, P = 0.0072). Immunohistochemistry confirmed the OPN protein was expressed mainly on cancer cells, and was positive in 12 of 30 HCC, most of which showed transcript overexpression. Both OPN transcript and OPN protein were significantly overexpressed in HCC with capsular infiltration, compared with HCC without capsular infiltration. Moreover, OPN-positive cancer cells were often dispersed in the periphery of cancer nodules and were adjacent to stromal cells. Although OPN overexpression was not related to vascular invasion or intrahepatic metastasis, OPN was suggested to play a role in HCC, especially in cancer-stromal interactions.

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Dysadherin, a cancer-associated cell membrane glycoprotein, down-regulates E-cadherin and promotes metastasis

Ino Yoshinori, Gotoh Masahiro, Sakamoto Michiie, Tsukagoshi Kiyomi, Hirohashi Setsuo

Proceedings of the National Academy of Sciences of the United States of America 99 （ 1 ） 365-370 2002年01月

研究論文（学術雑誌）, 共著

Epidermal growth factor receptor gene amplification is correlated with laminin-5 γ2 chain expression in oral squamous cell carcinoma cell lines

Ono Yukiko, Nakanishi Yukihiro, Gotoh Masahiro, Sakamoto Michiie, Hirohashi Setsuo

Cancer letters 175 （ 2 ） 197-204 2002年01月

研究論文（学術雑誌）, 共著

Overexpression of osteopontin in hepatocellular carcinoma

Gotoh Masahiro, Sakamoto Michiie, Kanetaka Kengo, Chuuma Makoto, Hirohashi Setsuko

Pathology international 52 （ 1 ） 19-24 2002年01月

研究論文（学術雑誌）, 共著

Expression Profiling in Multistage Hepatocarcinogenesis:Identification of HSP70 as a Molecular Marker of Early Hepatocellular Carcinoma

Chuma Makoto, Sakamoto Michiie, Yamazaki Ken, Ohta Tsutomu, Ohki Misao, Asaka Masahiro, Hirohashi Setsuo

Hepatology 37 （ 1 ） 198-207 2002年01月

研究論文（学術雑誌）, 共著

早期肝細胞癌・前癌病変の病理と自然経過，

坂元亨宇

肝細胞癌治療マニュアル 2002年

研究論文（学術雑誌）, 単著

Ras Farnesylation Inhibitor FTI-277 Restores the E-Cadhelin/Catenin Cell Adhension System in Human Cancer Cells and Reduces Cancer Metastasis

Nam JS, Ino Yoshinori, Sakamoto Michiie, Hirohashi Setsuo

Japanese journal of cancer reseach 93   1020-1028 2002年

研究論文（学術雑誌）, 共著

肝発癌の分子機構

金井弥栄，坂元亨宇

Annual Review消化器2002    113-118 2002年

研究論文（学術雑誌）, 共著