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論文 |
論文
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Ju, Xiaoli ; Ishikawa, Tomo-o ; Naka, Kazuhito ; Ito, Kosei ; Ito, Yoshiaki ; Oshima, Masanobu
概要:
RUNX3 is a tumor suppressor for a variety of cancers. RUNX3 suppresses the canonical Wnt signaling pathway by binding to
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the TCF4/β-catenin complex, resulting in the inhibition of binding of the complex to the Wnt target gene promoter. Here, we confirmed that RUNX3 suppressed Wnt signaling activity in several gastric cancer cell lines; however, we found that RUNX3 increased the Wnt signaling activity in KatoIII and SNU668 gastric cancer cells. Notably, RUNX3 expression increased the ratio of the Wnt signaling-high population in the KatoIII cells. although the maximum Wnt activation level of individual cells was similar to that in the control. As found previously, RUNX3 also binds to TCF4 and β-catenin in KatoIII cells, suggesting that these molecules form a ternary complex. Moreover, the ChIP analyses revealed that TCF4, β-catenin and RUNX3 bind the promoter region of the Wnt target genes, Axin2 and c-Myc, and the occupancy of TCF4 and β-catenin in these promoter regions is increased by the RUNX3 expression. These results suggest that RUNX3 stabilizes the TCF4/β-catenin complex on the Wnt target gene promoter in KatoIII cells, leading to activation of Wnt signaling. Although RUNX3 increased the Wnt signaling activity, its expression resulted in suppression of tumorigenesis of KatoIII cells, indicating that RUNX3 plays a tumor-suppressing role in KatoIII cells through a Wnt-independent mechanism. These results indicate that RUNX3 can either suppress or activate the Wnt signaling pathway through its binding to the TCF4/β-catenin complex by cell context-dependent mechanisms. © 2014 The Authors.
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| 2.
論文 |
論文
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Oshima, Hiroko ; Nakayama, Mizuho ; Han, Tae-Su ; Naoi, Kuniko ; Ju, Xiaoli ; Maeda, Yusuke ; Robine, Sylvie ; Tsuchiya, Kiichiro ; Sato, Toshiro ; Sato, Hiroshi ; Taketo, Makoto Mark ; Oshima, Masanobu
概要:
Genetic alterations in the TGFβ signaling pathway in combination with oncogenic alterations lead to cancer development i
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n the intestines. However, the mechanisms of TGFβ signaling suppression in malignant progression of intestinal tumors have not yet been fully understood. We have examined ApcΔ716 TGFβr2ΔIEC compound mutant mice that carry mutations in Apc and TGFβr2 genes in the intestinal epithelial cells. We found inflammatory microenvironment only in the invasive intestinal adenocarcinomas but not in noninvasive benign polyps of the same mice. We thus treated simple TGFβr2ΔIEC mice with dextran sodium sulfate (DSS) that causes ulcerative colitis. Importantly, these TGFβr2ΔIEC mice developed invasive colon cancer associated with chronic inflammation.Wealso found that TGFβ signaling is suppressed in human colitis-associated colon cancer cells. In the mouse invasive tumors, macrophages infiltrated and expressed MT1-MMP, causingMMP2activation. These results suggest that inflammatory microenvironment contributes to submucosal invasion of TGFβ signaling-repressed epithelial cells through activation of MMP2. We further found that regeneration was impaired in TGFβr2ΔIEC mice for intestinal mucosa damaged by DSS treatment or X-ray irradiation, resulting in the expansion of undifferentiated epithelial cell population. Moreover, organoids of intestinal epithelial cells cultured from irradiated TGFβr2ΔIEC mice formed "long crypts" in Matrigel, suggesting acquisition of an invasive phenotype into the extracellular matrix. These results, taken together, indicate that a simple genetic alteration in the TGFβ signaling pathway in the inflamed and regenerating intestinal mucosa can cause invasive intestinal tumors. Such a mechanism may play a role in the colon carcinogenesis associated with inflammatory bowel disease in humans.
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| 3.
その他 |
その他
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Adachi, Eri ; Ali, Mohamed A.E. ; Baba, Tomohisa ; Domoto, Takahiro ; Endo, Yoshio ; Enkhtuya, Radnaa ; Gunarta, I Ketut ; Han, Tae-Su ; Hayashi, Naoyuki ; Hirose, Mayumi ; Ishimura, Akihiko ; Ju, Xiaoli ; Kasada, Atsuo ; Kitajima, Shunsuke ; Kohno, Susumu ; Kushiyama, Hiroko ; Li, Zichen ; Nishimura, Tatsunori ; Ohta, Kumiko ; Sakai, Katsuya ; Sasaki, Nobunari ; Sato, Tokiharu ; Song, Yao ; Tadokoro, Yuko ; Yamada, Daisuke ; Yoshida, Akiyo ; Yoshimoto, Taisuke ; Zhao, Lu
概要:
International Symposium on Tumor Biology in Kanazawa & Symposium on Drug Discoverry in Academics 2014 [DATE]: January 23(Thu)-24(Fri),2014, [Place]:Kanazawa Excel Hotel Tpkyu, Kanazawa, Japan, [Organizers]:Kanazawa
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Association of Tumor Biologists / Cancer Research Institute, Kanazawa University
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| 4.
その他 |
その他
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Sasaki, Nobunari ; Uema, Noriyuki ; Ishikawa, Tomo-o ; Sasaki, Soichiro ; Kono, Yusuke ; Azuma, Masahiro ; Ju, Xiaoli ; Lu, Zhao ; Sato, Yumi ; Kashiba, Yui ; Yamamoto, Koji ; Lin, Yang ; Wang, Zhe ; Shimizu, Yuko ; Murata, Takayuki ; Domoto, Takahiro ; Oktyabri, Dulamsuren ; Sakai, Katsuya ; Hayashi, Naoyuki ; Kobayashi, Masahiko ; Yamakoshi, Nana ; Kobayashi, Akiko ; Tsuka, Eriko ; Yamada, Daisuke ; Sano, Takako ; Tange, Shoichiro ; Sato, Tokiharu ; Kohno, Susumu ; Muranaka, Hayato ; Hirose, Mayumi
概要:
The 3rd International Symposium on Carcinogenic Spiral & International Symposium on Tumor Biology in Kanazawa, [DATE]: January 24(Thu)-25(Fri),2013, [Place]:Kanazawa Excel Hotel Tpkyu, Kanazawa, Japan,
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[Organizers]:Infection/Inflammation-Assisted Acceleration of the Carcinogenic Spiral and its Alteration through Vector Conversion of the Host Response to Tumors / Scientific Research on Innovative Areas, a MEXT Grant-in Aid Project
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