徳島大学 教育・研究者情報データベース(EDB)

1. 徳島大学.医学部.医学科.生体防御腫瘍医学講座.呼吸器・膠原病内科学分野

1. (英) Kuramoto Takuya

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2. 後東 久嗣

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3. (英) Mitsuhashi Atsushi

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4. (英) Tabata Sho

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5. 小川 博久([徳島大学.大学院医歯薬学研究部.医学域.医科学部門.病理系.疾患病理学])

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6. 上原 久典([徳島大学.病院.診療科.病理診断科])

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7. 西條 敦郎

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8. 柿内 聡司

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9. 前川 洋一

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10. 安友 康二([徳島大学.大学院医歯薬学研究部.医学域.医科学部門.病理系.生体防御医学])

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11. 埴淵 昌毅([徳島大学.大学院医歯薬学研究部.医学域.連携研究部門(医学域).寄附講座系(医学域).地域呼吸器・血液・代謝内科学])

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12. 秋山 伸一

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13. 曽根 三郎

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14. 西岡 安彦([徳島大学.大学院医歯薬学研究部.医学域.医科学部門.内科系.呼吸器・膠原病内科学])

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(英) Dll4-Fc, an inhibitor of Dll4-Notch signaling, suppresses liver metastasis of small cell lung cancer cells through down-regulation of NF-kappa-B activity

(英) Notch signaling regulates cell-fate decisions during development and postnatal life. Little is known, however, about the role of Delta-like-4 (Dll4)-Notch signaling between cancer cells, or how this signaling affects cancer metastasis. We, therefore, assessed the role of Dll4-Notch signaling in cancer metastasis. We generated a soluble Dll4 fused to the IgG1 constant region (Dll4-Fc) that acts as a blocker of Dll4-Notch signaling and introduced it into human small cell lung cancer (SCLC) cell lines expressing either high levels (SBC-3 and H1048) or low levels (SBC-5) of Dll4. The effects of Dll4-Fc on metastasis of SCLC were evaluated using a mouse model. Although Dll4-Fc had no effect on the liver metastasis of SBC-5, the number of liver metastasis inoculated with SBC-3 and H1048 cells expressing Dll4-Fc was significantly lower than that injected with control cells. To study the molecular mechanisms of the effects of Dll4-Fc on liver metastasis, a PCR array analysis was conducted. Because the expression of NF-κB target genes was affected by Dll4-Fc, we conducted an electrophoretic mobility shift assay and observed that NF-κB activities, both with and without stimulation by TNF-α, were downregulated in Dll4-Fc-overexpressing SBC-3 and H1048 cells compared with control cells. Moreover, Dll4-Fc attenuates, at least in part, the classical and alternative NF-κB activation pathway by reducing Notch1 signaling. These results suggest that Dll4-Notch signaling in cancer cells plays a critical role in liver metastasis of SCLC by regulating NF-κB signaling.

1. (英) Animals
2. アポトーシス(apoptosis)
3. (英) Cell Growth Processes
4. (英) Cell Movement
5. (英) Down-Regulation
6. (英) Humans
7. (英) Liver Neoplasms, Experimental
8. (英) Lung Neoplasms
9. (英) Male
10. (英) Mice
11. (英) Mice, SCID
12. (英) NF-kappa B
13. (英) Receptors, Notch
14. (英) Recombinant Fusion Proteins
15. シグナル伝達(signal transduction)
16. (英) Small Cell Lung Carcinoma
17. (英) Transfection
18. (英) Xenograft Model Antitumor Assays

1. (英) Article.ELocationID: 10.1158/1535-7163.MCT-12-0640

2. (英) Article.Affiliation: Department of Respiratory Medicine and Rheumatology, Institute of Health Biosciences, The University of Tokushima Graduate School, Japan.

3. (英) Article.PublicationTypeList.PublicationType: Journal Article

4. (英) Article.PublicationTypeList.PublicationType: Research Support, Non-U.S. Gov't