A study on the senescence-inducing therapy to oral cancer by targeting IκB kinase

靶向IκB激酶的口腔癌衰老治疗研究

• 批准号: 13672104
• 负责人: IKEBE Tetsuro
• 金额: $ 2.18万
• 依托单位: Kumamoto University (2002)Kyushu University (2001)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13672104/
• 关键词: oral cancer; IKK; NF-κB; epithelial differentiation; involucrin; squamous cell carcinoma; NF-κB

We investigated the function of IκB kinase (IKK) α in oral squamous cell carcinoma (SCC).(1) At first, we examined the expressions of IKK as well as NF-κB in oral SCC tissues. IKK α is a kinase to activate NF-κB, and NF-κB is a transcription factor to transactivate anti-apoptotic genes. Thirty six biopsy specimens from patients with SCC were immunohistochemically stained. The results show that high expressions of IKKα and NF-κB p65 correlated with the invasiveness and the nodal involvement of oral SCC.(2) We caused cultured oral SCC cell line to overexpress IKKα or IKKβ by transfecting its expression vector. High levels of IKKα, but not IKKβ, inhibited the expressions of epithelial differentiation markers, involucrin and filaggrin, in SCC cells. Phorbol myristate acetate phosphorylated IKKα to inhibit the expressions of involucrin. Protein kinase C and IKKα may regulate the differentiation and senescence of SCC cells.The results described above suggest that high expressions of IKKα may contribute to the tumor survival by inhibiting the differentiation (and senescence) in SCC cells. Therefore, IKKα seems to be a therapeutic target molecule against oral cancer.

我们研究了IκB激酶（IKK）α在口腔鳞状细胞癌（SCC）中的功能。（1）首先，我们检测了口腔SCC组织中IKK和NF-κB的表达。 IKK α 是激活 NF-κB 的激酶，NF-κB 是反式激活抗凋亡基因的转录因子。对来自 SCC 患者的 36 份活检标本进行了免疫组织化学染色。结果表明，IKKα和NF-κB p65的高表达与口腔鳞状细胞癌的侵袭性和淋巴结受累相关。(2)通过转染口腔鳞状细胞癌的表达载体，使培养的口腔鳞状细胞癌细胞系过度表达IKKα或IKKβ。高水平的 IKKα（而非 IKKβ）抑制鳞状细胞癌细胞中上皮分化标记物、外皮蛋白和聚丝蛋白的表达。佛波醇肉豆蔻酸酯乙酸酯磷酸化 IKKα 以抑制外皮蛋白的表达。蛋白激酶C和IKKα可能调节SCC细胞的分化和衰老。上述结果表明IKKα的高表达可能通过抑制SCC细胞的分化（和衰老）来促进肿瘤的存活。因此，IKKα似乎是口腔癌的治疗靶分子。

项目成果

Hideki Nakayama, Tetsuro Ikebe, Kanemitsu Shirasuna: "High expression levels of nuclear factor κB, IκB kinase α and Akt kinase in squamous cell carcinoma of the oral cavity"Cancer. 92. 3037-3044 (2001)

Hideki Nakayama、Tetsuro Ikebe、Kanemitsu Shirasuna：“口腔鳞状细胞癌中核因子 κB、IκB 激酶 α 和 Akt 激酶的高表达水平”癌症。

Nakayama, H., Ikebe, T., Beppu, M., Shirasuna, K.: "High expression levels of nuclear factor κB, 1κB kinase a and Akt kinase in squamous cell carcinoma of the oral cavity"Cancer. 92. 3037-3044 (2001)

Nakayama, H.、Ikebe, T.、Beppu, M.、Shirasuna, K.：“口腔鳞状细胞癌中核因子 κB、1κB 激酶 a 和 Akt 激酶的高表达水平”癌症。 3044 (2001)

H.Nakayama, T.Ikebe, M.Beppu, K.Shirasuna: "High Expression Lavels of Nuclear Factor kB, IkB Kinase a and Akt Kinase in Squamous Cell Carcinoma of the Oral Cavity"Cancer. 92. 3037-3044 (2001)

H.Nakayama、T.Ikebe、M.Beppu、K.Shirasuna：“口腔鳞状细胞癌中核因子 kB、IkB 激酶 a 和 Akt 激酶的高表达”癌症。

M.Beppu, T.Ikebe, K.Shirasuna: "The inhibitory Effects of immunosuppressive factors, dexamethasone and interleukin-4, on NF-kB-mediated protease production by oral cancer"Biochimica et Biophysica Acta. 1586. 11-22 (2002)

M.Beppu、T.Ikebe、K.Shirasuna：“免疫抑制因子、地塞米松和白细胞介素 4 对口腔癌 NF-kB 介导的蛋白酶产生的抑制作用”Biochimica et Biophysicala Acta。

F.Sandra, N.Matsuki, H.Takeuchi, T.Ikebe et al.: "TNF inhibited the apoptosis by activation of Akt serine/threonine kinase in the human head and neck squamous cell carcinoma"Cellular Signalling. 14. 771-778 (2002)

F.Sandra、N.Matsuki、H.Takeuchi、T.Ikebe 等人：“TNF 通过激活人头颈鳞状细胞癌中的 Akt 丝氨酸/苏氨酸激酶来抑制细胞凋亡”细胞信号传导。