Research and development of anti-tumor therapy by anti-tumor chemokine BRAK

抗肿瘤趋化因子BRAK抗肿瘤治疗的研究进展

• 批准号: 23792390
• 负责人: YOJIRO Maehata
• 金额: $ 2.66万
• 依托单位: Kanagawa Dental College
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Young Scientists (B)
• 财政年份: 2011
• 资助国家: 日本
• 起止时间: 2011 至 2012
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-23792390/
• 关键词: 口腔癌; BRAK; Fasudil; CXCL14/BRAK; BRAK/CXCL14.; RhoA/ROCK経路

We previously reported that chemokine CXCL14/BRAK (BRAK) has antitumor activity in several carcinoma cells, and we also indicated that secretion of BRAK was suppressed in carcinoma cells. Meanwhile, Ras-homologous-small-GTPase (RhoA) and Rho-associated coiled-coil-containing protein kinase (ROCK) are important regulators of secretory processes, and activation of the RhoA/ROCK signaling pathway also stimulates tumor invasion and metastasis. We investigated the effects of fasudil which is a specific ROCK inhibitor on BRAK secretion and tumor progression in mesenchymal fibrosarcoma cells (MC57). We demonstrated the antitumor activity of secreted BRAK using MC57 transplantation of BRAK in overexpressing transgenic mice. Further, to eliminate the influence of change in the mRNA expression of endogenous BRAK, we produced stable MC57 cell lines expressing BRAK (MC57-BRAK) or mock vector (MC57-MOCK). Fasudil significantly increased BRAK secretion by MC57-BRAK cells in a dose-dependent manner. To determine the effect offasudil on tumor growth, MC57-BRAK and MC57-MOCK cells were transplanted into wild-type mice. Fasudil treatment suppressed tumor growth only in mice that had received MC57-BRAK cell allografts. These results indicate that fasudil inhibits fibrosarcoma growth by stimulating BRAK secretion and suggests that fasudil therapymight have clinical efficacy.

我们以前报道过趋化因子CXCL 14/BRAK（BRAK）在几种癌细胞中具有抗肿瘤活性，并且我们还指出在癌细胞中BRAK的分泌受到抑制。同时，Ras-同源-小-GT酶（RhoA）和Rho相关的含卷曲螺旋蛋白激酶（ROCK）是分泌过程的重要调节因子，RhoA/ROCK信号通路的激活也促进肿瘤的侵袭和转移。我们研究了一种特异性ROCK抑制剂法舒地尔对间充质纤维肉瘤细胞（MC 57）中BRAK分泌和肿瘤进展的影响。我们证明了分泌的BRAK的抗肿瘤活性，使用MC 57移植的BRAK在过表达转基因小鼠。此外，为了消除内源性BRAK的mRNA表达变化的影响，我们制备了表达BRAK（MC 57-BRAK）或模拟载体（MC 57-MOCK）的稳定MC 57细胞系。法舒地尔以剂量依赖性方式显著增加MC 57-BRAK细胞的BRAK分泌。为了确定法舒地尔对肿瘤生长的影响，将MC 57-BRAKE和MC 57-MOCK细胞移植到野生型小鼠中。法舒地尔治疗仅抑制了接受MC 57-BRAK细胞同种异体移植的小鼠的肿瘤生长。这些结果表明法舒地尔通过刺激BRAK分泌抑制纤维肉瘤生长，并提示法舒地尔治疗可能具有临床疗效。

项目成果

Fasdil, a specfic inhibitor of ROCK, stimulates secretion of CXCL14/BRAK and suppresses tumor growth in vivo

Fasdil 是 ROCK 的特异性抑制剂，可刺激 CXCL14/BRAK 的分泌并抑制体内肿瘤生长

• 发表时间: 2011
• 作者: Miyamoto C.;Maehata Y.;Ozawa S.;Ikoma T.;Komori R.;Hata R.-I.;Lee M-C
• 通讯作者: Lee M-C

Fasdil, a specfic inhibitor of ROCK, stimulates secretion of CXCL14/BRAK and suppresses tumor growth in vivo.

Fasdil 是 ROCK 的特异性抑制剂，可刺激 CXCL14/BRAK 的分泌并抑制体内肿瘤生长。

• 发表时间: 2011
• 作者: Miyamoto C.;Maehata Y.;Ozawa S.;Ikoma T.;Komori R.;Hata R.-I.;Lee M-C.
• 通讯作者: Lee M-C.

Calcium-calmodulin signaling induced by epithelial cell differentiation upregulates BRAK/CXCL14 expression via the binding of SP1 to the BRAK promoter region

• DOI: 10.1016/j.bbrc.2012.01.157
• 发表时间: 2012-04-06
• 期刊: BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
• 影响因子: 3.1
• 作者: Ikoma, Takeharu;Ozawa, Shigeyuki;Kubota, Eiro
• 通讯作者: Kubota, Eiro

ROCK阻害剤fasdilによるCXCL14/BRACK分泌促進を介した抗腫-効果の検討

ROCK抑制剂fasdil促进CXCL14/BRACK分泌的抗肿瘤效果研究

• 发表时间: 2012
• 作者: 岸本直隆;百田義弘;橋本典也;安東佳代子;大政健史;小谷順一郎;Ikoma T, Ozawa S, Suzuki K, Kondo T, Maehata Y., Lee MC, Hata R, Kubota E.;宮本千央,前畑洋次郎,小澤重幸,生駒丈晴,居作和人,畑隆一郎,李昌一
• 通讯作者: 宮本千央,前畑洋次郎,小澤重幸,生駒丈晴,居作和人,畑隆一郎,李昌一

ROCK Inhibitor fasudil suppresses growth of fibrosarcoma by stimulating secretion of chemokine CXCL14/BRAK

ROCK 抑制剂法舒地尔通过刺激趋化因子 CXCL14/BRAK 的分泌抑制纤维肉瘤的生长

• 发表时间: 2012
• 作者: Miyamoto C.;Maehata Y;Ozawa S.;Ikoma T.;Hata R;Lee M-C
• 通讯作者: Lee M-C