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Functional analysis of Gli1 molecule for developing a new inclusive therapy against many tumor species

Gli1 分子的功能分析，用于开发针对多种肿瘤的新的包容性疗法

基本信息

批准号：
21390363
负责人：
KATANO Mitsuo
金额：
$ 11.56万
依托单位：
Kyushu University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2009
资助国家：
日本
起止时间：
2009 至 2011
项目状态：
已结题

项目摘要

Gli1 is one of target genes in the hedgehog(Hh) pathway, and Gli1 also functions as a transcriptional factor. Importantly, Gli1 is reactivated in various types of malignancies. One of reasons of overexpression of Gli1 in many cancer species may be due to crosstalk between Hh pathway and several signaling pathways such as inflammation and endocrine pathways. During this research periods, we acquired following new findings on Gli1.(1) Ligand-dependent Gli1 induction through Shh overexpression via activation of nuclear factor-kappa B pathway.(2) Suppression of Wnt pathway by Gli1 overexpression in the colon and gastric cancers.(3) Estrogen receptor pathway-dependent Gli1 induction in the breast and gastric cancers.(4) Ligand-independent but Smo-dependent Gli1 induction under hypoxic conditions.(5) Paracrine Gli1 induction through Shh produced by cancer tissue-infiltrating monocytes in the gastric cancer. We also clarified the following new biological functions of Gli1.(1) Increase of proliferation and invasion abilities in the pancreatic, breast, and gastric cancer cells.(2) Possible contribution of Gli1 to tumor initiation and/or progression in the pancreatic and breast cancers.(3) Contributions of Gli1 to drug resistance and tumorigenicity in the breast cancer stem cells. These findings indicate that Gli1 is a useful therapeutic target against not only many cancer species but also cancer stem cells.

Gli1是hedgehog(Hh)通路的靶基因之一，Gli1还具有转录因子的功能。重要的是，Gli1 在多种类型的恶性肿瘤中被重新激活。 Gli1 在许多癌症物种中过度表达的原因之一可能是由于 Hh 通路与炎症和内分泌通路等多种信号通路之间的串扰。在本研究期间，我们获得了以下关于 Gli1 的新发现。(1) 通过激活核因子 kappa B 通路，通过 Shh 过表达诱导配体依赖性 Gli1。(2) 结肠癌和胃癌中 Gli1 过表达抑制 Wnt 通路。(3) 乳腺癌和胃癌中雌激素受体通路依赖性 Gli1 诱导。(4) 低氧条件下不依赖配体但依赖Smo的Gli1诱导。(5)通过胃癌中癌组织浸润单核细胞产生的Shh诱导旁分泌Gli1。我们还阐明了Gli1的以下新生物学功能。(1)增加胰腺癌、乳腺癌和胃癌细胞的增殖和侵袭能力。(2)Gli1对胰腺癌和乳腺癌肿瘤发生和/或进展的可能贡献。(3)Gli1对乳腺癌干细胞的耐药性和致瘤性的贡献。这些发现表明，Gli1 不仅是针对许多癌症物种而且针对癌症干细胞的有用治疗靶点。