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

Gli1是hedgehog（Hh）通路的靶基因之一，同时也是一个转录因子。重要的是，Gli1在各种类型的恶性肿瘤中被重新激活。Gli1在许多癌症物种中过表达的原因之一可能是Hh通路与多种信号通路如炎症和内分泌通路之间的串扰。在此研究期间，我们获得了以下关于Gli1的新发现。(1)通过激活核因子- κ B通路通过Shh过表达诱导Gli1的配体依赖性。(2)结肠癌和胃癌中Gli1过表达抑制Wnt通路。(3)雌激素受体通路依赖性Gli1在乳腺癌和胃癌中的诱导作用。(4)缺氧条件下Gli1诱导不依赖于配体，但依赖于smos。(5)胃癌组织浸润单核细胞产生Shh诱导旁分泌Gli1的作用。我们还阐明了Gli1的以下新的生物学功能。(1)胰腺癌、乳腺癌和胃癌细胞的增殖和侵袭能力增强。(2) Gli1在胰腺癌和乳腺癌肿瘤发生和/或进展中的可能作用。(3) Gli1在乳腺癌干细胞耐药和致瘤性中的作用。这些发现表明Gli1不仅是治疗多种癌症的有效靶点，而且也是治疗癌症干细胞的有效靶点。

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.