Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, No.17 Yongwai street, Donghu district, Nanchang, 330006, China.
Cell Oncol (Dordr). 2013 Oct;36(5):421-35. doi: 10.1007/s13402-013-0149-1. Epub 2013 Sep 13.
Previous studies have indicated that Hedgehog signaling is essential for gastric cancer development, but its precise role is still unclear. The aim of this study was to clarify the role of Hedgehog signaling in gastric cancer development.
The expression of key Hedgehog signaling components in clinical samples of sequential gastric cancer stages was assessed by immunohistochemistry. The roles and regulatory mechanisms of Hedgehog signaling in human gastric cancer cells and normal gastric epithelial cells were investigated using multiple cell biological approaches and cDNA microarray analyses.
Hedgehog signaling was found to be abnormally activated in a ligand-independent manner during gastric cancer development. Gli1 over-expression and reduced SuFu expression were found to be typical events in gastric cancer tissues. Gli1 over-expression was found to correlate with a poorly differentiated histology, advanced clinical stage, membrane serosa infiltration and lymph node metastasis in patients with gastric cancer. Data obtained from multiple cell biological assays showed that human gastric cancer cells require active Hedgehog signaling for survival, proliferation, migration and colony formation. N-Shh treatment significantly enhanced the migration, invasion and colony formation of gastric cancer cells. Moreover, the results of cDNA microarray analyses indicated that after treatment with cyclopamine or GANT61 (inhibitors of Hedgehog signaling), differentially expressed genes in gastric cancer cells were enriched in the apoptosis and MAPK pathways. Inhibitors of the Hedgehog pathway were found to suppress gastric cancer cell growth via apoptosis induction.
Our findings indicate a vital role of the activated Hedgehog signaling pathway in promoting gastric initiation and progression. The Hedgehog signaling pathway may serve as a target for gastric cancer therapy.
先前的研究表明 Hedgehog 信号通路对于胃癌的发生发展至关重要，但它的确切作用仍不清楚。本研究旨在阐明 Hedgehog 信号通路在胃癌发生发展中的作用。
采用免疫组织化学方法检测 Hedgehog 信号通路关键组成部分在连续胃癌阶段临床样本中的表达。采用多种细胞生物学方法和 cDNA 微阵列分析研究 Hedgehog 信号通路在人胃癌细胞和正常胃上皮细胞中的作用及其调控机制。
研究发现，Hedgehog 信号在胃癌发展过程中以配体非依赖的方式异常激活。Gli1 过表达和 SuFu 表达减少被发现是胃癌组织中的典型事件。Gli1 过表达与胃癌患者组织分化差、临床分期晚、膜浆浸润和淋巴结转移相关。多项细胞生物学实验结果表明，人胃癌细胞的存活、增殖、迁移和集落形成需要活跃的 Hedgehog 信号通路。N-Shh 处理显著增强了胃癌细胞的迁移、侵袭和集落形成能力。此外，cDNA 微阵列分析结果表明，在用 cyclopamine 或 GANT61（Hedgehog 信号通路抑制剂）处理后，胃癌细胞中差异表达的基因富集在凋亡和 MAPK 通路中。Hedgehog 通路抑制剂通过诱导细胞凋亡抑制胃癌细胞生长。
本研究结果表明，激活的 Hedgehog 信号通路在促进胃起始和进展中起着重要作用。Hedgehog 信号通路可能成为胃癌治疗的靶点。
