Department of Gastroenterology, Graduate school of Medicine, University of Tokyo, Tokyo 113-8655, Japan.
Proc Natl Acad Sci U S A. 2011 Jan 11;108(2):780-5. doi: 10.1073/pnas.1011418108. Epub 2010 Dec 27.
Mitogen-activated protein kinase (MAPK) pathways regulate multiple cellular functions and are highly active in many types of human cancers. Apoptosis signal-regulating kinase 1 (ASK1) is an upstream MAPK involved in apoptosis, inflammation, and carcinogenesis. This study investigated the role of ASK1 in the development of gastric cancer. In human gastric cancer specimens, we observed increased ASK1 expression, compared to nontumor epithelium. Using a chemically induced murine gastric tumorigenesis model, we observed increased tumor ASK1 expression, and ASK1 knockout mice had both fewer and smaller tumors than wild-type (WT) mice. ASK1 siRNA inhibited cell proliferation through the accumulation of cells in G1 phase of the cell cycle, and reduced cyclin D1 expression in gastric cancer cells, whereas these effects were uncommon in other cancer cells. ASK1 overexpression induced the transcription of cyclin D1, through AP-1 activation, and ASK1 levels were regulated by cyclin D1, via the Rb-E2F pathway. Exogenous ASK1 induced cyclin D1 expression, followed by elevated expression of endogenous ASK1. These results indicate an autoregulatory mechanism of ASK1 in the development of gastric cancer. Targeting this positive feedback loop, ASK1 may present a potential therapeutic target for the treatment of advanced gastric cancer.
丝裂原活化蛋白激酶（MAPK）途径调节多种细胞功能，在许多人类癌症中高度活跃。凋亡信号调节激酶 1（ASK1）是一种参与细胞凋亡、炎症和致癌作用的上游 MAPK。本研究探讨了 ASK1 在胃癌发展中的作用。与非肿瘤上皮相比，我们在人类胃癌标本中观察到 ASK1 表达增加。使用化学诱导的小鼠胃癌肿瘤发生模型，我们观察到肿瘤 ASK1 表达增加，ASK1 敲除小鼠的肿瘤数量和体积均小于野生型（WT）小鼠。ASK1 siRNA 通过细胞周期 G1 期细胞的积累抑制细胞增殖，并降低胃癌细胞中环素 D1 的表达，而这些作用在其他癌细胞中并不常见。ASK1 过表达通过 AP-1 激活诱导 cyclin D1 的转录，ASK1 水平通过 cyclin D1 通过 Rb-E2F 途径进行调节。外源性 ASK1 诱导 cyclin D1 的表达，随后内源性 ASK1 的表达升高。这些结果表明 ASK1 在胃癌发展中存在自调节机制。针对这个正反馈环，ASK1 可能成为治疗晚期胃癌的潜在治疗靶点。
