Department of Medicine, Gastroenterology Division, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104-6144, USA.
Neoplasia. 2013 May;15(5):472-80. doi: 10.1593/neo.122126.
Esophageal cancer is the eighth most common cancer in the world and has an extremely dismal prognosis, with a 5-year survival of less than 20%. Current treatment options are limited, and thus identifying new molecular targets and pathways is critical to derive novel therapies. Worldwide, more than 90% of esophageal cancers are esophageal squamous cell cancer (ESCC). Previously, we identified that Krüppel-like factor 5 (KLF5), a key transcriptional regulator normally expressed in esophageal squamous epithelial cells, is lost in human ESCC. To examine the effects of restoring KLF5 in ESCC, we transduced the human ESCC cell lines TE7 and TE15, both of which lack KLF5 expression, with retrovirus to express KLF5 upon doxycycline induction. When KLF5 was induced, ESCC cells demonstrated increased apoptosis and decreased viability, with up-regulation of the proapoptotic factor BAX. Interestingly, c-Jun N-terminal kinase (JNK) signaling, an important upstream mediator of proapoptotic pathways including BAX, was also activated following KLF5 induction. KLF5 activation of JNK signaling was mediated by KLF5 transactivation of two key upstream regulators of the JNK pathway, ASK1 and MKK4, and inhibition of JNK blocked apoptosis and normalized cell survival following KLF5 induction. Thus, restoring KLF5 in ESCC cells promotes apoptosis and decreases cell survival in a JNK-dependent manner, providing a potential therapeutic target for human ESCC.
食管癌是全球第八大常见癌症，预后极差，5 年生存率不足 20%。目前的治疗选择有限，因此确定新的分子靶点和途径对于开发新的治疗方法至关重要。在全球范围内，超过 90%的食管癌是食管鳞状细胞癌（ESCC）。此前，我们发现 Krüppel 样因子 5（KLF5）是一种在食管鳞状上皮细胞中正常表达的关键转录调节因子，在人类 ESCC 中丢失。为了研究在 ESCC 中恢复 KLF5 的作用，我们用逆转录病毒转导 TE7 和 TE15 这两种缺乏 KLF5 表达的人 ESCC 细胞系，在诱导四环素时表达 KLF5。当 KLF5 被诱导时，ESCC 细胞表现出增加的细胞凋亡和减少的细胞活力，同时促凋亡因子 BAX 上调。有趣的是，c-Jun N-末端激酶（JNK）信号通路，一种包括 BAX 在内的促凋亡途径的重要上游介质，也在 KLF5 诱导后被激活。KLF5 对 JNK 信号通路的激活是通过 KLF5 对 JNK 通路的两个关键上游调节剂 ASK1 和 MKK4 的反式激活介导的，而 JNK 的抑制阻断了 KLF5 诱导后的细胞凋亡并使细胞存活正常化。因此，在 ESCC 细胞中恢复 KLF5 以 JNK 依赖性方式促进细胞凋亡并减少细胞存活，为人类 ESCC 提供了一个潜在的治疗靶点。
