Liu Kun, Liu Feng, Zhang Nannan, Liu Shiying, Jiang Yuyang
Department of Chemistry, Tsinghua University, Beijing 100084, China.
The Ministry-Province Jointly Constructed Base for State Key Lab-Shenzhen Key Laboratory of Chemical Biology, the Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, China.
Int J Mol Sci. 2012;13(5):5818-5831. doi: 10.3390/ijms13055818. Epub 2012 May 15.
Pokemon is an important proto-oncogene that plays a critical role in cellular oncogenic transformation and tumorigenesis. Anoikis, which is regulated by Bim-mediated apoptosis, is critical to cancer cell invasion and metastasis. We investigated the role of Pokemon in anoikis, and our results show that Pokemon renders liver cells resistant to anoikis via suppression of Bim transcription. We knocked-down Pokemon in human hepatoma cells QGY7703 with small interfering RNAs (siRNA). Knockdown of Pokemon alone did not significantly affect the growth and survival of QGY7703 cells but notably enhanced their sensitivity to apoptotic stress due to the presence of chemical agents or cell detachment, thereby inducing anoikis, as evidenced by flow cytometry and caspase-3 activity assays. In contrast, ectopic expression of Pokemon in HL7702 cells led to resistance to anoikis. Dual-luciferase reporter and ChIP assays illustrated that Pokemon suppressed Bim transcription via direct binding to its promoter. Our results suggest that Pokemon prevents anoikis through the suppression of Bim expression, which facilitates tumor cell invasion and metastasis. This Pokemon-Bim pathway may be an effective target for therapeutic intervention for cancer.
Pokemon是一种重要的原癌基因，在细胞致癌转化和肿瘤发生中起关键作用。由Bim介导的凋亡所调控的失巢凋亡对癌细胞的侵袭和转移至关重要。我们研究了Pokemon在失巢凋亡中的作用，结果表明Pokemon通过抑制Bim转录使肝细胞对失巢凋亡产生抗性。我们用小干扰RNA（siRNA）敲低了人肝癌细胞QGY7703中的Pokemon。单独敲低Pokemon对QGY7703细胞的生长和存活没有显著影响，但由于化学试剂的存在或细胞脱离，显著增强了它们对凋亡应激的敏感性，从而诱导失巢凋亡，流式细胞术和caspase-3活性测定证明了这一点。相反，在HL7702细胞中异位表达Pokemon导致对失巢凋亡产生抗性。双荧光素酶报告基因和染色质免疫沉淀分析表明，Pokemon通过直接结合其启动子抑制Bim转录。我们的结果表明，Pokemon通过抑制Bim表达来防止失巢凋亡，这促进了肿瘤细胞的侵袭和转移。这种Pokemon-Bim途径可能是癌症治疗干预的有效靶点。
