Department of General Surgery, Shanghai Jiaotong University, Shanghai, China.
Int J Immunopathol Pharmacol. 2012 Oct-Dec;25(4):955-65. doi: 10.1177/039463201202500413.
High mobility group box B1 (HMGB1)-receptor for advanced glycation end products (RAGE) axis has been previously known to be involved in carcinogenesis and development of multiple malignancies. Some studies have confirmed that Ethyl pyruvate (EP), a potent inhibitor of HMGB1, exerts the therapeutic effects on metastatic live tumor from gastric cancer. However, the effects and possible molecular mechanisms of EP on gallbladder cancer (GBC) need to be further explored. In the present study, human GBC cell lines (GBC-SD and SGC-996) were treated with different concentrations of EP. Then, the expression levels of HMGB1, RAGE and some transcription factors were identified by Real-time PCR and Western blot assays. Cell proliferative activities indicated by MTT assay, invasive potential by Transwell assay and cell apoptosis and cycle distribution were performed for functional analysis of GBC cell lines in vitro. As a result, EP decreased the expression of HMGB11, RAGE, PCNA and matrix metallopeptidase-9 (MMP-9), while it increased the expression of p53. Moreover, EP administration decreased GBC cell proliferation, inhibited the invasive potential, and induced apoptosis and cycle arrest in S phase in GBC cells. In conclusion, EP administration inhibits growth and invasion of gallbladder cancer cells possibly via down-regulation of the HMGB1-RAGE axis, suggesting that EP may play a critical role in the treatment of cancer in conjunction with other therapeutic agents.
高迁移率族蛋白 B1（HMGB1）-晚期糖基化终产物受体（RAGE）轴先前已知参与多种恶性肿瘤的发生和发展。一些研究已经证实，高迁移率族蛋白 B1 的有效抑制剂乙基丙酮酸（EP）对转移性胃癌肿瘤具有治疗作用。然而，EP 对胆囊癌（GBC）的作用和可能的分子机制仍需要进一步探索。在本研究中，用人胆囊癌细胞系（GBC-SD 和 SGC-996）用不同浓度的 EP 处理。然后，通过实时 PCR 和 Western blot 分析鉴定 HMGB1、RAGE 和一些转录因子的表达水平。通过 MTT 分析测定细胞增殖活性，通过 Transwell 分析测定侵袭潜力，通过细胞凋亡和细胞周期分布进行体外 GBC 细胞系的功能分析。结果表明，EP 降低了 HMGB11、RAGE、PCNA 和基质金属蛋白酶-9（MMP-9）的表达，同时增加了 p53 的表达。此外，EP 给药可抑制 GBC 细胞增殖，抑制侵袭潜力，并诱导 GBC 细胞凋亡和 S 期细胞周期停滞。总之，EP 给药可能通过下调 HMGB1-RAGE 轴来抑制胆囊癌细胞的生长和侵袭，这表明 EP 可能与其他治疗剂一起在癌症治疗中发挥重要作用。
