Institute of Immunopharmacology and Immunotherapy, School of Pharmaceutical Sciences, Shandong University, 44 Wenhua West Road, Jinan, 250012, China.
Cancer Immunol Immunother. 2014 Apr;63(4):357-67. doi: 10.1007/s00262-014-1518-y. Epub 2014 Jan 23.
Toll-like receptors (TLRs) expressed on cancer cells are closely associated with tumor development. In this study, we investigated the biological functions of the TLR9 ligand, CpG oligodeoxynucleotide (CpG ODN), on TLR9 expressed in the cytoplasm of hepatocellular carcinoma (HCC) cells. In vitro, human HCC cell lines were transfected with phosphorothioate-modified oligodeoxynucleotides TLR9 agonist OND M362 and its negative control ODN M362 ctrl, which inhibited the proliferation of HCC cells by inducing apoptosis without altering the cell cycle. Interestingly, ODN M362 and ODN M362 Ctrl displayed a similar proapoptotic effect on HCC, possibly related to phosphorothioate modification of the structure of CpG ODN. Although both of them resulted in the upregulation of the TLR9 receptor, their effect on HCC apoptosis was independent of TLR9. They also upregulated inflammatory cytokines, but did not activate the NF-κB signaling pathway. Finally, the activities of ODN M362 and ODN M362 Ctrl were demonstrated in nude mice inoculated with HCC cells. These findings suggest that the phosphorothioate-modified TLR9 agonist ODN M362, and its control, elicit antitumor activity in HCC cells and may serve as a novel therapeutic target for HCC therapy.
Toll 样受体 (TLRs) 在癌细胞上的表达与肿瘤的发生发展密切相关。在本研究中，我们研究了 TLR9 配体 CpG 寡脱氧核苷酸 (CpG ODN) 在肝癌 (HCC) 细胞细胞质中表达的 TLR9 的生物学功能。在体外，用硫代修饰的寡脱氧核苷酸 TLR9 激动剂 OND M362 和其阴性对照 ODN M362 Ctrl 转染人 HCC 细胞系，通过诱导细胞凋亡而不改变细胞周期抑制 HCC 细胞的增殖。有趣的是，OND M362 和 ODN M362 Ctrl 对 HCC 表现出相似的促凋亡作用，可能与 CpG ODN 结构的硫代修饰有关。尽管它们都导致 TLR9 受体上调，但它们对 HCC 细胞凋亡的影响与 TLR9 无关。它们还上调了炎症细胞因子，但没有激活 NF-κB 信号通路。最后，在接种 HCC 细胞的裸鼠中证明了 ODN M362 和 ODN M362 Ctrl 的活性。这些发现表明，硫代修饰的 TLR9 激动剂 ODN M362 及其对照物在 HCC 细胞中具有抗肿瘤活性，可能成为 HCC 治疗的新治疗靶点。
