Huang Chao-Yuan, Tai Wei-Tien, Wu Szu-Yuan, Shih Chih-Ting, Chen Min-Hsuan, Tsai Ming-Hsien, Kuo Chiung-Wen, Shiau Chung-Wai, Hung Man-Hsin, Chen Kuen-Feng
Department of Oncology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan; Department of Radiological Technology, Yuanpei University, Hsinchu, Taiwan.
Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan; National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, Taipei, Taiwan.
Int J Radiat Oncol Biol Phys. 2016 Jun 1;95(2):761-71. doi: 10.1016/j.ijrobp.2016.01.016. Epub 2016 Jan 20.
Hepatocellular carcinoma (HCC) is among the most lethal human malignancies, and curative therapy is not an option for most patients. There is growing interest in the potential benefit of combining targeted therapies with radiation therapy (RT). This study aimed to characterize the efficacy and mechanism of an investigational drug, dovitinib, used in combination with RT.
HCC cell lines (PLC5, Hep3B, SK-Hep1, HA59T, and Huh-7) were treated with dovitinib, RT, or both, and apoptosis and signal transduction were analyzed.
Dovitinib treatment resulted in Src homology region 2 (SH2) domain-containing phosphatase 1 (SHP-1)-mediated downregulation of p-STAT3 and promoted potent apoptosis of HCC cells. Ectopic expression of STAT3, or inhibition of SHP-1, diminished the effects of dovitinib on HCC cells. By ectopic expression and purified recombinant proteins of various mutant forms of SHP-1, the N-SH2 domain of SHP-1 was found to be required for dovitinib treatment. Overexpression of STAT3 or catalytic-dead mutant SHP-1 restored RT-induced reduction of HCC cell survival. Conversely, ectopic expression of SHP-1 or activation of SHP-1 by dovitinib enhanced the effects of RT against HCC in vitro and in vivo.
SHP-1/STAT3 signaling is critically associated with the radiosensitivity of HCC cells. Combination therapy with RT and the SHP-1 agonist, such as dovitinib, resulted in enhanced in vitro and in vivo anti-HCC effects.
肝细胞癌（HCC）是最致命的人类恶性肿瘤之一，大多数患者无法选择治愈性治疗。将靶向治疗与放射治疗（RT）联合使用的潜在益处越来越受到关注。本研究旨在表征一种研究性药物多韦替尼与RT联合使用的疗效和机制。
用多韦替尼、RT或两者对HCC细胞系（PLC5、Hep3B、SK-Hep1、HA59T和Huh-7）进行处理，并分析细胞凋亡和信号转导。
多韦替尼治疗导致含Src同源区2（SH2）结构域的磷酸酶1（SHP-1）介导的p-STAT3下调，并促进HCC细胞的有效凋亡。STAT3的异位表达或SHP-1的抑制减弱了多韦替尼对HCC细胞的作用。通过SHP-1各种突变形式的异位表达和纯化重组蛋白，发现SHP-1的N-SH2结构域是多韦替尼治疗所必需的。STAT3的过表达或催化失活突变体SHP-1恢复了RT诱导的HCC细胞存活率降低。相反，SHP-1的异位表达或多韦替尼对SHP-1的激活增强了RT在体外和体内对HCC的作用。
SHP-1/STAT3信号传导与HCC细胞的放射敏感性密切相关。RT与SHP-1激动剂（如多韦替尼）联合治疗可增强体外和体内抗HCC效果。
