Tomimaru Yoshito, Aihara Arihiro, Wands Jack R, Aloman Costica, Kim Miran
Liver Research Center, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI, USA.
Department of Internal Medicine, Division of Digestive Diseases and Nutrition, Section of Hepatology, Rush University Medical Center, Chicago, IL, USA.
Transl Oncol. 2019 Oct;12(10):1345-1356. doi: 10.1016/j.tranon.2019.07.002. Epub 2019 Jul 25.
Immunomodulatory drugs such as lenalidomide (LEN) have shown significant anti-tumor activity against hematologic malignancies and they may have similar actions on solid tumors as well. We studied the effect of a new analog of the immunomodulatory drugs (CC-122) on the growth of hepatocellular carcinoma (HCC) and explored mechanisms of anti-tumor activity by analyzing expression of a novel oncogenic T-cell factor (TCF)-4 J and its downstream gene activation. LEN and CC-122 significantly reduced the expression levels of TCF-4 J and its target genes (SPP1, AXIN2, MMP7, ASPH, CD24, ANXA1, and CAMK2N1); however, CC-122 was more potent. In a xenograft tumor model with a HAK-1A-TCF-4 J derived stable cells, tumor growth was significantly inhibited by CC-122, but not by LEN or vehicle control. The mice with HCC xenograft tumors treated with CC-122 exhibited decreased TCF-4 J expression compared to LEN and control. Furthermore, expression of TCF-4 J-responsive target genes (SPP1, AXIN2, MMP7, ASPH, JAG1, CD24, ANXA1, and CAMK2N1) was reduced by CC-122 and not by LEN or control. These results suggest that CC-122 inhibits HCC tumor growth through downregulation of the oncogenic TCF-4 J isoform.
来那度胺（LEN）等免疫调节药物已显示出对血液系统恶性肿瘤具有显著的抗肿瘤活性，它们对实体瘤可能也有类似作用。我们研究了一种新型免疫调节药物类似物（CC - 122）对肝细胞癌（HCC）生长的影响，并通过分析一种新型致癌性T细胞因子（TCF）-4 J及其下游基因激活的表达来探索其抗肿瘤活性机制。LEN和CC - 122显著降低了TCF - 4 J及其靶基因（SPP1、AXIN2、MMP7、ASPH、CD24、ANXA1和CAMK2N1）的表达水平；然而，CC - 122的作用更强。在一个由HAK - 1A - TCF - 4 J衍生的稳定细胞构建的异种移植肿瘤模型中，CC - 122显著抑制了肿瘤生长，但LEN或溶剂对照则没有。与LEN和对照组相比，用CC - 122治疗的HCC异种移植肿瘤小鼠的TCF - 4 J表达降低。此外，CC - 122降低了TCF - 4 J反应性靶基因（SPP1、AXIN2、MMP7、ASPH、JAG1、CD24、ANXA1和CAMK2N1）的表达，而LEN或对照组则没有。这些结果表明，CC - 122通过下调致癌性TCF - 4 J异构体来抑制HCC肿瘤生长。
