A Novel Drug, CC-122, Inhibits Tumor Growth in Hepatocellular Carcinoma through Downregulation of an Oncogenic TCF-4 Isoform()()

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.