Figure 7. JNK inhibitor treatment reduces liver cancer development.

(A) Five months after DEN injection, mice were treated with JNK inhibitor peptide D-JNKI1 or control peptide TAT (5 mg/kg) twice a week for 3 months. Quantification of tumor mass, tumor size, and tumor number from D-JNKI1– or TAT-treated mice is shown. (B) Phosphorylation of JNK in DEN-induced liver cancers from D-JNKI1– or TAT-treated mice was analyzed by immunohistochemical staining on liver sections (brown nuclear staining). Proliferation of cancer cells was analyzed by immunostaining for Ki67. (C) Wild-type mice at 4 weeks of age were injected with D-JNKI1 or TAT at 5 mg/kg 2 days before DEN treatment and killed 24 hours after. DEN-induced cell death was analyzed by TUNEL staining on liver sections. TUNEL-positive cells (green-stained nucleus) were quantified. *P < 0.05, Student’s t test. Original magnification, ×200. (D) Schematic model of JNK1-dependent hepatocyte proliferation. JNK1 activation and decreased p21 levels are apparently important for cell proliferation during liver carcinogenesis and regeneration. p21, repressed by c-Myc, attenuates proliferation of liver cells, probably via suppressing cyclin D1. Importantly, this pathway is negatively regulated by p38α and NF-κB stress-signaling pathways and appears to be independent of c-Jun. Data are expressed as mean ± SD.