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Proliferation of human HCC cells and chemically induced mouse liver cancers requires JNK1-dependent p21 downregulation
Lijian Hui, … , Ewa Stepniak, Erwin F. Wagner
Lijian Hui, … , Ewa Stepniak, Erwin F. Wagner
Published November 6, 2008
Citation Information: J Clin Invest. 2008;118(12):3943-3953. https://doi.org/10.1172/JCI37156.
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Research Article Oncology Article has an altmetric score of 6

Proliferation of human HCC cells and chemically induced mouse liver cancers requires JNK1-dependent p21 downregulation

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Abstract

JNK proteins have been shown to be involved in liver carcinogenesis in mice, but the extent of their involvement in the development of human liver cancers is unknown. Here, we show that activation of JNK1 but not JNK2 was increased in human primary hepatocellular carcinomas (HCCs). Further, JNK1 was required for human HCC cell proliferation in vitro and tumorigenesis after xenotransplantation. Importantly, mice lacking JNK1 displayed decreased tumor cell proliferation in a mouse model of liver carcinogenesis and decreased hepatocyte proliferation in a mouse model of liver regeneration. In both cases, impaired proliferation was caused by increased expression of p21, a cell-cycle inhibitor, and reduced expression of c-Myc, a negative regulator of p21. Genetic inactivation of p21 in JNK1–/– mice restored hepatocyte proliferation in models of both liver carcinogenesis and liver regeneration, and overexpression of c-Myc increased proliferation of JNK1–/– liver cells. Similarly, JNK1 was found to control the proliferation of human HCC cells by affecting p21 and c-Myc expression. Pharmacologic inhibition of JNK reduced the growth of both xenografted human HCC cells and chemically induced mouse liver cancers. These findings provide a mechanistic link between JNK activity and liver cell proliferation via p21 and c-Myc and suggest JNK targeting can be considered as a new therapeutic approach for HCC treatment.

Authors

Lijian Hui, Kurt Zatloukal, Harald Scheuch, Ewa Stepniak, Erwin F. Wagner

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Figure 7

JNK inhibitor treatment reduces liver cancer development.

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JNK inhibitor treatment reduces liver cancer development.
(A) Five month...
(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.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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