Overexpression of c-Jun contributes to sorafenib resistance in human hepatoma cell lines.
BACKGROUND
Despite recent advances in treatment strategies, it is still difficult to cure patients with hepatocellular carcinoma (HCC). Sorafenib is the only approved multiple kinase inhibitor for systemic chemotherapy in patients with advanced HCC. The majority of advanced HCC patients are resistant to sorafenib. The mechanisms of sorafenib resistance are still unknown.


METHODS
The expression of molecules involved in the mitogen-activated protein kinase (MAPK) signaling pathway in human hepatoma cell lines was examined in the presence or absence of sorafenib. Apoptosis of human hepatoma cells treated with sorafenib was investigated, and the expression of Jun proto-oncogene (c-Jun) was measured.


RESULTS
The expression and phosphorylation of c-Jun were enhanced in human hepatoma cell lines after treatment with sorafenib. Inhibiting c-Jun enhanced sorafenib-induced apoptosis. The overexpression of c-Jun impaired sorafenib-induced apoptosis. The expression of osteopontin, one of the established AP-1 target genes, was enhanced after treatment with sorafenib in human hepatoma cell lines.


CONCLUSIONS
The protein c-Jun plays a role in sorafenib resistance in human hepatoma cell lines. The modulation and phosphorylation of c-Jun could be a new therapeutic option for enhancing responsiveness to sorafenib. Modulating c-Jun may be useful for certain HCC patients with sorafenib resistance.
Department of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, Chiba, Japan.
Yuki
Y
Haga
Department of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, Chiba, Japan.
Tatsuo
http://orcid.org/0000-0003-4672-9289
T
Kanda
Department of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, Chiba, Japan.
Masato
M
Nakamura
Department of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, Chiba, Japan.|Department of Molecular Virology, Chiba University, Graduate School of Medicine, Chiba, Japan.
Shingo
S
Nakamoto
Department of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, Chiba, Japan.
Reina
R
Sasaki
Department of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, Chiba, Japan.
Koji
K
Takahashi
Department of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, Chiba, Japan.
Shuang
S
Wu
Department of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, Chiba, Japan.
Osamu
O
Yokosuka
D000873:Anthracenes / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000473:pathology*; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D056945:Hep G2 Cells; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008113:Liver Neoplasms / Q000188:drug therapy / Q000473:pathology*; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D053495:Osteopontin / Q000096:biosynthesis; D010671:Phenylurea Compounds / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D000090063:Proto-Oncogene Mas; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D000077157:Sorafenib
D000873:Anthracenes; D000970:Antineoplastic Agents; C000715470:MAS1 protein, human; D010671:Phenylurea Compounds; D000090063:Proto-Oncogene Mas; D034741:RNA, Small Interfering; D053495:Osteopontin; C432165:pyrazolanthrone; D009536:Niacinamide; D000077157:Sorafenib; D048031:JNK Mitogen-Activated Protein Kinases; D053148:Caspase 3; D053179:Caspase 7