Activation of c-Jun predicts a poor response to sorafenib in hepatocellular carcinoma: Preliminary Clinical Evidence

• DOI: 10.1038/srep22976
• Publication Date: 2016-03-11T10:54:19Z
• Authors: Wei Chen; Weikai Xiao; Kunsong Zhang; Xiaoyu Yin; Jiaming Lai; Lijian Liang; Dong Chen
• Keywords: Adult; Male; Mitogen-Activated Protein Kinase Kinases; Niacinamide; 0301 basic medicine; 0303 health sciences; Carcinoma, Hepatocellular; Phenylurea Compounds; Liver Neoplasms; JNK Mitogen-Activated Protein Kinases; Apoptosis; Middle Aged; Sorafenib; Article; 3. Good health; Gene Expression Regulation, Neoplastic; 03 medical and health sciences; Drug Resistance, Neoplasm; Biomarkers, Tumor; Humans; Female; RNA, Messenger; Aged; Signal Transduction

AbstractWe determined the mitogen-activated protein kinase (MAPK) gene expression profile of acquired resistance in sorafenib-sensitive hepatocellular carcinoma (HCC) cells and aimed to identify c-Jun as an important molecule mediating the efficacy of sorafenib. Differences in gene expression of the MAPK signaling between untreated and sorafenib-treated HCC cell lines were investigated using real-time polymerase chain reaction array. Western blot and real-time PCR further evaluated the expression of c-Jun. Pathological specimens from 50 patients with advanced HCC were collected to measure p-c-Jun expression. Sorafenib-resistant HCC cells demonstrated greater levels of basal c-Jun mRNA and protein compared with sorafenib-sensitive HCC cells. Sorafenib activated p-c-Jun in a dose- and time-dependent manner in PLC/PRF/5 and MHCC97H cell lines. Decreased expression levels of 6 genes after sorafenib treatment suggested a robust inhibitory impact of sorafenib on MAPK signaling in HCC cells. c-Jun and p-c-Jun expression levels were inversely correlated with the efficacy of sorafenib; a high expression level of p-c-Jun was associated with resistance to sorafenib and poor overall survival in patients with clinical HCC. p-c-Jun may act as a biomarker for predicting responses of sorafenib treatment, thus advocating targeting of JNK/c-Jun signaling as an optimal therapeutic strategy in a subset of HCC.