title: Activation of c-Jun predicts a poor response to sorafenib in hepatocellular carcinoma: Preliminary Clinical Evidence.
abstract: We 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.
authors.affiliation: Department of Pancreatico-biliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, 510080 China.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Breast Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong Province, 510060 China.
authors.forename: Weikai
authors.initials: W
authors.lastname: Xiao
authors.affiliation: Department of Pancreatico-biliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, 510080 China.
authors.forename: Kunsong
authors.initials: K
authors.lastname: Zhang
authors.affiliation: Department of Pancreatico-biliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, 510080 China.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Yin
authors.affiliation: Department of Pancreatico-biliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, 510080 China.
authors.forename: Jiaming
authors.initials: J
authors.lastname: Lai
authors.affiliation: Department of Pancreatico-biliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, 510080 China.
authors.forename: Lijian
authors.initials: L
authors.lastname: Liang
authors.affiliation: Department of Pancreatico-biliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, 510080 China.
authors.forename: Dong
authors.initials: D
authors.lastname: Chen
mesh_terms: D000328:Adult; D000368:Aged; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000096:biosynthesis* / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000096:biosynthesis* / Q000235:genetics; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D020929:Mitogen-Activated Protein Kinase Kinases / Q000096:biosynthesis / Q000235:genetics; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives*; D010671:Phenylurea Compounds / Q000008:administration & dosage*; D012333:RNA, Messenger / Q000096:biosynthesis; D015398:Signal Transduction / Q000187:drug effects; D000077157:Sorafenib
chemical_list: D014408:Biomarkers, Tumor; D010671:Phenylurea Compounds; D012333:RNA, Messenger; D009536:Niacinamide; D000077157:Sorafenib; D048031:JNK Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases