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.
Highlights
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
We have demonstrated that pERK, a molecule in the MAPK pathway, may be a candidate related to the survival of patients with HCC treated with sorafenib22. c-Jun, a downstream target of Jun N-terminal kinase (JNKs), regulates cyclin D and VEGF, suppresses p53 pathway, and causes downregulation of p21, thereby promoting tumorigenesis[19,20,21,22,23]
The survival benefit from sorafenib is reported to be limited with low rates of tumor response, suggesting the existence of a drug resistance mechanism[27,28]
Summary
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. A higher proportion of patients with HCC are diagnosed at advanced stages of the disease when they are unsuitable for curative treatments such as surgical resection and orthotopic liver transplantation[2,5,6,7,8]. This may be attributable to the intrinsic diversity in pathogenesis, molecular heterogeneity, multicentric occurrence, and etiology of HCC9. This would aid in improving the healthcare outcomes in patients with HCC, markedly improving the medico-economic situation
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