Silencing activating transcription factor 2 promotes the anticancer activity of sorafenib in hepatocellular carcinoma cells. 2018

Lifang Luo, and Lijing Cai, and Laibang Luo, and Zhimou Tang, and Xiaohui Meng
Department of Pharmacy, Jiangxi Provincial People's Hospital, Nanchang, Jiangxi 330006, P.R. China.

The present study aimed to investigate the anticancer effect of sorafenib combined with silencing of activating transcription factor 2 (ATF2) in hepatocellular carcinoma (HCC) cells and to assess the underlying molecular mechanisms. Huh‑7 HCC cell line was selected for the present study. Small interfering RNA (siRNA)‑ATF2 sequence was constructed to silence ATF2 expression. The experiment was divided into 6 groups: i) Control; ii) vector; iii) sorafenib (6.8 µM); iv) vector+sorafenib; v) siRNA‑ATF2; and vi) siRNA‑ATF2+sorafenib groups. Cell proliferation, apoptosis, migration and invasion were detected following treatments with sorafenib and/or ATF2 silencing. Additionally, expression of tumor necrosis factor (TNF)‑α and c‑Jun N‑terminal kinase 3 (JNK3) was detected using reverse transcription‑quantitative polymerase chain reaction and western blotting. The current findings revealed that siRNA‑ATF2 significantly reduced ATF2 expression. Cell proliferation, migration and invasion abilities in the sorafenib and siRNA‑ATF2 groups were significantly reduced compared with the control group (P<0.05). Apoptotic rate in the sorafenib and siRNA‑ATF2 groups was significantly increased compared with the control group (P<0.05). The mRNA and protein expression levels of ATF2 in the sorafenib or siRNA‑ATF2 groups was significantly reduced when compared with control group. The phosphorylation of ATF2 was also reduced following sorafenib treatment or ATF2 silence. Although JNK3 mRNA expression level was not affected, the phosphorylation level of JNK3 was significantly promoted following sorafenib treatment or ATF2 silencing. Additionally, TNF‑α mRNA and protein expression levels were increased following sorafenib treatment or ATF2 silencing. It is of note that siRNA‑ATF2 treatment promoted the anticancer activity of sorafenib in Huh‑7 cells. Additionally, siRNA‑ATF2+sorafenib treatment combined additionally promoted TNF‑α expression and phosphorylation of JNK3. Combined siRNA‑ATF2 and sorafenib treatment had a greater anticancer effect compared with sorafenib or ATF2 silencing alone. The possible mechanism involved in the anticancer effect of sorafenib and ATF2 silencing may be associated with the activation of the TNF‑α/JNK3 signaling pathway.

UI MeSH Term Description Entries
D008113 Liver Neoplasms Tumors or cancer of the LIVER. Cancer of Liver,Hepatic Cancer,Liver Cancer,Cancer of the Liver,Cancer, Hepatocellular,Hepatic Neoplasms,Hepatocellular Cancer,Neoplasms, Hepatic,Neoplasms, Liver,Cancer, Hepatic,Cancer, Liver,Cancers, Hepatic,Cancers, Hepatocellular,Cancers, Liver,Hepatic Cancers,Hepatic Neoplasm,Hepatocellular Cancers,Liver Cancers,Liver Neoplasm,Neoplasm, Hepatic,Neoplasm, Liver
D009536 Niacinamide An important compound functioning as a component of the coenzyme NAD. Its primary significance is in the prevention and/or cure of blacktongue and PELLAGRA. Most animals cannot manufacture this compound in amounts sufficient to prevent nutritional deficiency and it therefore must be supplemented through dietary intake. Nicotinamide,Vitamin B 3,Vitamin PP,3-Pyridinecarboxamide,Enduramide,Nicobion,Nicotinsäureamid Jenapharm,Papulex,Vitamin B3,3 Pyridinecarboxamide,B 3, Vitamin,B3, Vitamin,Jenapharm, Nicotinsäureamid
D010671 Phenylurea Compounds Compounds that include the amino-N-phenylamide structure. Phenylcarbamides,Phenylurea Derivatives,Compounds, Phenylurea,Derivatives, Phenylurea
D002465 Cell Movement The movement of cells from one location to another. Distinguish from CYTOKINESIS which is the process of dividing the CYTOPLASM of a cell. Cell Migration,Locomotion, Cell,Migration, Cell,Motility, Cell,Movement, Cell,Cell Locomotion,Cell Motility,Cell Movements,Movements, Cell
D006528 Carcinoma, Hepatocellular A primary malignant neoplasm of epithelial liver cells. It ranges from a well-differentiated tumor with EPITHELIAL CELLS indistinguishable from normal HEPATOCYTES to a poorly differentiated neoplasm. The cells may be uniform or markedly pleomorphic, or form GIANT CELLS. Several classification schemes have been suggested. Hepatocellular Carcinoma,Hepatoma,Liver Cancer, Adult,Liver Cell Carcinoma,Liver Cell Carcinoma, Adult,Adult Liver Cancer,Adult Liver Cancers,Cancer, Adult Liver,Cancers, Adult Liver,Carcinoma, Liver Cell,Carcinomas, Hepatocellular,Carcinomas, Liver Cell,Cell Carcinoma, Liver,Cell Carcinomas, Liver,Hepatocellular Carcinomas,Hepatomas,Liver Cancers, Adult,Liver Cell Carcinomas
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000077157 Sorafenib A niacinamide and phenylurea derivative that inhibits multiple intracellular and cell surface kinases thought to be involved in ANGIOGENESIS, including RAF KINASES and VEGF RECEPTORS. It is used in the treatment of advanced RENAL CELL CARCINOMA and HEPATOCELLULAR CARCINOMA, and for treatment of THYROID CARCINOMA refractory to radioactive iodine therapy. 4-(4-(3-(4-Chloro-3-trifluoromethylphenyl)ureido)phenoxy)pyridine-2-carboxylic acid methyamide-4-methylbenzenesulfonate,BAY 43-9006,BAY 545-9085,BAY-545-9085,BAY-673472,Nexavar,Sorafenib N-Oxide,Sorafenib Tosylate,BAY 43 9006,BAY 439006,BAY 545 9085,BAY 5459085,BAY 673472,BAY5459085,Sorafenib N Oxide
D000970 Antineoplastic Agents Substances that inhibit or prevent the proliferation of NEOPLASMS. Anticancer Agent,Antineoplastic,Antineoplastic Agent,Antineoplastic Drug,Antitumor Agent,Antitumor Drug,Cancer Chemotherapy Agent,Cancer Chemotherapy Drug,Anticancer Agents,Antineoplastic Drugs,Antineoplastics,Antitumor Agents,Antitumor Drugs,Cancer Chemotherapy Agents,Cancer Chemotherapy Drugs,Chemotherapeutic Anticancer Agents,Chemotherapeutic Anticancer Drug,Agent, Anticancer,Agent, Antineoplastic,Agent, Antitumor,Agent, Cancer Chemotherapy,Agents, Anticancer,Agents, Antineoplastic,Agents, Antitumor,Agents, Cancer Chemotherapy,Agents, Chemotherapeutic Anticancer,Chemotherapy Agent, Cancer,Chemotherapy Agents, Cancer,Chemotherapy Drug, Cancer,Chemotherapy Drugs, Cancer,Drug, Antineoplastic,Drug, Antitumor,Drug, Cancer Chemotherapy,Drug, Chemotherapeutic Anticancer,Drugs, Antineoplastic,Drugs, Antitumor,Drugs, Cancer Chemotherapy
D014409 Tumor Necrosis Factor-alpha Serum glycoprotein produced by activated MACROPHAGES and other mammalian MONONUCLEAR LEUKOCYTES. It has necrotizing activity against tumor cell lines and increases ability to reject tumor transplants. Also known as TNF-alpha, it is only 30% homologous to TNF-beta (LYMPHOTOXIN), but they share TNF RECEPTORS. Cachectin,TNF-alpha,Tumor Necrosis Factor Ligand Superfamily Member 2,Cachectin-Tumor Necrosis Factor,TNF Superfamily, Member 2,TNFalpha,Tumor Necrosis Factor,Cachectin Tumor Necrosis Factor,Tumor Necrosis Factor alpha
D017209 Apoptosis A regulated cell death mechanism characterized by distinctive morphologic changes in the nucleus and cytoplasm, including the endonucleolytic cleavage of genomic DNA, at regularly spaced, internucleosomal sites, i.e., DNA FRAGMENTATION. It is genetically programmed and serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. Apoptosis, Extrinsic Pathway,Apoptosis, Intrinsic Pathway,Caspase-Dependent Apoptosis,Classic Apoptosis,Classical Apoptosis,Programmed Cell Death,Programmed Cell Death, Type I,Apoptoses, Extrinsic Pathway,Apoptoses, Intrinsic Pathway,Apoptosis, Caspase-Dependent,Apoptosis, Classic,Apoptosis, Classical,Caspase Dependent Apoptosis,Cell Death, Programmed,Classic Apoptoses,Extrinsic Pathway Apoptoses,Extrinsic Pathway Apoptosis,Intrinsic Pathway Apoptoses,Intrinsic Pathway Apoptosis

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