title: FGF19/FGFR4 signaling contributes to the resistance of hepatocellular carcinoma to sorafenib.
abstract: Sorafenib, a multi-kinase inhibitor, is used as a standard therapy for advanced hepatocellular carcinoma (HCC). However, complete remission has not been achieved and the molecular basis of HCC resistance to sorafenib remains largely unknown. Previous studies have shown that fibroblast growth factor 19 (FGF19) expression correlates with tumor progression and poor prognosis of HCC. Here, we demonstrate the novel role of FGF19 in HCC resistance to sorafenib therapy.
  
  
  
  FGF19 Knockdown cells were achieved by lentiviral-mediated interference, and FGFR4 knockout cells were achieved by CRISPR-Cas9. Protein levels of FGF19, FGFR4 and c-PARP in various HCC cell lines were measured by Western blotting analysis. Cell viability was determined by MTS assay, apoptosis was determined by DAPI nuclear staining and Western blot of c-PRAP, and ROS generation was determined by DCFH-DA staining and electrochemical biosensor.
  
  
  
  We showed that FGF19, when overexpressed, inhibited the effect of sorafenib on ROS generation and apoptosis in HCC. In contrast, loss of FGF19 or its receptor FGFR4 led to a remarkable increase in sorafenib-induced ROS generation and apoptosis. In addition, knockdown of FGF19 in sorafenib-resistant HCC cells significantly enhanced the sensitivity to sorafenib. Importantly, targeting FGF19/FGFR4 axis by ponatinib, a third-generation inhibitor of chronic myeloid leukemia, overcomes HCC resistance of sorafenib by enhancing ROS-associated apoptosis in sorafenib-treated HCC.
  
  
  
  Our results provide the first evidence that inhibition of FGF19/FGFR4 signaling significantly overcomes sorafenib resistance in HCC. Co-treatment of ponatinib and sorafinib may represent an effective therapeutic approach for eradicating HCC.
authors.affiliation: Department of Oral Biology, Dental College of Georgia, Augusta University, 1120 15th Street, Augusta, GA, 30912, USA.
authors.forename: Lixia
authors.initials: L
authors.lastname: Gao
authors.affiliation: Department of Radiology and Imaging Sciences, School of Medicine, University of Utah, Salt Lake City, UT, USA.|Experimental Therapeutics Program, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
authors.forename: Xuli
authors.initials: X
authors.lastname: Wang
authors.affiliation: Vascular Biology Center, Department of Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA.
authors.forename: Yaoliang
authors.initials: Y
authors.lastname: Tang
authors.affiliation: Department of Anatomy and Cell Biology, University of Florida College of Medicine, Gainesville, FL, USA.
authors.forename: Shuang
authors.initials: S
authors.lastname: Huang
authors.affiliation: Department of Biochemistry and Molecular Biology, University of New Mexico School of Medicine, Albuquerque, NM, USA.
authors.forename: Chien-An Andy
authors.initials: CA
authors.lastname: Hu
authors.affiliation: Department of Oral Biology, Dental College of Georgia, Augusta University, 1120 15th Street, Augusta, GA, 30912, USA. yteng@augusta.edu.|Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, 1120 15th Street, Augusta, GA, USA. yteng@augusta.edu.
authors.forename: Yong
authors.initials: Y
authors.lastname: Teng
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival; D019008:Drug Resistance, Neoplasm; D005346:Fibroblast Growth Factors / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D051499:Receptor, Fibroblast Growth Factor, Type 4 / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D000077157:Sorafenib; D015854:Up-Regulation
chemical_list: C117476:FGF19 protein, human; D010671:Phenylurea Compounds; D017382:Reactive Oxygen Species; D009536:Niacinamide; D005346:Fibroblast Growth Factors; D000077157:Sorafenib; C496371:FGFR4 protein, human; D051499:Receptor, Fibroblast Growth Factor, Type 4
keywords: Drug resistance; FGF19; FGFR4; Hepatocellular carcinoma; Sorafenib; Synergistic effect