FGF/FGFR Signaling in Hepatocellular Carcinoma: From Carcinogenesis to Recent Therapeutic Intervention
Authors: Yijun Wang
Limin Xia
Danfei Liu
Tongyue Zhang
Journal: Cancers (2021)
Discipline: CLINICAL MEDICINE
Keywords: FGF; FGFR; HCC; targeted therapies.
Affiliations: Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.

Abstract:  Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, ranking third in cancer deaths worldwide. Over the last decade, several studies have emphasized the development of tyrosine kinase inhibitors (TKIs) to target the aberrant pathways in HCC. However, the outcomes are far from satisfactory due to the increasing resistance and adverse effects. The family of fibroblast growth factor (FGF) and its receptors (FGFR) are involved in various biological processes, including embryogenesis, morphogenesis, wound repair, and cell growth. The aberrant FGF/FGFR signaling is also observed in multiple cancers, including HCC. Anti-FGF/FGFR provides delightful benefits for cancer patients, especially those with FGF signaling alteration. More and more multi-kinase inhibitors targeting FGF signaling, pan-FGFR inhibitors, and selective FGFR inhibitors are now under preclinical and clinical investigation. This review summarizes the aberrant FGF/FGFR signaling in HCC initiating, development and treatment status, and provide new insights into the treatment of HCC. 

Retracted: No

PubPeer comments:
 Structure with pdb code 2vwa is described in the paper. 2fo-fc electron density map at 1.0 sigma contour level does not show electron density for ligand phosphatidylethanolamine. rscc value is 0.48 which is very low. The ligand is not bound to protein and the inferences in the paper are invalid.![file] , 
 As clearly mentioned in the manuscript, of the 6 protein chains in the ASU, the ligand (PE) is well ordered in a few (in C and F). The RSCC values also show that in a few chains the ligand is bound well. You selectively quote the RSCC of chains B and E but the pdb validation report clearly shows molecules C and F with RSCC of 0.65 and 0.71. , 
 RSCC values of 0.65 and 0.71 also very poor. According to User guide to wwPDB X-ray validation reports: http: www.wwpdb.org validation 2016 XrayValidationReportHelp  A value above 0.95 normally indicates a very good fit. RSCC around 0.90 are generally OK. A poor fit results in a value around or below 0.80 that may well indicate the experimental data do not accord with the ligand placement. Look at Table 1 here https: www.ncbi.nlm.nih.gov pmc articles PMC4531100 The rscc values are poor because ligand not bound and there is no electron density for ligand in map. Conclusions in paper are not valid. , 
 Clearly the density of the ligand does not support results or conclusions drawn. Perhaps the authors should being in more rigor by doing different kinds of omit maps, showing Fo-Fc maps, and not 2Fo-Fc maps. The latter is the camoflouging trick used by crystallographers around the world, but the true picture would be available only when an omit Fo-Fc is presented. In this scenario, it is clear that crystals and ASU **DO NOT** show evidence of ligand-bound- conclusions drawn are clearly erroneous. , 
 I saw this thread because I am interested in lipid binding proteins. I made 2fo-fc maps and looked at them at a contour of 1.0 sigma. Contrary to what is mentioned in the paper or claimed by the corresponding author in #2, there is no density for the ligand for any of the monomers. The pictures of the maps can be seen in this post. A to F monomer from top to bottom.![file] ![file] ![file] ![file] ![file] ![file] , 
 ![file] , 
 There is barely any density visible in the Fo-Fc and 2Fo-Fc map shown in #6 . There is no density for a large part of the molecule in the polder map. If this is the best map for the ligand among the six monomers, then it is clear that the X-ray data does not support the claim that UIS3 binds to phosphatidylethanolamine. ,