Phenotypic and Signaling Consequences of a Novel Aberrantly Spliced Transcript FGF Receptor-3 in Hepatocellular Carcinoma.
Fibroblast growth factor receptor 3 (FGFR3) plays important roles in cell proliferation, differentiation, and angiogenesis. FGFR3 is abnormally upregulated in hepatocellular carcinoma (HCC), where it correlates positively with clinicopathologic index, HCC differentiation, and advanced nuclear grade. In this study, we describe an aberrantly spliced transcript of FGFR3, termed FGFR3Δ7-9, was identified as a high frequency even in HCC. FGFR3Δ7-9 lacks exons encoding the immunoglobulin-like III domain and promoted the proliferation, migration, and metastasis of HCC cells both in vitro and in vivo Coimmunoprecipation and surface plasmon resonance assays demonstrated that the binding affinity of the aberrant FGFR3Δ7-9 receptor to FGFs was significantly higher than wild-type FGFR3IIIc Furthermore, FGFR3Δ7-9 could be self-activated by homodimerization and autophosphorylation even in the absence of ligand. Finally, FGFR3Δ7-9 more potently induced phosphorylation of the ERK and AKT kinases, leading to abnormal downstream signaling through the ERK and PI3K/AKT/mTOR pathways. FGFR3Δ7-9 also upregulated the metastasis-associated molecules Snail, MMP-9, and downregulated E-cadherin, which associated directly with FGFR3Δ7-9 Thus, as a ligand-dependent or -independent receptor, FGFR3Δ7-9 exerted multiple potent oncogenic functions in HCC cells, including proliferation, migration, and lung metastatic capacity. Overall, FGFR3 mRNA missplicing in HCC contributes significantly to its malignant character, with implications for therapeutic targeting. Cancer Res; 76(14); 4205-15. ©2016 AACR.
Department of Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Ke
K
Li
Department of Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Baiyong
B
Shen
Department of Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Xi
X
Cheng
Department of Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Ding
D
Ma
Department of Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Xiaoqian
X
Jing
Department of Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Xinyu
X
Liu
Department of Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Weiping
W
Yang
Department of Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. drqwh2003@126.com drqwh2003@yahoo.com.
Chenghong
C
Peng
Department of Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. drqwh2003@126.com drqwh2003@yahoo.com.
Weihua
W
Qiu
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D051379:Mice; D009154:Mutation; D010641:Phenotype; D012326:RNA Splicing; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000737:chemistry / Q000235:genetics*; D015398:Signal Transduction / Q000502:physiology*
C496365:FGFR3 protein, human; D051498:Receptor, Fibroblast Growth Factor, Type 3