Phenotypic and Signaling Consequences of a Novel Aberrantly Spliced Transcript FGF Receptor-3 in Hepatocellular Carcinoma

Abstract

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 FGFR3 D7-9 , was identified as a high frequency even in HCC. FGFR3 D7-9 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 FGFR3 D7-9 receptor to FGFs was significantly higher than wild-type FGFR3 IIIc . Furthermore, FGFR3 D7-9 could be self-activated by homodimerization and autophosphorylation even in the absence of ligand. Finally, FGFR3 D7-9 more potently induced phosphorylation of the ERK and AKT kinases, leading to abnormal downstream signaling through the ERK and PI3K/AKT/mTOR pathways. FGFR3 D7-9 also upregulated the metastasis-associated molecules Snail, MMP-9, and downregulated E-cadherin, which associated directly with FGFR3 D7-9 . Thus, as a ligand-dependent or -independent receptor, FGFR3 D7-9 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. Ó2016 AACR.

Interaction of FGF9 with FGFR3‐IIIb/IIIc, a putative driver of growth and aggressive behaviour of hepatocellular carcinoma

“…Higher FGFR3 protein levels occurred in 24% of HCC harbouring a FGFR3 gene with single nucleotide mutations in exon 9, 11 or 12 27 . Every third HCC expresses a FGFR3 splice variant lacking partly Ig‐like‐III domain but binding FGF1/2 at normal levels 28 . Another splice variant, found in every tenth HCC, lacks Ig‐like‐III domain and shows higher affinities for FGF1/2 than native FGFR3‐IIIc 28 .…”

Pseudomonas aeruginosa-mannose-sensitive hemagglutinin inhibits pancreatic cancer cell proliferation and induces apoptosis via the EGFR pathway and caspase signaling

“…Caspase-3 functions in the last step of caspase activation and plays an important role in apoptosis [24]. PA has been shown to induce apoptosis through the caspase pathway [25].…”

A Novel FGFR3 Splice Variant Preferentially Expressed in African American Prostate Cancer Drives Aggressive Phenotypes and Docetaxel Resistance

“…Three other splicing events within FGFR3 have been previously identified, but all take place within the extracellular Ig-like domains: IIIb (inclusion of exon 8 and exclusion of exon 9), IIIc (inclusion of exon 9 and exclusion of exon 8), and D7-9 variant (skipping of exons 7-9; refs. 24,25). To the best of our knowledge, exon skipping events involving the kinase domain have only been identified in one other RTK, RON.…”