Tumor Fibroblast Growth Factor Receptor 4 Level Predicts the Efficacy of Lenvatinib in Patients With Advanced Hepatocellular Carcinoma

Tumor Fibroblast Growth Factor Receptor 4 Level Predicts the Efficacy of Lenvatinib in Patients With Advanced Hepatocellular Carcinoma

Objective: biomarkers to optimize treatment outcomes with lenvatinib in patients with advanced hepatocellular carcinoma remains to be established though research intensive and comprehensive genome. Lenvatinib characterized by leading potential inhibition of fibroblast growth factor receptor (FGFR) 4 compared with the prior tyrosine kinase inhibitor. Thus, in this study, we focus on simple quantification of FGFR4 in tumor as a potential predictive indicator.


Methods: According to The Cancer Genome Atlas data collection curation, FGFR4 RNA is widely expressed on hepatocellular carcinoma in the absence of changes in genes. Gene set enrichment analysis revealed that tumor aggressiveness was closely tied to the level of FGFR4. To confirm the relationship between the benefits lenvatinib and tumor addiction to FGFR4 pathway, we analyzed the protein levels in tumors and peripheral blood obtained from 57 patients enrolled prospectively treated with lenvatinib.


Results: Positive immunohistochemical (> 10% of tumor cells) of FGFR4 in biopsy samples before treatment was associated with longer progression-free survival (2.5 vs. 5.5 months, P = 0.01) and objective response rate benefit ( 31% vs 81%, P = 0.006). In contrast, soluble FGFR4 concentration in peripheral blood were measured by enzyme-linked ELISA test was not associated with survival results, due to fluctuations that reflect liver fibrosis. Additional analysis of RNA sequencing using archival surgical specimens (n ​​= 90) suggested that alternative RNA splicing of FGFR4 in cancer also may explain this difference.

Tumor <em>Fibroblast</em> <em>Growth</em> <em>Factor</em> Receptor <em>4</em> Level Predicts the Efficacy of Lenvatinib in Patients With Advanced Hepatocellular Carcinoma
Tumor Fibroblast Growth Factor Receptor 4 Level Predicts the Efficacy of Lenvatinib in Patients With Advanced Hepatocellular Carcinoma

mir-7-5p Increase hepatic stellate cells activation by targeting Fibroblasts Growth Factor Receptor 4

Objective: fibroblast growth factor receptor 4 (FGFR4) is a key mediator to protect the liver from chronic injury. MicroRNA-7 (miR-7) is a tumor suppressor and associated with lipid homeostasis in the liver. This study was designed to examine the role of miR-7-5p / FGFR4 axis in liver fibrogenesis.


Methods:
TargetScan employed to predict microRNAs target FGFR4 in the 3′-translated region (3′-UTR). mir-7-5p and FGFR4 expression in liver tissue pathological and LX-2 cells was determined by using qRT-PCR and immunoblotting test. A dual-luciferase test performed to validate the prediction target. A Cell Counting Lit-8 assay was performed to assess the ability of the proliferation of LX-2 cells. Hydroxyproline content in LX-2 cells was measured using the test tool hidroksiprolin. Expression of liver stellate cells (HSC) activation markers examined using qRT-PCR and immunoblotting test.


Results: FGFR4 is suspected targets of miR-7-5p. In the LX-2 cells, miR-7-5p targeted to FGFR4 to bind a 3′-UTR. FGFR4 was downregulated, but miR-7-5p is markedly improved in the sample of the liver as liver fibrosis level rise. mir-7-5p negatively associated with FGFR4 expression in the liver tissue. Inhibitor of miR-7-5p blocked lipopolysaccharide-induced proliferation and activation of LX-2 cells, and FGFR4 LX-2 inhibits excessive cell proliferation and activation induced by miR-7-5p.


Conclusion: miR-7-5p promote HSC proliferation and activation by downregulating FGFR4. Syndecan-4 is a member of the syndecan family of transmembrane heparan sulfate proteoglycans, and is involved in cell protection, proliferation, and coagulation-fibrinolytic system of blood in vascular endothelial cells. heparan sulfate chains allows the fibroblast growth factor-2 (FGF-2) to form a complex with the receptor and transduce signals for cell growth.

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In this study, cows were cultured aortic endothelial cells, and intracellular signaling pathways that mediate the regulation of syndecan-4 expression in dense and sparse culture by FGF-2 were analyzed.

April

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