FGF19/FGFR4 signaling contributes to the resistance of hepatocellular carcinoma to sorafenib

Gao, Lixia; Wang, Xiuli; Tang, Yaoliang; Huang, Shuang; Hu, Chien An A.; Teng, Yong

doi:10.1186/s13046-016-0478-9

Cited by 137 publications

(102 citation statements)

References 40 publications

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“…Up-regulation of FGFR4 is associated with multiple oncogenic functions in cancer, including cell survival, proliferation, apoptosis, migration, and chemoresistance [14, 18]. A role for FGFR4 in chemoresistance has recently been described for hepatocellular carcinoma and colorectal cancer [35, 36]. Here, using a loss-of-function study, we showed that FGFR4 knockdown improves the chemotherapy response of ADR-R cells to ADR treatment and suppresses glycolytic flux.…”

Section: Discussionmentioning

confidence: 87%

FGFR4 Links Glucose Metabolism and Chemotherapy Resistance in Breast Cancer

Xu¹,

Chen²,

Yang³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Poor response to chemotherapy leads to the relapse and metastatic progression of tumors. Reprogrammed glucose metabolism is one of the important hallmarks of cancer that facilitates cancer cell survival, proliferation and chemoresistance. However, the precise fate of glucose metabolism and its role in therapy responsiveness in cancers remains largely unexplored. Methods: The glycolytic phenotype of doxorubicin (ADR)-resistant breast cancer cells and their parental cells was assessed by measuring glucose uptake, lactate release, and extracellular acidification rate (ECAR). Protein expression was detected by Western blotting analysis and mRNA expression was detected using q-PCR. Cell survival ratio was determined by the cell counting kit 8 assay. The role of fibroblast growth factor receptor 4 (FGFR4) in glycolysis, chemoresistance, and the underlying mechanisms were studied by using gene expression microarray and short hairpin RNA-mediated gene knockdown. Results: We found that glycolytic flux are increased in two doxorubicin (ADR)-resistant breast cancer cell lines compared with their parental wild type cells, as demonstrated by increased glucose uptake, lactate release, and extracellular acidification rate (ECAR). By gene expression microarray, we identified FGFR4 as a critical modulator of ADR resistance and enhanced glucose metabolism. Genetic silencing of FGFR4 increased the chemosensitivity and suppressed the enhanced glycolytic flux in ADR-resistant cells. Mechanistically, activation of FGFR4 signaling in ADR-resistant cells led to the phosphorylation of FGF receptor substrate 2 (FRS2) and further activated the downstream MAPK/ERK signaling. Pharmacological inhibition of FGFR4-FRS2-ERK signaling pathway significantly blocked the chemoresistant and glycolytic phenotypes of ADR-resistant cells. Conclusion: Our findings suggest that high levels of FGFR4 can increase glucose metabolism and lead to chemoresistance in breast cancer and reveal the mechanistic basis for targeting FGFR4 as a therapeutic opportunity for chemoresistant tumors.

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Section: Discussionmentioning

confidence: 87%

FGFR4 Links Glucose Metabolism and Chemotherapy Resistance in Breast Cancer

Xu¹,

Chen²,

Yang³

et al. 2018

Cell Physiol Biochem

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“…A recent clinical report showed that FGF19 expression is associated with cancer progression and poor prognosis in HCC . Other preclinical studies have demonstrated that FGF19 may serve as a predictive biomarker for primary resistance to sorafenib in HCC, as FGF19 silencing in sorafenib‐resistant cells significantly increased the sensitivity to sorafenib . In breast cancer, neutralization of extracellular FGF19 by anti‐FGF19 antibody or siRNA‐mediated knockdown of FGF19 can decrease the p‐AKT level, suppress cancer cell growth, and enhance doxorubicin sensitivity …”

Section: Discussionmentioning

confidence: 99%

“…The interaction of ligand and receptor mediates almost all related biological activities at both the N and C terminals of FGF19. A previous study suggested that the FGF19‐FGFR4 signaling axis may be a crucial player, contributing to the development of a certain type of hepatocellular carcinoma (HCC), drawing great attention to therapeutic intervention of the FGF19/FGFR4 autocrine loop in this disease setting . Small interfering RNA (siRNA)‐mediated silencing of FGF19 was also reported to decrease AKT phosphorylation, inhibit cancer cell growth, and sensitize doxorubicin treatment in both FGFR4 and FGF19 positive breast cancer cells.…”

Section: Introductionmentioning

confidence: 99%

FGF19 genetic amplification as a potential therapeutic target in lung squamous cell carcinomas

et al. 2017

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BackgroundAlthough FGF 19 gene aberrations are associated with carcinogenesis and progression in human cancers, the roles of FGF 19 genetic amplification and expression in Chinese patients with lung squamous cell carcinoma (LSCC) and FGF 19 amplification as a potential therapeutic target for LSCC are not well understood.MethodsFluorescence in situ hybridization analysis and quantitative real‐time‐PCR was used to detect FGF 19 genetic amplification and FGF 19 messenger RNA expression in LSCC tumor and paired adjacent samples. Small interfering RNA and short hairpin RNA were used to knockdown FGF19 in vitro and in vivo. Results FGF 19 amplification was identified in a subset of LSCC patients (37.5%, 15/40), and upregulation of FGF 19 expression was found in 60% (24/40) of tumor tissues compared to adjacent non‐tumorous tissues. Correlation analysis with clinicopathologic parameters showed that FGF 19 upregulation was significantly associated with heavy smoking. Small interfering RNA knockdown of FGF 19 led to the significant inhibition of cell growth and induced apoptosis in LSCC cells carrying the amplified FGF 19 gene, but these effects was not observed in non‐amplified LSCC cells. Interfering FGF 19 expression with short hairpin RNA also resulted in tumor growth inhibition and induced apoptosis in LSCC xenografts with amplified FGF 19 in tumor cells.ConclusionOur results suggested that FGF 19 signaling activation is required for cell growth and survival of FGF 19 amplified LSCC cells, both in vitro and in vivo. Intervention of FGF 19 activation could be a potential therapeutic strategy for LSCC patients with FGF 19 amplification.

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“…Gao et al found that FGF19 is essential for sorafenib efficacy and resistance in the treatment of HCC 61. The authors have demonstrated that elevated FGF19 expression or hyperactivation of FGF19/FGFR4 signaling in HCC cells is one of the main mechanisms of sorafenib resistance 61.…”

Section: Drug Resistancementioning

confidence: 99%

Targeted therapy and personalized medicine in hepatocellular carcinoma: drug resistance, mechanisms, and treatment strategies

Galun

Srdiċ-Rajiċ²,

Bogdanović

et al. 2017

JHC

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Hepatocellular carcinoma (HCC) is characterized by a growing number of new cases diagnosed each year that is nearly equal to the number of deaths from this cancer. In a majority of the cases, HCC is associated with the underlying chronic liver disease, and it is diagnosed in advanced stage of disease when curative treatment options are not applicable. Sorafenib is a treatment of choice for patients with performance status 1 or 2 and/or macrovascular invasion or extrahepatic spread, and regorafenib is the only systemic treatment found to provide survival benefit in HCC patients progressing on sorafenib treatment. Other drugs tested in different trials failed to demonstrate any benefit. Disappointing results of numerous trials testing the efficacy of various drugs indicate that HCC has low sensitivity to chemotherapy that is in great part caused by multidrug resistance. Immunotherapy for HCC is a new challenging treatment option and involves immune checkpoint inhibitors/antibody-based therapy and peptide-based vaccines. Another challenging approach is microRNA-based therapy that involves two strategies. The first aims to inhibit oncogenic miRNAs by using miRNA antagonists and the second strategy is miRNA replacement, which involves the reintroduction of a tumor-suppressor miRNA mimetic to restore a loss of function.

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FGF19/FGFR4 signaling contributes to the resistance of hepatocellular carcinoma to sorafenib

Cited by 137 publications

References 40 publications

FGFR4 Links Glucose Metabolism and Chemotherapy Resistance in Breast Cancer

FGFR4 Links Glucose Metabolism and Chemotherapy Resistance in Breast Cancer

FGF19 genetic amplification as a potential therapeutic target in lung squamous cell carcinomas

Targeted therapy and personalized medicine in hepatocellular carcinoma: drug resistance, mechanisms, and treatment strategies

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