Fibroblast growth factor receptor 4: a putative key driver for the aggressive phenotype of hepatocellular carcinoma

Gauglhofer, Christine; Paur, Jakob; Schrottmaier, Waltraud C.; Wingelhofer, Bettina; Hüber, Daniela; Naegelen, Isabelle; Pirker, Christine; Mohr, Thomas; Heinzle, Christine; Holzmann, Klaus; Marian, Brigitte; Schulte‐Hermann, Rolf; Berger, Walter; Krupitza, Georg; Grusch, Michael; Grasl‐Kraupp, Bettina

doi:10.1093/carcin/bgu151

Cited by 38 publications

(37 citation statements)

References 35 publications

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“…FGFR4 contributes to angiogenesis, tissue differentiation and repair. FGFR4 is highly expressed in embryonic tissues and overexpressed in many tumor tissues, such as prostate, breast, and pancreatic cancers, and HCC [22-25]. Data show that FGFR4 has an oncogenic role in HCC and chemotherapeutic resistance, and tumor invasion is related to high expression of FGFR4 [26-27].…”

Section: Discussionmentioning

confidence: 99%

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TGF-β1 Promotes Hepatocellular Carcinoma Invasion and Metastasis via ERK Pathway-Mediated FGFR4 Expression

Huang¹,

Qiu²,

Wan³

et al. 2018

Cell Physiol Biochem

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Background/Aims: TGF-β1 is beneficial during early liver disease but is tumor-progressive during late stages especially for hepatocellular carcinoma (HCC). Thus, exploring the underlying mechanisms may provide information about a potentially therapeutic role of TGF-β1 in HCC. Methods: Western blot and real-time quantitative PCR were used to quantify FGFR4 expression in HCC cell lines and a normal liver cell line. After constructing the best silencing FGFR4 expression vector, migration and invasiveness of TGF-β1 in HCC was studied in vitro and in vivo. Western blot was used to study the mechanism of TGF-β1 induction on FGFR4 expression with various inhibitors. Results: HepG2 cell lines had the most FGFR4 expression, and data show that silencing FGFR4 suppressed cell proliferation, invasion and migration in HCC induced by TGF-β1 in vitro and in vivo. Moreover, TGF-β1 induced FGFR4 expression through the ERK pathway. Conclusion: Promoting FGFR4 expression via the ERK pathway, TGF-β1 contributes to HCC invasion and metastasis.

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Section: Discussionmentioning

confidence: 99%

“…Data show that FGFR4 has an oncogenic role in HCC and chemotherapeutic resistance, and tumor invasion is related to high expression of FGFR4 [26-27]. However, high expression of FGFR4 contributes to apoptosis and better prognoses [25]. The role of FGFR4 is likely influenced by cellular context and crosstalk with other signaling pathways.…”

Section: Discussionmentioning

confidence: 99%

TGF-β1 Promotes Hepatocellular Carcinoma Invasion and Metastasis via ERK Pathway-Mediated FGFR4 Expression

Huang¹,

Qiu²,

Wan³

et al. 2018

Cell Physiol Biochem

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“…Its stimulation either by treatment with FGF19 or overexpression of FGFR4, and its inhibition by knocking down FGF19, FGFR4 or KLB, or by the overexpression of dominant-negative FGFR4 variants, has been shown to impact on HCC cell proliferation, survival, epithelial-mesenchymal transition (EMT), migration and invasion [33,37,38,49,50,55,58,60,61] . Interestingly, FGF19 may amplify its biological effects on HCC [62] and the EGFR ligand amphiregulin (AREG) in HCC cells, and that the growth-stimulating effects of FGF19 were mediated in part by autocrine AREG production [33] .…”

Section: Defining a Role For The Fgf19-fgfr4/klb Signaling System In mentioning

confidence: 99%

Fibroblast Growth Factor 15/19 in Hepatocarcinogenesis

Álvarez‐Sola

Uriarte²,

Latasa³

et al. 2017

Dig Dis

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Background: Advanced hepatocellular carcinoma (HCC) is a neoplastic disease with a very bad prognosis and increasing worldwide incidence. HCCs are resistant to conventional chemotherapy and the multikinase inhibitor sorafenib is the only agent that has shown some clinical efficacy. It is therefore important to identify key molecular mechanisms driving hepatocarcinogenesis for the development of more efficacious therapies. However, HCCs are heterogeneous tumors and different molecular subclasses have been characterized. This heterogeneity may underlie the poor performance of most of the targeted therapies so far tested in HCC patients. The fibroblast growth factor 15/19 (FGF15/19), FGF receptor 4 (FGFR4) and beta-Klotho (KLB) correceptor signaling system, a key regulator of bile acids (BA) synthesis and intermediary metabolism, is emerging as an important player in hepatocarcinogenesis. Key Messages: Aberrant signaling through the FGF15/19-FGFR4 pathway participates in the neoplastic behavior of HCC cells, promotes HCC development in mice and its overexpression has been characterized in a subset of HCC tumors from patients with poorer prognosis. Pharmacological interference with FGF15/19-FGFR4 signaling inhibits experimental hepatocarcinogenesis, and specific FGFR4 inhibitors are currently being tested in selected HCC patients with tumoral FGF19-FGFR4/KLB expression. Conclusions: Interference with FGF19-FGFR4 signaling represents a novel strategy in HCC therapy. Selection of candidate patients based on tumoral FGF19-FGFR4/KLB levels as biomarkers may result in increased efficacy of FGFR4-targeted drugs. Nevertheless, attention should be paid to the potential on target toxic effects of FGFR4 inhibitors due to the key role of this signaling system in BA metabolism.

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“…The mRNA expression level was evaluated using evaluated threshold cycle (Cq) values. The Cq values were normalized to the expression levels of GAPDH and the relative amount of mRNA specific to each of the target genes was determined using the 2 -ΔΔCq method (18)(19)(20)(21)(22). qPCR was performed with the BIO-RAD CFK96 TM Real-Time System (Bio-Rad Laboratories, Inc., Hercules, CA, USA).…”

Section: Total Rna Extraction and Reverse Transcription-quantitative mentioning

confidence: 99%

“…The incidence of HCC is higher in South East Asia and Africa compared with other regions of the world (18). The crucial etiological factors involved in the development of HCC include infection with hepatitis virus, the structural or functional mutation of oncogenes and tumor suppressor genes (19)(20)(21). Long non-coding RNA URHC regulates cell proliferation and apoptosis by zinc-activated channels via the extracellular signal-related kinase/mitogen-activated protein kinase (MAPK) signaling pathway in HCC (22), and microRNA-24 may modify aflatoxin B1-related HCC prognosis and tumorigenesis (23).…”

Section: Introductionmentioning

confidence: 99%

Sperm-associated antigen 9 is upregulated in hepatocellular carcinoma tissue and enhances QGY cell proliferation and invasion inï¿½vitro

Ren

Zou

et al. 2017

Oncol Lett

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Abstract.The incidence and mortality rates of hepatocellular carcinoma (HCC) are higher in China compared with in other countries. Further research is required in order to improve the diagnosis and treatment of HCC. Sperm-associated antigen 9 (SPAG9) protein has been revealed to serve an important function in cancer progression; however, the underlying mechanisms remain to be elucidated. The present study investigated the expression level of SPAG9 in HCC tissues using quantitative-polymerase chain reaction, immunohistochemistry and western blotting, and the results demonstrated that SPAG9 was overexpressed in HCC tissues compared with the adjacent non-cancerous tissues. To explore the potential mechanisms underlying SPAG9 in HCC, the effect of SPAG9 on cell proliferation, cell cycle, migration and invasion capacities were investigated in the QGY HCC cell line by RNA interference. It was revealed that inhibition of SPAG9 mRNA in QGY cells significantly inhibited the expression level of SPAG9 compared with the control. Depletion of SPAG9 expression decreased cell proliferation (P<0.01) and increased the percentage of cells in the G 1 /G 2 cell cycle phase. The percentage of cells in the S phase was decreased, and cell migration and invasion capabilities in vitro were reduced (P<0.01). In summary, the results of the present study suggested that SPAG9 was upregulated in HCC and may serve an important function in cancer cell proliferation, differentiation and invasion. Whether SPAG9 is a potential diagnostic marker and therapeutic target of human HCC requires additional study. IntroductionSperm-associated antigen 9 (SPAG9) has characteristics of a scaffold protein and is involved in the c-Jun N-terminal kinase JNK signaling pathway, binding to JNK, which suggests that it is involved in physiological processes, including apoptosis, survival, proliferation and tumorigenesis (1,2). SPAG9 is a member of the cancer/testis antigen family expressed from a single copy gene located on human chromosome 17q21. Proteins in the cancer/testis antigen family are overexpressed in a variety of types of cancer (3,4). SPAG9 is also expressed in a variety of tumors (5-9). SPAG9 has been proposed as a novel biomarker for early diagnosis of multiple human tumors, including ovarian, cervical and breast cancers (10-12). Certain studies have revealed that small interfering RNA inhibits expression of SPAG9 and inhibits the growth of various types of tumor cells (13,14). SPAG9 protein has been demonstrated to be involved in cancer progression; however, the underlying mechanisms remain unknown (15,16).Hepatocellular carcinoma (HCC) is the sixth most common type of cancer globally and is the third most common cause of cancer-associated mortality (17). The incidence of HCC is higher in South East Asia and Africa compared with other regions of the world (18). The crucial etiological factors involved in the development of HCC include infection with hepatitis virus, the structural or functional mutation of oncogenes and tumor suppressor genes (19-21...

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Fibroblast growth factor receptor 4: a putative key driver for the aggressive phenotype of hepatocellular carcinoma

Cited by 38 publications

References 35 publications

TGF-β1 Promotes Hepatocellular Carcinoma Invasion and Metastasis via ERK Pathway-Mediated FGFR4 Expression

TGF-β1 Promotes Hepatocellular Carcinoma Invasion and Metastasis via ERK Pathway-Mediated FGFR4 Expression

Fibroblast Growth Factor 15/19 in Hepatocarcinogenesis

Sperm-associated antigen 9 is upregulated in hepatocellular carcinoma tissue and enhances QGY cell proliferation and invasion inï¿½vitro

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