Targeting FER Kinase Inhibits Melanoma Growth and Metastasis

Ivanova, Iordanka A.; Arulanantham, Shinthujah; Barr, Kevin; Cepeda, Mario; Parkins, Katie M.; Hamilton, Amanda M.; Johnston, Danielle; Peñuela, Silvia; Hess, David A.; Ronald, John A.; Dagnino, Lina

doi:10.3390/cancers11030419

Cited by 18 publications

(13 citation statements)

References 57 publications

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“…FER regulates cell-cell adhesion, promotes cell migration, and mediates signaling from the cell surface to the cytoskeleton via growth factor receptors [26]. A recent study also showed that targeting FER kinase can inhibit melanoma growth and metastasis [27].…”

Section: Discussionmentioning

confidence: 99%

Identification of a Three-gene Signature Acting as a Novel Prognostic Biomarker in Intrahepatic Cholangiocarcinoma Patients

Tang¹,

Hunag²,

Li³

et al. 2020

Preprint

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Background: Intrahepatic cholangiocarcinoma (iCCA) patients have poor outcomes due to the lack of biomarkers for the selection of treatment options. The present study was conducted to find biomarkers with independent prognostic vaule in iCCA patients. Methods: Gene transcriptome profiles of E-MTAB-6389, TCGA-CHOL and GSE26566 were obtained from ArrayExpress, The Cancer Genome Atlas and the Gene Expression Omnibus databases, respectively. Bioinformatic analyses were performed to screen novel biomarkers for predicting the prognosis of iCCA patients. Using multivariate Cox regression analyses, a 3-gene signature (BTD-FER-COL12A1) with potential prognostic value was identified and validated in both a training cohort and two validation cohorts. Results: A total of 177 iCCA patients were included in this study. From the key gene modules significantly associated with liver cirrhosis and overall survival (OS) of iCCA patients, we identified 89 hub genes for functional analyses. Cox-regression analyses in both the training and validation cohort indicate that FER, COL12A1 and BTD were independent risk factors for iCCA patients. A 3-gene signature (BTD-FER-COL12A1) with independent prognostic value in iCCA patients was validated in the training cohort, as well as in two validation cohorts. In terms of predicting the prognosis of iCCA patients, the receiver operating characteristics (ROC) curves showed that this 3-gene signature had superior prediction power to BTD, FER, and COL12A1 alone, as well as known biomarkers (MUC1, MUC13) of iCCA. Immunohistochemical staining of samples from The Human Protein Atlas showed that FER and COL12A1 were positively expressed in iCCA tissue, although BTD was not, while none of these genes was detected in normal tissue. These findings were consistent with the expression status of BTD, FER and COL12A1 at the transcriptional level. In addition, we found that FER and COL12A1 were significantly associated with the degree of infiltration by tumor-infiltrating immune cells. Conclusion: We discovered a three-gene signature with independent prognostic value as a novel biomarker for prediction prognosis of iCCA patients. Our findings may help to find novel therapeutic targets for precision treatment of iCCA.

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Section: Discussionmentioning

confidence: 99%

Identification of a Three-gene Signature Acting as a Novel Prognostic Biomarker in Intrahepatic Cholangiocarcinoma Patients

Tang¹,

Hunag²,

Li³

et al. 2020

Preprint

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“…FER is ubiquitously expressed, and it is structurally characterized by an F-BAR domain, an SH2 domain, and a COOH-terminal tyrosine kinase domain ( 4 , 5 ). FER is overexpressed in various cancers, including pancreatic ductal adenocarcinomas ( 6 ), bladder urothelial cell carcinoma ( 7 ), melanoma ( 8 ), renal cell carcinoma ( 3 ), and breast cancer ( 9 ), and has been shown to enhance tumor cell metastasis and proliferation. However, the exact function of FER in HCC progression and the relevant biological molecular mechanism require further elucidation.…”

Section: Introductionmentioning

confidence: 99%

FER Regulated by miR-206 Promotes Hepatocellular Carcinoma Progression via NF-κB Signaling

et al. 2021

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ObjectivesFeline sarcoma-related protein (FER) is known to play a critical regulatory role in several carcinomas. However, the exact biological function of FER in hepatocellular carcinoma (HCC) still needs to be investigated. The primary objective of this research was to investigate the unknown function and molecular mechanisms of FER in HCC.Materials and MethodsThe expression level of FER in HCC tissue samples and cells was examined by RT-qPCR, immunohistochemistry and western blot. Cellular and animal experiments were used to explore the effect of FER on the proliferative and metastatic capacities of HCC cells. The crosstalk between FER and NF-κB signaling was explored by western blot. The upstream factors that regulate FER were evaluated through dual-luciferase experiments and western blot assays.ResultsFER was overexpressed in HCC specimens and HCC cell lines. FER expression levels were positively associated with unfavorable clinicopathological characteristics. The higher the expression of FER was, the worse the overall survival of HCC patients was. The results of loss-of-function and gain-of-function experiments indicated that knockdown of FER decreased, while overexpression of FER increased, the proliferation, invasion and metastasis of HCC cells in vitro and in vivo. Mechanistically, we found that FER activated the NF-κB signaling pathway and stimulated epithelial-to-mesenchymal transition (EMT). We also found that FER was directly regulated by miR-206, and the downregulation of miR-206 was associated with proliferation and metastatic progression in HCC.ConclusionsThe present research was the first to reveal that a decrease in miR-206 levels results in an increase in FER expression in HCC, leading to enhanced cell growth and metastatic abilities via activation of the NF-κB signaling pathway.

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“…In addition to motility, FER expression has also been associated with proliferation of tumor cells (8,(20)(21)(22)(23). However, due to the limited number of known substrates, the molecular basis for its pro-proliferation activity remains enigmatic.…”

Section: Introductionmentioning

confidence: 99%

FER-mediated tyrosine phosphorylation and PIK3R2/p85β recruitment on IRS4 promotes the PI3K-AKT signaling pathway and tumorigenesis in ovarian cancer

Zhang

Xiong

Zhu

et al. 2020

Preprint

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Tyrosine phosphorylation, orchestrated by tyrosine kinases and phosphatases, modulates a multi-layered signaling network in a time and space dependent manner. Dysregulation of this post-translational modification is inevitably associated with pathological diseases. Our previous work has demonstrated that non-receptor tyrosine kinase FER is upregulated in ovarian cancer. Knockdown of the kinase attenuates metastatic phenotypes in tumor cells. Here we employed mass spectrometry and biochemical approaches to identify IRS4 as a novel substrate of FER. Using a proximity-based tagging system, we determined that FER-mediated phosphorylation of Tyr779 enables IRS4 to recruit PIK3R2/p85β, the regulatory subunit of PI-3K, and activate the PI3K-AKT pathway. Rescuing IRS4-null ovarian tumor cells with phosphorylation-defective mutant, but not WT IRS4, delayed tumor cell proliferation both in vitro and in vivo. Overall, we revealed a kinase-substrate regulatory mode between FER and IRS4, and the pharmacological inhibition of FER kinase may be beneficial for ovarian cancer patients with PI3K-AKT hyperactivation.

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Targeting FER Kinase Inhibits Melanoma Growth and Metastasis

Cited by 18 publications

References 57 publications

Identification of a Three-gene Signature Acting as a Novel Prognostic Biomarker in Intrahepatic Cholangiocarcinoma Patients

Identification of a Three-gene Signature Acting as a Novel Prognostic Biomarker in Intrahepatic Cholangiocarcinoma Patients

FER Regulated by miR-206 Promotes Hepatocellular Carcinoma Progression via NF-κB Signaling

FER-mediated tyrosine phosphorylation and PIK3R2/p85β recruitment on IRS4 promotes the PI3K-AKT signaling pathway and tumorigenesis in ovarian cancer

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