Abstract
ObjectivesCell migration has a key role in cancer metastasis, which contributes to drug resistance and tumour recurrence. Better understanding of the mechanisms involved in this process will potentially reveal new drug targets for cancer therapy. Fer is a non‐receptor protein tyrosine kinase aberrantly expressed in various human cancers, whereas its role in tumour progression remains elusive.Materials and MethodsTransgenic flies and epigenetic analysis were employed to investigate the role of Drosophila Fer (FER) in cell migration and underlying mechanisms. Co‐immunoprecipitation assay was used to monitor the interaction between FER and Drosophila JNK (Bsk). The conservation of Fer in regulating JNK signalling was explored in mammalian cancer and non‐cancer cells.ResultsOverexpression of FER triggered cell migration and activated JNK signalling in the Drosophila wing disc. Upregulation and downregulation in the basal activity of Bsk exacerbated and eliminated FER‐mediated migration, respectively. In addition, loss of FER blocked signal transduction of the JNK pathway. Specifically, FER interacted with and promoted the activity of Bsk, which required both the kinase domain and the C‐terminal of Bsk. Lastly, Fer regulated JNK activities in mammalian cells.ConclusionsOur study reveals FER as a positive regulator of JNK‐mediated cell migration and suggests its potential role as a therapeutic target for cancer metastasis.
Highlights
Cell migration is a critical characteristic of cancer progression
Our results demonstrate that FER promotes cell migration in the wing disc, and the JNK signalling pathway mediates FER‐induced cell mi‐ gration
These results indicate that FER‐induced cell migration in the wing discs is mainly attributed to the activation of the JNK signalling pathway
Summary
Cell migration is a critical characteristic of cancer progression. This process facilitates cancer cells moving towards distant sites from the primary tumour and induces drug resistance.[1,2] cancer metastasis contributes to >90% of the cancer mortality.[3]. Drosophila, a classic model organism for developmental biological research, has recently been used to investigate the cancer‐related processes.[14] many cellular regulating systems and signalling. Recent studies show that Fer is implicated in numer‐ ous cellular processes such as cell cycle, cell proliferation, and migra‐ tion.[19] In addition, several lines of evidence support a role of Fer in cancer promotion. It has been reported that Fer is aberrantly upregulated or activated in various cancers such as breast, prostate, hepatic and lung cancers.[20,21,22,23] Secondly, the high expression of Fer is significantly correlated with poor prognosis in renal cell carcinoma.[24] Besides, a recent research reports that Fer overexpression activates NF‐κB pathway and confers quinacrine resistance to several cancer cell lines.[25] due to the complexity of cancer develop‐ ment and the limitations of our understanding of Fer, the molecu‐ lar mechanism by which Fer promotes tumour progression remains elusive. A/P compartment boundary of the wing discs expressing ptc‐Gal[4] UAS‐GFP/+; UAS‐GFP/pucE69 (E), ptc‐Gal[4] UAS‐GFP/+; UAS‐FER/ UAS‐GFP (F), ptc‐Gal[4] UAS‐ GFP/UAS‐GFP; UAS‐FER/pucE69 (G), ptc‐ Gal[4] UAS‐GFP/+; UAS‐FER/UAS‐bskDN (H)
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