PRL-3 facilitates Hepatocellular Carcinoma progression by co-amplifying with and activating FAK

Abstract

Background: In addition to protein tyrosine kinases, accumulating evidence has shown that protein tyrosine phosphatases (PTPs) are suitable therapeutic targets in cancer. PRL-3 is a PTP member that has been well studied in many malignant tumours. The goal of the present study was to elucidate the role of PRL-3 in hepatocellular carcinoma (HCC), which remains largely unknown. Methods: Bioinformatic and immunohistochemical analyses were performed to analyse PRL-3 expression in HCC tissue samples and determine its clinical relevance. PRL-3 gene copy number variations were evaluated by bioinformatic analysis and quantitative-genomic polymerase chain reaction. The biological functions of PRL-3 were investigated in vivo and vitro. Gene microarray assays, RT-qPCR, western blotting and luciferase experiments were performed to identify the downstream effectors of PRL-3 that mediate its functions in HCC. Results: PRL-3 expression was upregulated in HCC samples from public databases and in cohort samples from our centre. High PRL-3 expression was associated with poor prognosis. Copy number gains and amplification of chromosome 8q24.3 in HCC were determined to be positively correlated with the PRL-3 overexpression. PRL-3 overexpression promoted HCC cell proliferation, migration and adhesion, while its loss had the opposite effects. Further study showed that focal adhesion kinase (FAK) was co-amplified and co-expressed with PRL-3 in HCC. Interestingly, PRL-3 also promoted the phosphorylation of FAK, which subsequently mediated the oncogenic functions of PRL-3 in HCC cells. Moreover, TGFB1 was identified as a downstream molecule of PRL-3. TGF-β signalling was shown to mediate the PRL-3-induced activation of FAK. Furthermore, the p38 and PI3K/AKT pathways were observed to mediate the PRL-3-induced expression of TGFB1 and the subsequent activation of FAK, while the activation of FAK in turn stimulated activation of the p38 and PI3K/AKT pathways, forming a PRL-3-triggered AKT/p38/TGFB1/FAK positive feedback loop. Conclusion: Collectively, our findings indicate that the PTP PRL-3 plays a crucial role in the progression of HCC and provides an example of how co-amplified genes work together in HCC.

FGF19 Is Coamplified With CCND1 to Promote Proliferation in Lung Squamous Cell Carcinoma and Their Combined Inhibition Shows Improved Efficacy

“…It is reported that CDK4 and Phosphoinositide 3-kinase enhancer (PIKE-A) are co-localized on chromosomal 12q13.1-14 and co-amplified in glioblastoma and form a protein complex with each other to promote tumorigenesis ( 38 ). Similar mechanism was found for ACTL6A and p63 in head and neck squamous cell carcinoma ( 7 ), PRL-3 and FAK in hepatocellular carcinoma ( 39 ). Differently, S100A7, S100A8 and S100A9 are co-amplified on chromosome 1q21.3 in breast cancer, have similar functions and cooperate with each other to induce target protein phosphorylation leading to tumor recurrence and chemoresistance ( 6 ).…”

INPP5F translocates into cytoplasm and interacts with ASPH to promote tumor growth in hepatocellular carcinoma

“…Deregulation of phosphatases contributes to tumorigenesis and tumor progression, so phosphatases are exciting targets for HCC drug discovery [25]. As for the role of phosphatase in HCC, our previous studies have reported that PRL-1 promotes HCC cell migration and invasion through endothelial-mesenchymal transition induction [26], and that PRL-3 facilitates HCC progression by coamplifing with FAK as well as enhancing FAK phosphorylation [27]. Inositol polyphosphate 5-phosphatases are a group of phosphatases involved in regulating phosphorylation of phosphoinositide.…”

INPP5F Translocates Into Cytoplasm And Interacts With ASPH To Promote Tumor Growth in Hepatocellular Carcinoma

“…Deregulation of phosphatases contributes to tumorigenesis and tumor progression, so phosphatases are exciting targets for HCC drug discovery [25]. As for the role of phosphatase in HCC, our previous studies have reported that PRL-1 promotes HCC cell migration and invasion through endothelial-mesenchymal transition induction [26], and that PRL-3 facilitates HCC progression by co-ampli ng with FAK as well as enhancing FAK phosphorylation [27]. Inositol polyphosphate 5-phosphatases are a group of phosphatases involved in regulating phosphorylation of phosphoinositide.…”