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PRL-3 facilitates Hepatocellular Carcinoma progression by co-amplifying with and activating FAK.
- Source :
-
Theranostics [Theranostics] 2020 Aug 18; Vol. 10 (22), pp. 10345-10359. Date of Electronic Publication: 2020 Aug 18 (Print Publication: 2020). - Publication Year :
- 2020
-
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.<br />Competing Interests: Competing Interests: The authors have declared that no competing interest exists.<br /> (© The author(s).)
- Subjects :
- Animals
Carcinoma, Hepatocellular pathology
Cell Line, Tumor
Cell Movement genetics
Cell Proliferation genetics
DNA Copy Number Variations genetics
Disease Progression
Female
Gene Expression Regulation, Neoplastic genetics
Humans
Liver Neoplasms pathology
Mice
Mice, Inbred BALB C
Mice, Nude
Oncogenes genetics
Phosphatidylinositol 3-Kinases genetics
Phosphorylation genetics
Prognosis
Signal Transduction genetics
Up-Regulation genetics
Carcinoma, Hepatocellular genetics
Focal Adhesion Kinase 1 genetics
Liver Neoplasms genetics
Neoplasm Proteins genetics
Protein Tyrosine Phosphatases genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1838-7640
- Volume :
- 10
- Issue :
- 22
- Database :
- MEDLINE
- Journal :
- Theranostics
- Publication Type :
- Academic Journal
- Accession number :
- 32929353
- Full Text :
- https://doi.org/10.7150/thno.42069