BackgroundProstate cancer (PCa) is one of the most common cancers in male worldwide. Oxidative stress has been recognized as one of the driving signals pathologically linked to PCa progression. Nevertheless, the association of oxidative stress with PCa progression remains unclear.MethodsWestern blot, q-RT-PCR and bioinformatics analyses were used to examine PAGE4 expression. Comet assay and Annexin V/ PI dual staining assay were performed to investigate DNA damage and cell death under oxidative stress. Mouse xenograft model of PCa cells was established to verify the role of PAGE4 in vivo. Transcriptomic analysis was performed to investigate the underlying mechanism for the function of PAGE4 under oxidative stress. Western blot assay was conducted to determine the status of MAPK pathway. Immunohistochemistry was used to identify protein expression of PAGE4 in tumor tissues.ResultsIn this study, we found that PAGE4 expression was increased in PCa cells under oxidative stress condition. PAGE4 overexpression protected PCa cells from oxidative stress-inducing cell death by reducing DNA damage. PAGE4 overexpression promoted PCa cells growth in vivo. Mechanistically, PAGE4 promoted the survival of prostate cancer cells through regulating MAPK pathway which reflected in decreasing the phosphorylation of MAP2K4, JNK and c-JUN but increasing phosphorylation of ERK1/2.ConclusionOur findings indicate that PAGE4 protects PCa cells from DNA damage and apoptosis under oxidative stress by modulating MAPK signalling pathway. PAGE4 expression may serve as a prognostic biomarker for clinical applications.Electronic supplementary materialThe online version of this article (10.1186/s13046-019-1032-3) contains supplementary material, which is available to authorized users.
It is now widely recognized that carcinoma‐associated fibroblasts which are believed to be myofibroblasts, promote the transformation of prostate epithelial cells to cancer cells, enhance their proliferation and invasiveness, and induce the acquisition of resistance to cancer therapy and immune evasiveness. Prostate‐associated gene 4 (PAGE4) is an intrinsically disordered protein that is remarkably prostate‐specific. PAGE4 is also a stress‐response protein that functions as a transcriptional regulator and is upregulated in early‐stage prostate cancer (PCa) and its precursor lesions. However, PAGE4 is downregulated in high‐grade PCa and metastatic disease. Here, we show that PAGE4 is highly expressed in the stromal cells surrounding the cancer‐adjacent “normal” glands and low‐grade PCa lesions but not in lesions proximal to high‐grade PCa. Overexpression of PAGE4 in a stromal cell line inhibits the migration and invasion of PCa epithelial cells in multiple coculture systems. PAGE4 overexpression also inhibits the downregulation of E‐cadherin in PCa epithelial cells when cocultured with stromal cells. Furthermore, signaling via tumor necrosis factor‐α and transforming growth factor‐β pathways is decreased in the stromal cells overexpressing PAGE4 suggesting that PAGE4 appears to play a protective role against disease progression by perturbing interactions between epithelial cells and stromal cells in PCa. Taken together, these findings support previous observations that upregulation of PAGE4 in PCa correlates with a better prognosis and highlight PAGE4 as a novel therapeutic target for early‐stage “low‐risk” disease.
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