Downregulation of PARVA promotes metastasis by modulating integrin-linked kinase activity and regulating MAPK/ERK and MLC2 signaling in prostate cancer

Metastasis is the predominant cause of mortality in prostate cancer (PCa); however, the underlying mechanisms are largely uncharted. Here, we found that Parvin alpha (PARVA) is downregulated in PCa and its loss is associated with clinical metastasis. We further explored the mechanistic basis of this finding.

Our study revealed that loss of PARVA expression in PCa promotes metastasis by releasing the inhibition of ILK activity, followed by the activation of MAPK/ERK and MLC2 signaling.

The mRNA expression of PARVA was identified by analysis of the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) data sets. Immunohistochemistry (IHC) analysis was performed to evaluate the PARVA expression pattern in 198 PCa tissues, and 36 metastatic lymph node tissues. The function and molecular mechanism by which PARVA affects PCa were investigated in vitro using knockdown and overexpression cell lines. The effect of PARVA in cell proliferation, migration, and invasion in PCa cells was detected by MTS assay and Transwell assay. Real-time polymerase chain reaction (PCR) and Western blot analysis were used to assess the gene expression in mRNA and protein level.

The microarray data analysis indicated that PARVA was drastically downregulated in primary and metastatic PCa compared with normal and primary samples, respectively (all P<0.001). Multivariate Cox regression analysis suggested that downregulation of PARVA in PCa was an independent prognostic factor for poor biochemical recurrence (BCR)-free survival (P<0.01). IHC analysis confirmed that PARVA was frequently downregulated in metastatic and primary PCa tissues (All P<0.001). Furthermore, PARVA expression was found to be associated with Gleason score, pathological stage, extracapsular extension, and lymph node invasion (All P<0.05). Knockdown of PARVA triggered cell migration and invasion in vitro, whereas overexpression of PARVA reverted the invasive phenotypes. Mechanistic investigations identified that overexpression of PARVA repressed the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) phosphorylation via inhibiting the integrin-linked kinase (ILK) biological function. With knockdown of ILK, the downregulated MAPK/ERK phosphorylation and Myosin Light Chain 2 (MLC2) expression by PARVA overexpression were abolished, indicating that the PARVA effect on PCa is ILK/MAPK/ERK pathway dependent. Conclusions: Our study revealed that loss of PARVA expression in PCa promotes metastasis by releasing the inhibition of ILK activity, followed by the activation of MAPK/ERK and MLC2 signaling.