PRR11 Regulates Cell Motility Via Recruiting ARP2/3 Complex In Non-small Cell Lung Cancer Cells

Lung cancer is a malignant tumor with high morbidity and mortality in China,and the metastasis and spread of cancer cells is the key cause of its high mortality.Abnormal migration of cancer cells is a key event in the metastasis of malignant tumors,but the specific molecular mechanism involved is still unclear.Research on the regulation mechanism of abnormal migration of cancer cells is of great scientific significance not only for expanding the basic theory of tumor biology,but also for realizing accurate diagnosis and targeted therapy of cancer and improving patient survival rate.Filopodia is a finger-like structure located at the leading edge of moving cells.It originates from plasma membrane processes driven by the aggregation of microfilament skeleton proteins,and plays an important role in cell migration and movement.However,the mechanism by which ARP2/3complex driven microfilament cytoskeleton aggregation regulates filopodia in non-small cell lung cancer cells remains unclear.We previously have proved that PRR11 interacts with the ARP2/3 complex in non-small cell lung cancer cells to regulate cytoskeleton-nuclear skeleton assembly and chromatin remodeling.In this study,we further demonstrate that PRR11 regulated filopodia formation,focal adhesion turnover and cell migration through the ARP2/3 complex.Cell phenotype assays revealed that silencing PRR11 expression significantly increased cellular size and inhibited cell motility in NSCLC cells.Mechanistically,PRR11 recruited and co-localized with ARP2 at the membrane protrusion to promote filopodia formation but not lamellipodia formation.Notably,overexpression of wild-type PRR11significantly induced filopodia formation,but PRR11 mutant deletion of the proline-rich region 2（ΔPR2,amino acid residues 185-200）abrogated the effect of filopodia formation.In addition,silencing of PRR11 expression in NSCLC cells has been shown to inhibit the filopodial actin filaments assembly and increased the level of active integrinβ1 in the cell surface,whereas reduced the phosphorylation level of focal adhesion kinase(FAK^Y397)to repress focal adhesion turnover and cell motility in NSCLC cells.Taken together,our findings indicate that PRR11 has critical roles in controlling filopodia formation,focal adhesion turnover and cell motility by recruiting the ARP2/3 complex to regulate the actin filament cytoskeleton aggregation in NSCLC cell,thus dysregulated expression of PRR11potentially facilitates tumor metastasis in NSCLC cells.