RAC1 genomic aberrations in head and neck cancer

Abstract

Ras-Related C3 botulinum toxin substrate 1(RAC1), which is a member of the Ras superfamily of small guanosine triphosphatases (GTPase), is known to regulate cytoskeletal organization, actin dynamics, cell migration and proliferation. In particular, Rac1-mediated signalling is essential to control cell polarization, lamellopodia proteolysis and cell movement. Under pathological condition, RAC1-mediated activities appear critical to malignant transformation in cancer development. Cumulative evidences suggested that aberrations of Rac1 expression in cancer might be associated with cancer cell growth and invasion. Recent genomic studies identified mutational events of RAC1 in melanoma, as well as breast and head and neck squamous cell carcinomas (HNSCC). Yet, its oncogenic signalling in HNSCC has not been clearly understood. Here, we performed a functional analysis to investigate the driver activity and invasiveness of RAC1 mutations in our PCI-52-SD1 cells model. RAC1 P29S, RAC1 K116N and RAC1 A159V mutations, which are frequently found in HNSCC, were assessed in both growth assay and invasion assay. We found that RAC1 P29S, RAC1 K116N and RAC1 A159V mutations were identified as the drivers for HNSCC cell proliferation. In particular, RAC1 A159V mutation, which is associated with the strongest proliferation activity, is identified as a novel mutation in driving marked activation of PI3K/AKT signalling in HNSCC cells. Furthermore, we demonstrated for the first time that a novel RAC1 K116N mutation displayed a highly invasive phenotype. Although the potential oncogenic signalling driving cell growth and cell invasion has not been fully established in the present study, we hope our findings can facilitate the understanding of the basic biology of RAC1 mutation, potentially benefit the therapeutic development for HNSCC.