Abstract
Actin protrusion at the cell periphery is central to the formation of invadopodia during tumor cell migration and invasion. Although RUFY3 (RUN and FYVE domain containing 3)/SINGAR1 (single axon-related1)/RIPX (Rap2 interacting protein X) has an important role in neuronal development, its pathophysiologic role and relevance to cancer are still largely unknown. The purpose of this study was to elucidate the molecular mechanisms by which RUFY3 involves in gastric cancer cell migration and invasion. Here, our data show that overexpression of RUFY3 leads to the formation of F-actin-enriched protrusive structures at the cell periphery and induces gastric cancer cell migration. Furthermore, P21-activated kinase-1 (PAK1) interacts with RUFY3, and promotes RUFY3 expression and RUFY3-induced gastric cancer cell migration; inhibition of PAK1 attenuates RUFY3-induced SGC-7901 cell migration and invasion. Importantly, we found that the inhibitory effect of cell migration and invasion is significantly enhanced by knockdown of both PAK1 and RUFY3 compared with knockdown of RUFY3 alone or PAK1 alone. Strikingly, we found significant upregulation of RUFY3 in gastric cancer samples with invasive carcinoma at pathologic TNM III and TNM IV stages, compared with their non-tumor counterparts. Moreover, an obvious positive correlation was observed between the protein expression of RUFY3 and PAK1 in 40 pairs of gastric cancer samples. Therefore, these findings provide important evidence that PAK1 can positively regulate RUFY3 expression, which contribute to the metastatic potential of gastric cancer cells, maybe blocking PAK1-RUFY3 signaling would become a potential metastasis therapeutic strategy for gastric cancer.
Highlights
Human RUFY3 (RUN and FYVE domain containing 3), known as RIPX (Rap[2] interacting protein X) or Singar[1], is a 469-amino-acid protein and is the highly expressed in brain tissue
We showed a positive relationship between P21-activated kinase-1 (PAK1) and RUFY3, and that increased expression of RUFY3 is positively correlated with clinical gastric cancer samples
The results showed that high levels of PAK1 and RUFY3 appear to be associated with the progression and metastasis of human gastric cancer, which indicated that the expression level of RUFY3 by immunohistochemistry are correlated with PAK1, consistent with western blot results
Summary
Human RUFY3 (RUN and FYVE domain containing 3), known as RIPX (Rap[2] interacting protein X) or Singar[1] (single axon-related1), is a 469-amino-acid protein and is the highly expressed in brain tissue. The PAKs, a family of serine/threonine protein kinases, have pivotal roles in cytoskeletal reorganization,[19] survival,[20] motility[21,22] and tumorigenesis.[23] There has been mounting evidence that PAK1 is tightly related to the progression and metastasis of cancer and may become a promising diagnostic and therapeutic target for cancer.[24,25]. Elevated PAK1 expression is correlated with cancer progression and lymph node metastases in gastric cancer tissues.[26,27] it is worthwhile to study the novel binding partners of PAK1. RUFY3-mediated gastric cancer cell migration and invasion by regulating its expression. We showed a positive relationship between PAK1 and RUFY3, and that increased expression of RUFY3 is positively correlated with clinical gastric cancer samples. This report is the first investigation focused on exploring the role of RUFY3 in cancer cells and the relationship between PAK1 and RUFY3
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