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Pak1-ATF2 signaling axis induces miR-132 to inhibit hematogenous metastasis

ABSTRACT: P21-activated kinase 1 (Pak1) is a key oncogenic kinase and a lot of work about the mechanism of Pak1 action in cancer have been reported, while it remains unknown whether Pak1 could potentially regulate the biology of regulatory miRNAs by new interacting substrate. Here, we identified that Pak1 modulated the miR-132 expression in gastric cancer cells. Pak1 interacted with and phosphorylated activating transcription factor-2 (ATF2) on Serine 62 (Ser62), which blocked ATF2 translocation into cell nucleus. We further demonstrated that ATF2 induced miR-132 transcription via binding to the miR-132 promoter in the -30 to -39 region. Moreover, overexpression of miR-132 in gastric cancer cells significantly reduced cell adhesion, migration and invasion in vitro and hematogenous metastasis in vivo. MiR-132 targeted CD44 and fibronectin (FN) and promoted lymphocytes to gather around gastric cancer cells and kill them. More importantly, downregulation of miR-132 in gastric cancer was specifically associated with hematogenous metastasis, instead of lymph node or implantation metastasis. Taken together, miR-132 is a key negative regulator in the hematogenous metastasis of gastric cancer. A novel cell signaling pathway Pak1-ATF2-miR-132-CD44/FN is established and may be a new therapeutic target for hematogenous metastasis of gastric caner.

ORGANISM(S): Rattus norvegicus Mus musculus Homo sapiens

PROVIDER: GSE84290 | GEO | 2017/07/31

SECONDARY ACCESSION(S): PRJNA328599

REPOSITORIES: GEO

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Project description:Pak1-ATF2 signaling axis induces miR-132 to inhibit hematogenous metastasis

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Pak1-ATF2 signaling axis induces miR-132 to inhibit hematogenous metastasis

Project description:Pak1 as a serine/threonine kinase, has been implicated in cytoskeletal remodelling, cell motility, apoptosis and transformation. Pak1 plays important roles in multiple signal pathways. Pak1 protects cells from apoptosis through at least three different pathways including forkhead box O1 (FOXO1), B-cell CLL/lymphoma 2 (Bcl-2) and DLC1. Pak1 also regulates activity of Raf and Aurora kinases to affect cellular proliferation. Overexpression of Pak1 is involved in the regulation of actin assembly and disassembly through phosphorylations of LIM Kinase and cytoskeletal associated proteins such as Filamin A, Paxillin, Caldesmon, Cortactin and Arp2/3. Pak1 also regulates microtubule dynamics via activation of tubulin cofactor B (TCoB) and DLC1, and inhibition of stathmin. In spite of a large body of work about the mechanism of Pak1 action in cancer, it remains unknown whether Pak1 signaling could potentially regulate the biology of regulatory miRNAs. This is particularly relevant for gastric cancer because Pak1 can activate many regulators of miRNAs expression in gastric cancer cells including NF-kappaB and ERK, and Pak1 signaling has profound phenotypic effects on the biology of gastric cancer cells. We constructed Pak1 knockdown stable cell lines. The stable Pak1 knockdown gastric cancer BGC823 cells and control cells were performed miRNA chip analysis by CapitalBio company. Gastric cancer BGC823 cells with stable Pak1 knockdown and BGC-823 gastric cancer cells transfected with U6 were used in this experiment. Total RNA was extracted by trizol,Here we use a Capitalbio mammal microRNA V3.0(CapitalBio, Beijing, China) containing 509 well-characterized human, mouse and rat miRNAs and various controls to profile the expression levels of miRNA in 16 and conU6 group.three chip were test in each group, and the procedure was repeated twice.

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