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

ABSTRACT: 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.

ORGANISM(S): Mus musculus Rattus norvegicus Homo sapiens

PROVIDER: GSE84298 | GEO | 2016/07/16

SECONDARY ACCESSION(S): PRJNA328789

REPOSITORIES: GEO

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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.

2016-07-16 | E-GEOD-84298 | biostudies-arrayexpress

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

Project description: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.

2017-07-31 | GSE84290 | GEO

Comparative gene profiling study: Pak1 deficient mouse breast cancer cells vs Pak1 wt breast cancer cells

Project description:To identify differentially regulated genes between wild-type and Pak1 deficient mouse breast cancer cells, we performed a comparative gene profiling study by using mouse whole genome arrays. We compared the gene expression profiles of Her2 positive : Pak1 deficient cells vs Her2 positive : Pak1 wild type cells. All the experiments were performed in duplicate using tumor derived cells from two different tumors per group.

2016-07-23 | E-GEOD-71282 | biostudies-arrayexpress

Affymetrix miRNA chip showed the differential miRNA expression in TRAIL‐resistant BGC823 and TRAIL‐sensitive MKN45 cells

Project description:In order to explore the effect of miRNA on TRAIL sensitivity of gastric cancer, we selected TRAIL-sensitive MKN45 and TRAIL-resistant BGC823 gastric cancer cell line. The expression of miRNA in MKN45 and BGC823 was detected by miRNA chip. "3" is the miRNA expression file of BGC823. "4" is the miRNA expression file of MKN45.

2020-05-24 | E-MTAB-9151 | biostudies-arrayexpress

Comparative gene profiling study: Pak1 deficient human breast cancer cells vs Pak1 wt breast cancer cells

Project description:To identify differentially regulated genes between wild-type and Pak1 deficient human breast cancer cells, we performed a comparative gene profiling study by using human whole genome arrays. We compared the gene expression profiles of MCF10A.B2 cells (MCF10A cells expressing a chemically activatable form of Her2) stably expressing a Tet inducible shRNA directed against Pak1 gene. All the experiments were performed in duplicate using tumor derived cells from two different tumors per group.

2016-07-23 | E-GEOD-71283 | biostudies-arrayexpress

Comparative gene profiling study: Pak1 deficient human breast cancer cells vs Pak1 wt breast cancer cells

2016-07-23 | GSE71283 | GEO

Comparative gene profiling study: Pak1 deficient mouse breast cancer cells vs Pak1 wt breast cancer cells

2016-07-23 | GSE71282 | GEO

Effect of GAGE12I and SPIN4 on the gene expression profile of BGC823 gastric cancer cells

Project description:To investigate the effect of GAGE12I and SPIN4 on the gene expression profile in gastric cancer cells, genome-wide mRNA changes were analyzed by mRNA microarray upon overexpressing GAGE12I and SPIN4 in BGC823 gastric cancer cells.

2018-06-15 | GSE92627 | GEO

PAK1 is a Therapeutic Target in Acute Myeloid Leukemia and Myelodysplastic Syndrome

Project description:Poor clinical outcome of Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS) has been attributed to failure of current chemotherapeutic regimens to target leukemic stem cells. We recently identified p21-activated kinase (PAK1) as a downstream effector molecule of H2.0-like homeobox (HLX), a gene functionally relevant for AML pathogenesis. In this study, we find that inhibition of PAK1 activity by small molecule inhibitors or by RNA interference leads to profound leukemia-inhibitory effects both in vitro and in vivo. Inhibition of PAK1 induces differentiation and apoptosis of AML cells through downregulation of MYC oncogene and a core network of MYC target genes. Moreover, we find that PAK1 up-regulation occurs during disease progression and is relevant for patient survival in MDS. Importantly, we find that inhibition of PAK1 inhibits primary human leukemic cells including immature leukemic stem cell-enriched populations. Our studies highlight PAK1 as a novel target in AML and MDS, and support the use of PAK1 inhibitors as a therapeutic strategy in these diseases. To obtain insight into the molecular mechanism for the induction of apoptosis and differentiation resulting from PAK1 inhibition in AML, we performed gene expression microarrays following treatment with either IPA-3 or FRAX-597. RNA was isolated from THP-1 cells after 5 hours of treatment with IPA-3 (6 ug/mL), FRAX-597 (2 ug/mL) or an equal volume of DMSO using Trizol Reagent (Invitrogen).

2015-07-11 | E-GEOD-70791 | biostudies-arrayexpress

Phospho-antibody microarray analyses for wild-type and Pak1-deficient breast cancer cells

Project description:To identify differentially phosphorylated proteins between wild-type and Pak1-deficient mouse breast cancer cells, we performed a comparative study by using phospho-antibody arrays.

2021-12-24 | GSE192492 | GEO

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