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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): Mus musculus Rattus norvegicus Homo sapiens

PROVIDER: GSE84290 | GEO | 2017/07/31

SECONDARY ACCESSION(S): PRJNA328599

REPOSITORIES: GEO

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Homo sapiens

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

| PRJNA328789 | ENA

Homo sapiens

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

| PRJNA328599 | ENA

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

Quantitative phosphoproteomic analysis of human Arl4A upon fibronectin stimulation

Project description:The extracellular matrix (ECM) fibronectin (FN) not only provides the framework for cell invasion and deposition of collagens and other ECMs from wound studies, but also guide collective tumor migration during cancer progression. p21-activated kinase 1 (Pak1) and Arf-like (Arl) GTPase Arl4A have previously been found to recruit each other on the plasm membrane to promote cell migration, and their plasma membrane translocation are robustly potentiated by FN. Under FN stimulation, we found that Pak1 kinase activity is required for Arl4A protein stabilization. How FN-induced Pak1 activity enhances Arl4A protein stability is unknown. Given that the Pak1-Arl4A interaction is direct, we hypothesized that alternation of Pak1-dependent phosphorylation on Arl4A leads to its protein stabilization upon FN stimulation. We herein applied the SILAC method to identify the phosphorylation sites on Arl4A upon FN treatment through MS analysis and found that S141/143 site(s) increased phosphorylation under FN stimulation. We further validated that phosphorylation on S143 of Arl4A and corresponding site on S144 of Arl4D (closest Arl member of Arl4A) are indeed dependent on Pak1 kinase and contribute to their protein stability. By dissecting the phosphorylation property on S143/S144 of Arl4A/D, we revealed an Arl4A/D specific chaperon protein HYPK as the underlying mechanism to mask and protect the phospho-form of Arl4A/D from fast proteasome degradation. This study provides how FN signaling cascade promotes cell migration on a molecular basis by regulating Arl4A/D phosphorylation.

2022-07-29 | PXD032397 | Pride

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

2016-07-16 | GSE84298 | GEO

Hematogenous metastasis of ovarian cancer: Re-thinking mode of spread

Project description:Ovarian cancer has a clear predilection for metastasis to the omentum, but the underlying mechanisms involved in ovarian cancer spread are not well understood. Here, we used a parabiosis model that demonstrates preferential hematogenous metastasis of ovarian cancer to the omentum. Our studies revealed that the ErbB3-neuregulin1 (NRG1) axis is a dominant pathway responsible for hematogenous omental metastasis. Elevated levels of ErbB3 in ovarian cancer cells and NRG1 in the omentum allowed for tumor cell localization and growth in the omentum. Depletion of ErbB3 in ovarian cancer substantially impaired omental metastasis. Our results highlight hematogenous metastasis as a previously under-recognized mode of ovarian cancer metastasis. These findings have implications for designing new strategies aimed at preventing and treating ovarian cancer metastasis.

2014-07-14 | GSE52999 | GEO

microRNA suppresses prostate cancer stem cells and metastasis by inhibiting a cohort of pro-metastasis targets including CD44, Rho GTPases and EZH2

Project description:microRNA plays important roles in tumor initiation and progression. Here we showed that, one of the miR-200 family member, miR-141 is drastically under-expressed in several prostate cancer stem cell populations in both xenograft and primary patient samples. Enforced expression of miR-141 in CD44+ PCa cells suppressed tumor initation and metastasis. Cancer stem cell related properties including clonal and sphere formation ability as well as migration and invasion abilites were blocked by miR-141. Moreover, under-expression of miR-141 in prostate cancer stem cells is important in maintaining a partial mesenchymal status. Whole genome sequencing revealed novel pathways that are regulated by miR-141 including Rho GTPase signaling pathway. Stem cell related molecules including CD44 and EZH2 are also validated as direct targets of miR-141 mediating the tumor and metastasis suppressive function. Altogether, these data suggests that on e signal miRNA, miR-141 could utilize multiple mechanisms to obstruct tumor progression and metstasiss. Total transcriptome profiles of prostate cancer cells Du145 and LAPC9 transfected with 30nM miR-141 mimicking oligonucleotides or negative control (NC) oligonucleotides were generated by deep sequencing, in duplicates, using Illumina HiSeq 2000.

2016-08-15 | E-GEOD-71756 | biostudies-arrayexpress

Gene expression profile of gastric cancer stem cells after CD44 knockdown

Project description:We did the microarray to further compare the changes of gene expression between gastric cancer stem cells with CD44 knockdown by lentivirus and gastric cancer stem cells by scamble short hairpin RNA. Gastric cancer stem cells (Lentivirus) were infected with lentivirus that expressed human CD44-speciï¬c short hairpin RNA (shRNA). Control group of gastric cancer stem cells (Vector group) were only infected with scramble shRNA.

2015-12-31 | E-GEOD-58143 | biostudies-arrayexpress

Gastric cancer cells treated with exosomes derived from Fusobacterium nucleatum infected MKN-28 cells [RNA-seq]

Project description:To investigate the role of Fusobacterium nucleatum (Fn) in the development of gastric cancer, we extracted exosomes from the culture supernatant of MKN-28 cells treated with Fn or PBS, co-cultured them with AGS cells, and analyzed their RNA-seq data for gene expression profiling.

2023-06-07 | GSE214817 | GEO

Gastric cancer cells treated with exosomes derived from Fusobacterium nucleatum infected MKN-28 cells [miRNA-seq]

2023-06-07 | GSE213833 | GEO

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