Browse
Submit Data
Databases
API
Help

Dataset Information

28 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Loss of Par3 promotes lung adenocarcinoma metastasis through 14-3-3? protein.

ABSTRACT: Partitioning defective protein 3 (Par3) can activate the Tiam1/Rac pathway to inhibit invasion and metastasis in many cancers; however, the role of Par3 in lung adenocarcinoma remains unknown. Here we show that Par3 is downregulated in lung adenocarcinoma tissues and is associated with higher rates of lymph node metastasis and recurrence. Our functional study demonstrated that knock-down of Par3 promoted lung adenocarcinoma cell growth, cell migration, tumor formation, and metastasis, all of which were effectively inhibited when 14-3-3? was silenced. We found that Par3 binded with 14-3-3? protein and also showed that Par3 abrogated the binding of 14-3-3? to Tiam1, which was responsible for Rac1 activation. Knock-down of 14-3-3? inhibited Tiam1/Rac-GTP activation and blocked the invasive behavior of cells lacking Par3. These data suggest that loss of Par3 promotes metastatic behavior in lung adenocarcinoma cells through 14-3-3? protein.

SUBMITTER: Song T

PROVIDER: S-EPMC5325440 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Loss of Par3 promotes lung adenocarcinoma metastasis through 14-3-3ζ protein.

Song Tong T Tian Xia X Kai Fan F Ke Jiang J Wei Zhai Z Jing-Song Li L Si-Hua Wang W Jian-Jun Wang W

Oncotarget 20160901 39

Partitioning defective protein 3 (Par3) can activate the Tiam1/Rac pathway to inhibit invasion and metastasis in many cancers; however, the role of Par3 in lung adenocarcinoma remains unknown. Here we show that Par3 is downregulated in lung adenocarcinoma tissues and is associated with higher rates of lymph node metastasis and recurrence. Our functional study demonstrated that knock-down of Par3 promoted lung adenocarcinoma cell growth, cell migration, tumor formation, and metastasis, all of whi ...[more]

PMID: 27588399

Similar Datasets

Loss of ubiquitin-specific peptidase 18 destabilizes 14-3-3ζ protein and represses lung cancer metastasis.

Project description:Cancer metastasis is a major cause of cancer-related mortality. Strategies to reduce metastases are needed especially in lung cancer, the most common cause of cancer mortality. We previously reported increased ubiquitin-specific peptidase 18 (USP18) expression in lung and other cancers. Engineered reduction of USP18 expression repressed lung cancer growth and promoted apoptosis. This deubiquitinase (DUB) stabilized targeted proteins by removing the complex interferon-stimulated gene 15 (ISG15). This study explores if the loss of USP18 reduced lung cancer metastasis. USP18 knock-down in lung cancer cells was independently achieved using small hairpin RNAs (shRNAs) and small interfering RNAs (siRNAs). USP18 knock-down reduced lung cancer growth, wound-healing, migration, and invasion versus controls (P < .001) and markedly decreased murine lung cancer metastases (P < .001). Reverse Phase Protein Arrays (RPPAs) in shRNA knock-down lung cancer cells showed that 14-3-3ζ protein was regulated by loss of USP18. ISG15 complexed with 14-3-3ζ protein reducing its stability. Survival in lung adenocarcinomas (P < .0015) and other cancers was linked to elevated 14-3-3ζ expression as assessed by The Cancer Genome Atlas (TCGA). The findings were confirmed and extended using 14-3-3ζ immunohistochemical assays of human lung cancer arrays and syngeneic murine lung cancer metastasis models. A direct 14-3-3ζ role in controlling lung cancer metastasis came from engineered 14-3-3ζ knock-down in lung cancer cell lines and 14-3-3ζ rescue experiments that reversed migration and invasion inhibition. Findings presented here revealed that USP18 controlled metastasis by regulating 14-3-3ζ expression. These data provide a strong rationale for developing a USP18 inhibitor to combat metastases.

| S-EPMC8993103 | biostudies-literature

Loss of the Par3 polarity protein promotes breast tumorigenesis and metastasis.

Project description:Loss of epithelial organization is a hallmark of carcinomas, but whether polarity regulates tumor growth and metastasis is poorly understood. To address this issue, we depleted the Par3 polarity gene by RNAi in combination with oncogenic Notch or Ras(61L) expression in the murine mammary gland. Par3 silencing dramatically reduced tumor latency in both models and produced invasive and metastatic tumors that retained epithelial marker expression. Par3 depletion was associated with induction of MMP9, destruction of the extracellular matrix, and invasion, all mediated by atypical PKC-dependant JAK/Stat3 activation. Importantly, Par3 expression is significantly reduced in human breast cancers, which correlates with active aPKC and Stat3. These data identify Par3 as a regulator of signaling pathways relevant to invasive breast cancer.

| S-EPMC3500525 | biostudies-literature

Loss of polarity protein Par3, via transcription factor Snail, promotes bladder cancer metastasis.

Project description:Bladder cancer (BLCA) remains the leading cause of cancer-related mortality among genitourinary malignancies worldwide. BLCA metastasis represents the primary reason for its poor prognosis. In this study, we report that decreased expression of partitioning defective 3 (Par3), a polarity protein (encoded by PARD3), is associated with tumor aggressive phenotypes and poor prognosis in BLCA patients. Consistently, ablation of Par3 promotes the metastasis and invasion of BLCA cells in vitro and in vivo. Further studies reveal that zinc finger protein Snail represses the expression of Par3 by binding to E2-box (CAGGTG) of PARD3 promoter-proximal. Inhibition of GSK-3β promotes the expression and nuclear localization of Snail and then reduces the expression of Par3, resulting in the metastasis and invasion of BLCA cells. Moreover, we detected the interaction between Par3 (936-1356 aa) and ZO-1 (1372-1748 aa), which is involved in the maintenance of tight junction. Together, our results demonstrate that the GSK-3β/Snail/Par3/ZO-1 axis regulates BLCA metastasis, and Snail is a major regulator for Par3 protein expression in BLCA.

| S-EPMC8253273 | biostudies-literature

Loss of Par3 promotes breast cancer metastasis by compromising cell-cell cohesion.

Project description:The mechanisms by which tumour cells metastasize and the role that cell polarity proteins play in this process are not well understood. We report that partitioning defective protein 3 (Par3) is dysregulated in metastasis in human breast cancer, and is associated with a higher tumour grade and ErbB2-positive status. Downregulation of Par3 cooperated with ErbB2 to induce cell invasion and metastasis in vivo. Interestingly, the metastatic behaviour was not associated with an overt mesenchymal phenotype. However, loss of Par3 inhibited E-cadherin junction stability, disrupted membrane and actin dynamics at cell-cell junctions and decreased cell-cell cohesion in a manner dependent on the Tiam1/Rac-GTP pathway. Inhibition of this pathway restored E-cadherin junction stability and blocked invasive behaviour of cells lacking Par3, suggesting that loss of Par3 promotes metastatic behaviour of ErbB2-induced tumour epithelial cells by decreasing cell-cell cohesion.

| S-EPMC4577246 | biostudies-literature

PGC1α Loss Promotes Lung Cancer Metastasis through Epithelial-Mesenchymal Transition.

Project description:PGC1α oppositely regulates cancer metastasis in melanoma, breast, and pancreatic cancer; however, little is known about its impact on lung cancer metastasis. Transcriptome and in vivo xenograft analysis show that a decreased PGC1α correlates with the epithelial-mesenchymal transition (EMT) and lung cancer metastasis. The deletion of a single Pgc1α allele in mice promotes bone metastasis of KrasG12D-driven lung cancer. Mechanistically, PGC1α predominantly activates ID1 expression, which interferes with TCF4-TWIST1 cooperation during EMT. Bioinformatic and clinical studies have shown that PGC1α and ID1 are downregulated in lung cancer, and correlate with a poor survival rate. Our study indicates that TCF4-TWIST1-mediated EMT, which is regulated by the PGC1α-ID1 transcriptional axis, is a potential diagnostic and therapeutic target for metastatic lung cancer.

| S-EPMC8068195 | biostudies-literature

GALNT6 promotes invasion and metastasis of human lung adenocarcinoma cells through O-glycosylating chaperone protein GRP78.

Project description:Lung adenocarcinoma remains a threat to human health due to its high rate of recurrence and distant metastasis. However, the molecular mechanism underlying lung adenocarcinoma metastasis remains yet incompletely understood. Here, we show that upregulated expression of polypeptide N-acetylgalactosaminyltransferase6 (GALNT6) in lung adenocarcinoma is associated with lymph node metastasis and poor prognosis. In lung adenocarcinoma cells, GALNT6 over-expression promoted epithelial-mesenchymal transition (EMT), wound healing, and invasion which could be significantly reversed by GALNT6 silencing. GALNT6 silencing also mitigated the metastasis of lung adenocarcinoma and prolonged the survival of xenograft tumor-bearing mice. Furthermore, GALNT6 directly interacted with, and O-glycosylated chaperone protein GRP78, which promoted EMT by enhancing the MEK1/2/ERK1/2 signaling in lung cancer cells. Therefore, GALNT6 is emerging as novel positive regulator for the malignancy of human lung adenocarcinoma. Targeting GALNT6-GRP78-MEK1/2/ERK1/2 may thus represent a new avenue to develop therapeutics against lung cancer metastasis.

| S-EPMC7214460 | biostudies-literature

14-3-3ζ promotes TGF-β-induced bone metastasis program in 231 cells

Project description:To explore the regulatory role of 14-3-3ζ in TGF-β induced bone metastasis program in 231 cells, we generated MDA-MB-231 human breast cancer cell sublines with 14-3-3ζ shRNA knockdown (231.ZKD-4 and 231.ZKD-5) and scrambled shRNA (231.Scr) We performed cDNA microarray analysis on these cells treated with vehicle or TGF-β (5ng/ml, 2 hours) respectively in vitro Total RNA were extracted from 231.scr, 231.ZKD-4, 231.ZKD-5 cells treated with vehicle or TGF-β, and subjected to illumina Human HT-12 v4 arrays analysis

2013-11-05 | E-GEOD-52066 | biostudies-arrayexpress

14-3-3ζ promotes TGF-β-induced bone metastasis program in 231 cells

2013-11-05 | GSE52066 | GEO

GalNAc-T14 promotes metastasis through Wnt dependent HOXB9 expression in lung adenocarcinoma.

Project description:While metastasis, the main cause of lung cancer-related death, has been extensively studied, the underlying molecular mechanism remains unclear. A previous clinicogenomic study revealed that expression of N-acetylgalactosaminyltransferase (GalNAc-T14), is highly inversely correlated with recurrence-free survival in those with non-small cell lung cancer (NSCLC). However, the underlying molecular mechanism(s) has not been determined. Here, we showed that GalNAc-T14 expression was positively associated with the invasive phenotype. Microarray and biochemical analyses revealed that HOXB9, the expression of which was increased in a GalNAc-T14-dependent manner, played an important role in metastasis. GalNAc-T14 increased the sensitivity of the WNT response and increased the stability of the ?-catenin protein, leading to induced expression of HOXB9 and acquisition of an invasive phenotype. Pharmacological inhibition of ?-catenin in GalNAc-T14-expressing cancer cells suppressed HOXB9 expression and invasion. A meta-analysis of clinical genomics data revealed that expression of GalNAc-T14 or HOXB9 was strongly correlated with reduced recurrence-free survival and increased hazard risk, suggesting that targeting ?-catenin within the GalNAc-T14/WNT/HOXB9 axis may be a novel therapeutic approach to inhibit metastasis in NSCLC.

| S-EPMC4747198 | biostudies-literature

GPR87 Promotes Metastasis through the AKT-eNOS-NO Axis in Lung Adenocarcinoma.

Project description:Lung adenocarcinoma is one of the leading causes of cancer-related deaths. Despite the availability of advanced anticancer drugs for lung cancer treatment, the prognosis of patients still remains poor. There is a need to explore novel oncogenic mechanisms to overcome these therapeutic limitations. The functional experiments in vitro and in vivo were performed to evaluate the role of GPR87 expression on lung adenocarcinoma metastasis. The public lung adenocarcinoma dataset was used to determine the clinical relevance of GPR87 expression in patients with lung adenocarcinoma. GPR87 is upregulated in various cancer; however, the biological function of GPR87 has not yet been established in lung adenocarcinoma. In this study, we found that GPR87 expression is upregulated in lung adenocarcinoma and is associated with poor patient prognosis. Additionally, we showed that GPR87 overexpression promotes invasiveness and metastasis of lung adenocarcinoma cells. Furthermore, we demonstrated that AKT-eNOS-NO signaling is a novel downstream pathway of GPR87 in lung adenocarcinoma. Conversely, we confirmed that silencing of GPR87 expression suppressed these phenotypes. Our results reveal the oncogenic function of GPR87 in cancer progression and metastasis through the activation of eNOS as a key mediator. Therefore, we propose that targeting eNOS could be a novel therapeutic strategy to improve the clinical treatment of lung adenocarcinoma.

| S-EPMC8750422 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data