Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Downregulation of iNOS/NO Promotes Epithelial-Mesenchymal Transition and Metastasis in Colorectal Cancer

ABSTRACT: Metastasis is the major cause of cancer-related death in patients with colorectal cancer. Although inducible nitric oxide synthase (iNOS) is a crucial regulator of cancer development and progression, its roles in epithelial-mesenchymal transition (EMT) and the pathogenesis of metastatic colorectal cancer have not been fully investigated. Primary colorectal cancer and liver metastatic tissue specimens were analyzed showing 90% of liver metastatic colorectal cancer with reduced expressions of iNOS compared with 6% of primary colorectal cancer. The Cancer Genome Atlas database analyses via cBioPortal reveal that mRNA expression of iNOS negatively correlated with selected EMT markers in colorectal cancer in a cancer type-dependent manner. The transcriptomic profiling (RNA sequencing data) indicates that iNOS knockdown in SW480 colorectal cancer cells induced an EMT program with upregulated expression of selected stem-cell markers. iNOS knockdown did not alter E-cadherin mRNA expression but re-localized it from membrane to cytoplasm through iNOS-GATA4-Crb2-E-cadherin pathway. iNOS knockdown induced a change in cell morphology, and promoted cell invasion and migration in vitro, and metastasis in vivo.

ORGANISM(S): Homo sapiens

PROVIDER: GSE178862 | GEO | 2022/07/13

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Role of epithelial to mesenchymal transition (EMT) in spontaneous breast cancer metastasis

Project description:Epithelial-mesenchymal transition (EMT) has been linked to cancer progression and metastatic propensity. The 4T1 tumor is a clinically relevant model of spontaneous breast cancer metastasis. Here we characterize 4T1-derived cell lines for EMT, in vitro invasiveness and in vivo metastatic ability. Contrary to expectations, the 67NR cells, which form primary tumors but fail to metastasize, express vimentin and N-cadherin, but not E-cadherin. 4T1 cells, however, express E-cadherin, are highly migratory and invasive, and metastasize to multiple sites. The 66cl4 metastatic cells display mixed epithelial and mesenchymal markers, but are less migratory and invasive than 67NR cells. These findings demonstrate that the metastatic ability of breast cancer cells does not correlate with genotypic and phenotypic properties of EMT per se, and suggest that other processes may govern metastatic capability. Gene expression analysis also has not identified differences in EMT markers, but has identified several candidate genes that may influence metastatic ability. Keywords: cell type comparison

2008-08-01 | GSE11259 | GEO

Transcription profiling of mouse BALB/c strain animals injected with breast cancer 4T1-derived cells to investigate the role of epithelial to mesenchymal transition (EMT) in spontaneous breast cancer metastasis

2009-03-07 | E-GEOD-11259 | biostudies-arrayexpress

Oleanolic acid inhibits epithelial–mesenchymal transition of hepatocellular carcinoma by promoting iNOS dimerization

Project description:Oleanolic acid (OA) exhibits extensive pharmacological activities and takes significant anti-tumor effects. Its pharmacological mechanism, however, are still remained to be further clarified. In this study, we demonstrated that OA attenuated the migration and invasion abilities, resulting in the suppression of the EMT process in liver cancer cells, and inhibited the tumor growth of the PLC-bearing mice. We further proved that inducible nitric oxide synthase (iNOS) may be the potential target of OA. We confirmed that OA could promote the dimerization of iNOS, activating it and subsequently increasing the production of nitric oxide (NO). Further experiments indicated that OA promoted the nitration of specific proteins and consequently suppressed their epithelial–mesenchymal transition (EMT)-related biological functions. Furthermore, it has been confirmed that OA enhanced the anti-tumor effects of regorafenib in liver cancer treatment. These results deepened our understanding of the pharmacological mechanism of the antitumor effect OA, and the importance of NOS as a therapeutic target for liver cancer treatment.

2018-09-22 | GSE120311 | GEO

PRRX1 deficiency induces mesenchymal-epithelial transition through PITX2/miR-200-dependent SLUG/CTNNB1 regulation in hepatocellular carcinoma

Project description:Metastasis is a major obstacle to better prognosis in patients with hepatocellular carcinoma (HCC). Mesenchymal-epithelial transition (MET) is the driving force for metastatic colonization in which E-cadherin reexpression is a critical procedure. It has been reported that the loss of paired-related homeobox transcription factor 1 (PRRX1) is required for cancer cell metastasis in vivo. However, the role of PRRX1 in MET and how its downregulation triggers E-cadherin reexpression are unknown. In this study, we performed a systematic, mechanistic study regarding the role of PRRX1 in MET of HCC. We observed PRRX1 downregulation in HCC tissues which correlated with early metastasis and short overall survival time. Overexpression of PRRX1 induced EMT, but did not promote metastasis formation, while knockdown of PRRX1 promoted metastasis and colonization of circulating HCC cells as shown in in situ liver tumor model and colonization model. PRRX1 protein levels reversely correlated with E-cadherin levels in HCC cell lines. PRRX1 knockdown promoted E-cadherin reexpression and cell proliferation, inhibited cell invasion and migration. The microarray results showed that PRRX1 deficiency regulated extracellular matrix (ECM) interaction, focal adhesion, TGF-β signaling and cancer pathways. PRRX1 knockdown upregulated PITX2 (paired like homeodomain 2) and inhibited CTNNB1 (catenin beta 1) and SLUG. Silencing of PITX2 reversed CTNNB1 and SLUG inhibition and E-cadherin reexpression. PITX2 upregulation increased miR-200a and miR-200b/429, which further inhibited the transcription of CTNNB1 and SLUG, respectively, thus abrogating the inhibitory effect on E-cadherin. In conclusion, our data showed that the downregulation of PRRX1 induced E-cadherin reexpression through PITX2/miR-200a/CTNNB1 and PITX2/miR-200b/429/SLUG pathway, making PRRX1 a novel prognostic factor for HCC.

2020-04-18 | GSE148851 | GEO

Proteomics and liquid biopsy characterization of human EMT-related metastasis in colorectal cancer

Project description:Tumor cells undergo epithelial-mesenchymal transition (EMT), however, there is a room of disagreement in role of EMT heterogeneity to colorectal cancer metastasis (mCRC) evolution. To uncover new EMT-related metastasis proteins and pathways, we addressed the EMT status in colorectal cancer liver metastasis patient-derived CTCs to identify proteins that promote their distant metastasis. And then, we performed a comparative proteomic analysis in matched pairs of primary tumor tissues, adjacent mucosa tissues and liver metastases tissues. By integrative analysis we show that, unstable Epithelial/Mesenchymal (E/M)-type CTCs had the strongest liver metastases formation ability and the proportion of E/M-type CTCs correlated with distant metastases. Using an optimized proteomic workflow including data independent acquisition (DIA) and parallel reaction monitoring (PRM), we identified novel EMT-related protein cluster (e.g., GNG2, COL6A1, COL6A2, DCN, COL6A3, LAMB2, TNXB, CAVIN1) and well-described (e.g., KRAS and ERBB2) core protein level changes in EMT-related metastasis progression, and the proteomic data indicate KRAS, ERBB2, COL6A1 and CAVIN1 are promising EMT-related metastatic biomarker candidates. This study contributes to catch on EMT in CRC metastasis and in favor of heterogeneous EMT phenotypes as a key piece for tumor outcome and treatment. We further propose that therapies targeting this aggressive subset (E/M-type) of CTCs and related protein may be worthy of exploration as potential suppressors of metastatic evolution

2022-05-09 | PXD033788 | iProX

Comparison of metastatic derivatives of colon cancer cell line selected in vivo

Project description:Using a human colorectal cancer cell line we incremented its metastatic capacity in a mouse model of liver and lung metastasis. Afterwards, a comparison between the different metastatic derivatives is done. Metastatic derivatives were selected by the use of a balb/c nude mouse model. Once the metastasis appeared, the cells were extracted and expanded in culture. Thereafter RNA was extracted and hybridized

2014-04-22 | E-GEOD-33350 | biostudies-arrayexpress

T cell cancer therapy requires CD40-CD40L activation of TNFα-iNOS-producing dendritic cells

Project description:The effectiveness of new cancer therapies such as checkpoint blockade and adoptive cell transfer of activated anti-tumor T cells requires overcoming immunosuppressive tumor microenvironments. We found that the activation of tumor-infiltrating myeloid cells to produce local nitric oxide is a prerequisite for adoptively transferred CD8+ cytotoxic T cells to destroy tumors. These myeloid cells are phenotypically similar to ‘Tip-DCs’ or nitric oxide- and TNFα-producing dendritic cells. The nitric oxide-dependent killing was tempered by coincident arginase 1 expression, which competes with iNOS for arginine, the substrate for nitric oxide production. Depletion of immunosuppressive CSF-1R-dependent arginase 1+ myeloid cells enhanced nitric oxide-dependent tumor killing. Tumor killing via iNOS was independent of the microbiota but dependent on the CD40-CD40L pathway and, in part, lymphotoxin alpha. We extended our findings in mice to uncover a strong correlation between iNOS, CD40 and TNF expression and survival in colorectal cancer patients. Our results identify a network of anti-tumor targets to boost the efficacy of cancer immunotherapies.

2016-09-14 | GSE74427 | GEO

RNA-seq of NIC+,CdGAPwt/wt and NIC+,CdGAPfx/fx tumors

Project description:CdGAP/ARHGAP31 is a molecular target of TGFb-mediated EMT and required for Her2-positive breast cancer growth and metastasis Metastasis is the leading cause of death in breast cancer patients. The epithelial-to-mesenchymal transition (EMT) has a crucial role in metastasis and is highly critical for tumor cell dissemination. CdGAP/ARHGAP31 is highly expressed in breast cancer tissues and is associated with poor clinical outcome in breast cancer patients. CdGAP cooperates in a GAP-independent manner with the transcriptional repressor Zeb2 to function as a critical modulator of breast cancer through repression of E-cadherin transcription. In this study, we used a murine model of Her2+ breast cancer to investigate further the role of CdGAP in breast tumorigenesis. We found that CdGAP was essential for tumor formation and metastasis to the lungs in the Her2+ mouse breast cancer model. We determined that CdGAP is required for intravasation and growth at the metastatic sites. By using global gene expression approaches, we found that CdGAP depletion in Her2+ primary tumors was associated with an EMT signature, including a decreased expression of the metastatic factor claudin-2 and an increase in E-cadherin expression. In Her2+ breast cancer cells, CdGAP expression is positively regulated by the TGFb canonical pathway in a smad-dependent manner and regulates cell proliferation, migration, invasion, and adhesion. CdGAP was found to interact with the focal adhesion protein Talin and regulates focal adhesion dynamics in breast cancer cells. Collectively, CdGAP appears as a potential anti-metastatic target for the treatment of Her2+ breast cancer.

2023-07-13 | GSE167457 | GEO

RNAi profiling of human mammary epithelial cells - analysis of the effects of loss of E-cadherin and cell adhesion

Project description:Loss of the epithelial adhesion molecule E-cadherin is thought to enable metastasis by disrupting intercellular contactsâan early step in metastatic dissemination. To further investigate the molecular basis of this notion, we use two methods to inhibit E-cadherin function that distinguish between E-cadherinâs cell-cell adhesion and intracellular signaling functions. While the disruption of cell-cell contacts alone does not enable metastasis, the loss of E-cadherin protein does, through induction of an epithelial-to-mesenchymal transition, invasiveness and anoikis-resistance. We find the E-cadherin binding partner ï¢-catenin to be necessary but not sufficient for induction of these phenotypes. In addition, gene expression analysis shows that E-cadherin loss results in the induction of multiple transcription factors, at least one of which, Twist, is necessary for E-cadherin loss-induced metastasis. These findings indicate that E-cadherin loss in tumors contributes to metastatic dissemination by inducing wide-ranging transcriptional and functional changes. Experiment Overall Design: Gene expression changes induced by knockdown of E-cadherin, expression of dominant-negative E-cadherin and double knockdown of E-cadherin and Beta-catenin in immortalized human mammary epithelial cells Experiment Overall Design: Four groups, three biological replicates per group. shCntrl expressing cells are the control group

2008-11-06 | E-GEOD-9691 | biostudies-arrayexpress

Metabolomic analysis of colorectal cancer cells using mass spectrometry

Project description:Colorectal cancer (CRC) is one of the most prevalent tumors, with a high mortality rate. Nearly half of CRC patients develop metastasis, which accounts for as many as 90% of CRC-related deaths. In the metastasis process, cancer cells exhibit altered dependency on specific metabolic pathways and some of the metabolites discovered might be useful as potential diagnostic biomarkers. To identify metabolic pathway dependencies in CRC metastasis, mass spectrometry-based untargeted metabolomic analysis was performed in two pairs of CRC cell lines with different metastatic abilities. Each pair of cell lines was comprised of primary and metastatic colorectal cancer cell lines (SW480 vs. SW620; HT-29 vs. COLO 205). Relative levels of intracellular metabolites distinguished high-metastatic CRC cells from low-metastatic CRC cells.

2022-10-06 | ST002341 | MetabolomicsWorkbench

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

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