Sequential treatment with activin and hepatocyte growth factor(HGF) induces FOXM1 to promote colorectal cancer liver metastasis
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE205986 | GEO | 2023/01/04
REPOSITORIES: GEO
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Project description:BackgroundCancer stem cells (CSCs) are involved in liver metastasis in colorectal cancer (CRC). Activin and hepatocyte growth factor (HGF) are important regulators of stem cell properties. This study was performed to explore the effect of activin and HGF on CRC invasion and metastasis. The key genes involved in the action of activin and HGF in CRC were identified.MethodsHCT116 CRC cells were sequentially treated with activin and HGF and examined for migration and invasion in vitro and liver metastasis in vivo. RNA sequencing was performed to identify differentially expressed genes in response to activin and HGF.ResultsSequential treatment with activin and HGF-enhanced CRC cell migration, invasion, and metastasis. CXCR4 and AFP expressions were increased by activin and HGF treatment. Knockdown of FOXM1 blocked liver metastasis from HCT116 cells pretreated with activin and HGF and suppressed CXCR4 and AFP expression. Activin alone increased the mRNA and protein expression of FOXM1. In contrast, HGF alone enhanced the phosphorylation of FOXM1, without altering the total protein level of FOXM1. SMAD2 was required for activin-mediated FOXM1 induction. FOXM1 transactivated CXCR4 by directly binding to the promoter of CXCR4. Additionally, CXCR4 regulated AFP expression through the NF-κB pathway.ConclusionsSequential treatment with activin and HGF accelerates CRC invasion and liver metastasis, which involves the upregulation and activation of FOXM1 and induction of CXCR4 and AFP.
| S-EPMC9803576 | biostudies-literature
Project description:Liver regeneration is characterized by a scheduled sequence of inner and intra-cellular signaling events. It starts with an initial inflammatory phase, followed by a period of rapidly proliferating hepatocytes and stopping abruptly when the liver mass is restored. The cytokines hepatocellular growth factor (HGF) and interleukin 6 (IL-6) play a pivotal role during this process with the former driving proliferation that is enhanced by the latter. While the individual importance of HGF and IL6 has been studied comprahensively the role of cross-talk in control of hepatic proliferation is jet largely unknown. To this end, we performed time-resolved transcriptional profiling of of murine hepatocytes stimulated with HGF and IL-6 indiviually as well as in combination. Thorough systematic investigation performing statistical analysis, mathematical formalization of cross-talk effects on the transcriptional level as well as gene-regulatory network inference revealed the transcriptional program of the cross-talk initiated by HGF and IL-6. Using the proliferation associated Hepcidin (Hamp) and Amphiregulin (Areg) as marker genes for liver regeneration we perform exthensive in-silico experiments with the inferred gene-regulatory network for the identification of the most important players in regulation of the proliferation process. Among other genes, this predicted chemokine (C-X-C motif) ligand 10 (Cxcl10) as an important factor in the temporal regulation of proliferation. These predictions were validated by independent in vitro expression data as well as independent in vivo literature data. While Cxcl10 is known to be involved in liver regeneration, our study extend its role towards its temporal orchestration. Cells were stimulated with either 40 ng/ml rmHGF (all R&D Systems) and 40 ng/ml rhIL-6 alone or in combination. Cells were left untreated as unstimulated control. RNA was extracted at 1,2,3,4,5,6,7,8,9,10,12,24 hours. Cells were treated with IL6 alone for the first 4 hours and then additionally with HGF from hours 4-24. Controls were taken at -5,0,4,8,12,24 hours.
2016-06-01 | E-GEOD-69935 | biostudies-arrayexpress
Project description:Liver regeneration is characterized by a scheduled sequence of inner and intra-cellular signaling events. It starts with an initial inflammatory phase, followed by a period of rapidly proliferating hepatocytes and stopping abruptly when the liver mass is restored. The cytokines hepatocellular growth factor (HGF) and interleukin 6 (IL-6) play a pivotal role during this process with the former driving proliferation that is enhanced by the latter. While the individual importance of HGF and IL6 has been studied comprahensively the role of cross-talk in control of hepatic proliferation is jet largely unknown. To this end, we performed time-resolved transcriptional profiling of of murine hepatocytes stimulated with HGF and IL-6 indiviually as well as in combination. Thorough systematic investigation performing statistical analysis, mathematical formalization of cross-talk effects on the transcriptional level as well as gene-regulatory network inference revealed the transcriptional program of the cross-talk initiated by HGF and IL-6. Using the proliferation associated Hepcidin (Hamp) and Amphiregulin (Areg) as marker genes for liver regeneration we perform exthensive in-silico experiments with the inferred gene-regulatory network for the identification of the most important players in regulation of the proliferation process. Among other genes, this predicted chemokine (C-X-C motif) ligand 10 (Cxcl10) as an important factor in the temporal regulation of proliferation. These predictions were validated by independent in vitro expression data as well as independent in vivo literature data. While Cxcl10 is known to be involved in liver regeneration, our study extend its role towards its temporal orchestration.
2016-06-01 | GSE69935 | GEO
Project description:HGF stimulates mitogenesis, motogenesis and morphogenesis in most epithelial target cells. Selective inhibition of HGF signaling blocks spontaneous metastasis, but not primary tumor growth, in the prostate adenocarcinoma derived PC3M cell xenograft model. To identify the HGF activated genes and pathways that contribute to cell motility and invasion, i.e. the HGF invasive program, expression profiling was performed on PC3M cells that were untreated or were treated with human HGF (hHGF), which drives all 3 primary activities, or with human HGF/NK2 (hNK2) or murine HGF (mHGF), which drive motility and invasion but not proliferation in human cells. Differences in gene expression profiles among these four groups were used to distiniguish between events associated with invasion (resulting from hNK2 or mHGF treatment) from those associated with the combination of invasion and proliferation (resulting from hHGF treatment).
2015-08-25 | GSE71404 | GEO
Project description:HGF stimulates mitogenesis, motogenesis and morphogenesis in most epithelial target cells. Selective inhibition of HGF signaling blocks spontaneous metastasis, but not primary tumor growth, in the prostate adenocarcinoma derived PC3M cell xenograft model. To identify the HGF activated genes and pathways that contribute to cell motility and invasion, i.e. the HGF invasive program, expression profiling was performed on PC3M cells that were untreated or were treated with human HGF (hHGF), which drives all 3 primary activities, or with human HGF/NK2 (hNK2) or murine HGF (mHGF), which drive motility and invasion but not proliferation in human cells. Differences in gene expression profiles among these four groups were used to distiniguish between events associated with invasion (resulting from hNK2 or mHGF treatment) from those associated with the combination of invasion and proliferation (resulting from hHGF treatment). PC3M cells were left untreated or treated with hHGF, hNK2 or mHGF for 8, 16 or 32 hours prior to RNA extraction, cDNA preparation and array hybridization.
2015-08-25 | E-GEOD-71404 | biostudies-arrayexpress
Project description:The routine study of human malaria liver-stage biology in vitro is hampered by low infection efficiency of human hepatocellular carcinoma (HCC) lines (<0.1%), poor understanding of steady-state HCC biology, and lack of appropriate tools for trace sample analysis. HC-04 is the only HCC that supports complete development of human malaria parasites. We hypothesized that HCCs are in various intermediate stages of the epithelial-mesenchymal transition (EMT) and HC-04s retain epithelial characteristics that permit infection. We developed an novel analytical approach to test this hypothesis viz. the HC-04 response to hepatocyte growth factor (HGF). We used online two-dimensional liquid chromatography tandem mass spectrometry (2D-LC-MS/MS) to quantify protein expression profiles in HC-04 pre-/post-HGF treatment and validated these results by RT-qPCR and microscopy. We successfully increased protein identification efficiency over offline-2D methods by 12-fold using less sample material, allowing robust protein quantification. We observed expected up-regulation and down-regulation of EMT protein markers in response to HGF, but also unexpected cellular responses. HC-04 is thus susceptible to HGF-mediated signaling but to a lesser degree than what we observed for HepG2, a widely used, but poor malaria HCC model. Our analytical approach to understanding the basic biology of HC-04 helps us understand the factors that may influence its utility as a model for malaria liver-stage development. We observed that HC-04 treatment with HGF prior to the addition of Plasmodium falciparum sporozoites did not facilitate cell invasion, arguing for unlinking the effect of HGF on malaria liver stage development from hepatocyte invasion. Finally, our 2D-LC-MS/MS approach and broadly applicable experimental strategy should prove useful in the analysis of various hepatocyte-pathogen interactions, tumor progression and early disease events.
2014-02-17 | PXD000682 | Pride
Project description:The routine study of human malaria liver-stage biology in vitro is hampered by low infection efficiency of human hepatocellular carcinoma (HCC) lines (<0.1%), poor understanding of steady-state HCC biology, and lack of appropriate tools for trace sample analysis. HC-04 is the only HCC that supports complete development of human malaria parasites. We hypothesized that HCCs are in various intermediate stages of the epithelial-mesenchymal transition (EMT) and HC-04s retain epithelial characteristics that permit infection. We developed an novel analytical approach to test this hypothesis viz. the HC-04 response to hepatocyte growth factor (HGF). We used online two-dimensional liquid chromatography tandem mass spectrometry (2D-LC-MS/MS) to quantify protein expression profiles in HC-04 pre-/post-HGF treatment and validated these results by RT-qPCR and microscopy. We successfully increased protein identification efficiency over offline-2D methods by 12-fold using less sample material, allowing robust protein quantification. We observed expected up-regulation and down-regulation of EMT protein markers in response to HGF, but also unexpected cellular responses. HC-04 is thus susceptible to HGF-mediated signaling but to a lesser degree than what we observed for HepG2, a widely used, but poor malaria HCC model. Our analytical approach to understanding the basic biology of HC-04 helps us understand the factors that may influence its utility as a model for malaria liver-stage development. We observed that HC-04 treatment with HGF prior to the addition of Plasmodium falciparum sporozoites did not facilitate cell invasion, arguing for unlinking the effect of HGF on malaria liver stage development from hepatocyte invasion. Finally, our 2D-LC-MS/MS approach and broadly applicable experimental strategy should prove useful in the analysis of various hepatocyte-pathogen interactions, tumor progression and early disease events.
2016-07-20 | MSV000079959 | MassIVE
Project description:Effect of Hepatocyte Growth Factor (HGF) on lymphatic endothelial cells.
2005-02-01 | E-MEXP-256 | biostudies-arrayexpress
Project description:We report the high-throughput profiling of HGF treated liver cancer cell (HepG2) for differentiated genes analysis. We generated HGF stimulated and paired control HepG2 cells for 4 days. We find that tumor suppressor genes that are overexpressed and some tumor associated genes were downregulated, therefore reflect cell state and HGF induced anti-tumor potential. This study provides a potential framework for the research of HGF induced critical genes in the application of liver cancer therapy.
2021-12-30 | GSE133424 | GEO
Project description:Next Generation Sequencing Facilitates Quantitative Analysis of HGF treated (HGF+) and matched control (HGF-) HepG2 cells
| PRJNA551437 | ENA