Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Recapitulation of pharmacogenomic data reveals that invalidation of SULF2 enhance sorafenib susceptibility in liver cancer

ABSTRACT: Gene mutations play critical roles during cancer development and progression, and therefore represent targets for precision medicine. Here we recapitulated the pharmacogenomic data to delineate novel candidates for actionable mutations and therapeutic target drugs. As a proof-of-concept, we demonstrated that the loss-of-function of SULF2 by mutation (N491K) or inhibition enhanced sorafenib sensitivity in liver cancer cells and in vivo mouse models. This effect was mediated by deregulation of EGFR signaling and downstream expression of LCN2. We also report that the liver cancer patients non-responding to sorafenib treatment exhibit higher expression of SULF2 and LCN2. In conclusion, we suggest that SULF2 plays a key role in sorafenib susceptibility and resistance in liver cancer via deregulation of LCN2. Diagnostic or therapeutic targeting of SULF2 (e.g., OKN-007) and/or LCN2 can be a novel precision strategy for sorafenib treatment in cancer patients.

ORGANISM(S): Homo sapiens

PROVIDER: GSE88744 | GEO | 2018/05/15

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Investigating the role of GLI1 in SULF2-potentiated liver tumorigenesis

Project description:The expression of the extracellular sulfatase, SULF2, has been strongly associated with increased hepatocellular carcinoma (HCC) tumor growth and poorer patient survival. However, to date, the molecular mechanisms underlying this phenomenon remain in part unclear. To address this issue, we developed a transgenic mouse overexpressing Sulf2 in hepatocytes under the control of the transthyretin promoter. In this mouse model Sulf2 overexpression potentiated DEN-induced HCC. Further analysis demonstrated a central role for the zinc finger transcription factor Gli1 as a mediator of Sulf2 during HCC development. The cross of the Sulf2 transgenic with Gli1 knockout mice showed that the inactivation of this transcription factor impaired Sulf2-induced HCC. Transcriptomic analysis revealed a Stat3 gene signatures associated with Sulf2 overexpression. Interestingly, Gli1 knockout abrogates Sulf2-induction of several Stat3 target genes including Socs2/3, Pim1 and Flt4. Human orthologues were similarly regulated by SULF2 and dependent on intact GLI1 and STAT3 function in human HCC cells. SULF2 overexpression not only resulted in GLI1 and STAT3 interaction, but also promoted enrichment of GLI1 and STAT3 at consensus sites at the target gene promoters. Interestingly, GLI1 was found to be enriched at select STAT3 consensus sites with SULF2 overexpression and vice versa. siRNA-mediated knockdown of STAT3 or GLI1 reduced promoter binding of GLI1 and STAT3 respectively. Finally, chromatin capture PCR confirmed long-range co-regulation of SOCS2 and FLT3 through changes in promoter conformation. Thus, these findings define a novel mechanism by which SULF2 drives HCC and highlights the role of GLI1-STAT3 transcriptional complex as an effector of this sulfatase.

2019-10-25 | GSE139374 | GEO

Transcriptome profile in SULF2 knockdown pancreatic tumor cells

Project description:We constructed the SULF2 knockdown cell lines and its controls in CFPAC-1 cells using CRISPR-cas9 system, followed by transcriptome sequencing.

2022-03-02 | GSE197531 | GEO

Identification of SULF2 as a novel transcriptional target of p53 by use of integrated genomic analyses.

Project description:Microarray analysis has been useful for identifying the targets of many transcription factors. However, gene expression changes in response to transcription factor perturbation reveal both direct transcriptional targets and secondary gene regulation. By integrating RNA interference, gene expression profiling, and chromatin immunoprecipitation technologies, we identified a set of 32 direct transcriptional targets of the tumor suppressor p53. Of these 32 genes, 11 are not currently associated with the core p53 pathway. From among these novel pathway members, we focused on understanding the connection between p53 and SULF2, which encodes an extracellular heparan sulfate 6-O-endosulfatase that modulates the binding of growth factors to their cognate receptors and that has been shown to function as a tumor suppressor. Genetic and pharmacologic perturbation of p53 directly influences SULF2 expression, and similar to silencing of TP53, RNA interference-mediated suppression of SULF2 results in an impaired senescence response of cells to genotoxic stress. Thus, our integrated genomic approach has led to the identification of a novel mediator of p53 network biology. Expression profiling experiments were performed to perturb the p53 status in cancer cell lines as a means of identifying novel members of the p53 pathway.

2010-06-20 | E-GEOD-15440 | biostudies-arrayexpress

Investigating the role of GLI1 in SULF2-potentiated liver tumorigenesis

Project description:Investigating the role of GLI1 in SULF2-potentiated liver tumorigenesis

| PRJNA579397 | ENA

To examine the expression of Sulf1 and Sulf2, as well as other glycan-related genes, in human Idiopathic pulmonary fibrosis (IPF) lungs compared to normal lung samples

Project description:Microarray analysis to examine glycan-related gene expression in idiopathic pulmonary fibrosis Heparan sulfate 6-O-endosulfatases (Sulf1 and Sulf2) remove 6-O sulfate groups from heparan sulfate intra-chain sites on the cell surface and in the extracellular matrix, and modulate the functions of many growth factors and morphogens including FGF, Wnt and TGF-beta. Works from our laboratory have shown that TGF-beta 1 induces Sulf1 and Sulf2 expression in a cell-type specific manner in the lung, specifically Sulf1 in lung fibroblasts and Sulf2 in type II alveolar epithelial cells. Interestingly TGF-beta 1-induced Sulf1 and Sulf2 in turn modulate TGF-beta 1 function in culture. The aim of this study is to examine the expression of Sulf1 and Sulf2 as well as other glycan-related genes (heparan biosynthetic enzymes, TGF-beta, FGF and Wnt signaling pathway components) in human idiopathic pulmonary fibrosis (IPF) lungs compared to normal lung samples. We will examine gene expression in triplicate samples from RNA of total lung homogenates from IPF and control (normal) lungs

2011-09-05 | E-GEOD-31934 | biostudies-arrayexpress

To examine the expression of Sulf1 and Sulf2, as well as other glycan-related genes, in human Idiopathic pulmonary fibrosis (IPF) lungs compared to normal lung samples

2011-09-06 | GSE31934 | GEO

Identification of SULF2 as a novel transcriptional target of p53 by use of integrated genomic analyses.

2009-04-01 | GSE15440 | GEO

Homo sapiens

Project description:Recapitulation of pharmacogenomic data reveals that invalidation of SULF2 enhance sorafenib susceptibility in liver cancer

| PRJNA348449 | ENA

Transcriptome profile in SULF2 knockdown pancreatic tumor cells

Project description:Transcriptome profile in SULF2 knockdown pancreatic tumor cells

| PRJNA810844 | ENA

Chip array data for human PDAC Suit2-007 in primary (pancreas) secondary organs (liver and lungs) of a PDAC rat model

Project description:We report the gene expression profile of human PDAC Suit2-007 in primary (pancreas) secondary organs (liver and lungs) of a PDAC rat model

2020-09-01 | GSE152305 | GEO

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