Dataset Information

NOTCH3 Promotes Malignant Progression of Bladder Cancer by Directly Regulating SPP1 and Activating PI3K/AKT Pathway

ABSTRACT: The biological role and precise molecular mechanisms of Notch receptor 3 (NOTCH3) in the malignant progression of bladder cancer (BLCA) remain unclear. In this study, we found that NOTCH3 was significantly upregulated and associated with poor prognosis in BLCA patients. Functional experiments demonstrated that NOTCH3 knockdown inhibited BLCA cell proliferation, migration, invasion and significantly suppressed tumor growth and metastasis in vivo as well. Mechanically, chromatin immunoprecipitation and dual-luciferase reporter assays confirmed that NOTCH3 could promote the transcription of secreted phosphoprotein 1(SPP1), a potential downstream target gene of NOTCH3，by binding to the CSL elements in the SPP1 promoter. Moreover, we also found that targeting NOTCH3 inhibited BLCA growth and metastasis by suppressing the SPP1-PI3K/AKT axis. Our study highlights the critical role of NOTCH3-SPP1-PI3K/AKT axis in the malignant progression of BLCA, suggesting that NOTCH3 may be a potential therapeutic target for BLCA.

ORGANISM(S): Homo sapiens

PROVIDER: GSE279910 | GEO | 2024/11/27

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Abstract: Cancer-associated fibroblasts (CAFs) play an important role in the induction of chemo-resistance. The objectives of this study were to clarify the mechanism underlying CAF-mediated sorafenib/lenvatinib resistance and identify a novel therapeutic target to overcome resistance to sorafenib/lenvatinib in hepatocellular carcinoma (HCC). Methods: Whole transcriptome sequencing (WTS) data of nine pairs of CAFs and para-cancer-associated fibroblasts (PAFs) were analyzed to identify key molecules that induce resistance to tyrosine kinase inhibitors (TKIs). In vitro and in vivo experiments were performed to validate selected targets and related mechanisms. Plasma secreted phosphoprotein 1 (SPP1) expression levels prior to sorafenib/lenvatinib treatment as well as progression-free survival (PFS) and overall survival (OS) of an advanced HCC cohort (n=42) were evaluated using Kaplan–Meier analysis. Results: Co-culturing CAFs and HCC cells significantly reduced the responsiveness of HCC cells to sorafenib/lenvatinib, in vitro and in vivo. Systematic integrative analysis of the WTS data of CAFs/PAFs and publicly available gene expression data indicated that CAF-derived SPP1 (CAF-SPP1) was suitable for use as a candidate molecule to induce sorafenib/lenvatinib resistance. An evaluation of the mechanisms involved indicated that CAF-SPP1 increased phosphorylation of PKCɑ, which then activated rapidly accelerated fibrosarcoma (RAF)-extracellular signal-related kinase 1/2-signal transducer and activator of transcription 3 (STAT3) and phosophoinositide 3-kinase (PI3K)-AKT-mechanistic target of rapamycin kinase (mTOR) in HCC cells. SPP1 inhibitors reversed CAF-induced sorafenib/lenvatinib resistance in vitro and in vivo. Patients showing high plasma SPP1 prior to sorafenib/lenvatinib treatment exhibited significantly poor PFS (P=0.005) and OS (P=0.041). Conclusions: CAF-SPP1 enhances sorafenib/lenvatinib resistance in HCC by alternatively activating oncogenic pathways via PKCɑ phosphorylation. Inhibition of CAF-SPP1 may be utilized as a therapeutic strategy against TKI resistance in HCC. Plasma SPP1 level prior to TKI treatment shows potential as a promising biomarker for predicting sorafenib/lenvatinib response in advanced HCC patients.

Dataset Information

NOTCH3 Promotes Malignant Progression of Bladder Cancer by Directly Regulating SPP1 and Activating PI3K/AKT Pathway

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets