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Published on: January 22, 2013
Anoikis-related genes predicts prognosis and therapeutic response in renal cell carcinoma
Lizhi Zhou1,2, Hengcheng Lu3, Bin Fu1
1Jiangxi Provincial Key Laboratory of Urinary System Diseases, Department of Urology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, P.R. China.
Background:
Metastasis represents the primary cause of cancer-related mortality, with a high incidence observed in renal cell carcinoma (RCC). Anoikis, a specialized form of apoptosis, plays a crucial role in preventing displaced cells from adhering to new extracellular matrices (ECM), thus inhibiting their aberrant growth. Notably, cancer cells, especially metastatic ones, exhibit resistance to anoikis. However, the exact mechanisms of anoikis resistance in RCC are not well understood.
Methods:
This study integrates bioinformatics, single-cell RNA sequencing and experimental validation to investigate the role of anoikis-related genes (ARG) in RCC, with a focus on MMP9. RNA-seq data from 518 RCC patients and 71 healthy controls (TCGA-KIRC) and external validation cohorts (E-MTAB-1980, GSE22541) were analyzed to construct an ARG-based prognostic model. Single-cell RNA sequencing (scRNA-seq, GSE159115) was used to assess tumour heterogeneity, while in vitro experiments in RCC cell lines validated MMP9's impact on anoikis resistance, migration and invasion.
Results:
We collected all RNA-seq and single-cell RNA-seq (scRNA-seq) data from multiple online databases and utilized these datasets to develop a novel ARG-based prognostic model called ARGs. Using Cox regression and machine learning, our model achieved a 5-year area under curve (AUC) of 0.79, surpassing existing models in predictive performance. Enrichment analysis revealed distinct immune and metabolic landscapes between ARGs high- and low-risk groups. At the single-cell level, tumour cells were categorized based on ARG expression, revealing heterogeneous anoikis resistance mechanisms. MMP9 was identified as a key prognostic gene (HR = 1.5, p = 0.016) associated with anoikis resistance and RCC metastasis. Functional assays confirmed that MMP9 knockdown increased anoikis by 59% and significantly reduced wound-healing migration by about 30% and transwell invasion by 50%, reinforcing its role in RCC progression.
Conclusions:
Targeting anoikis-related genes, particularly MMP9, enhances anoikis sensitivity and reduces RCC invasiveness, offering a potential therapeutic strategy to mitigate metastasis and improve clinical outcomes.
Insights
This study reveals that targeting anoikis-related genes, especially MMP9, can enhance anoikis sensitivity and reduce renal cell carcinoma (RCC) metastasis. This offers a promising therapeutic strategy for improving patient outcomes.
Area of Science:
- Oncology
- Molecular Biology
- Bioinformatics
Background:
- Metastasis in renal cell carcinoma (RCC) is a leading cause of cancer mortality.
- Anoikis, a form of programmed cell death, normally prevents cancer cell spread, but metastatic RCC cells often resist it.
- The precise mechanisms of anoikis resistance in RCC remain poorly understood.
Purpose of the Study:
- To investigate the role of anoikis-related genes (ARGs) in renal cell carcinoma (RCC) progression and metastasis.
- To develop a prognostic model for RCC based on ARGs.
- To identify key genes, such as MMP9, involved in anoikis resistance in RCC.
Main Methods:
- Integrated bioinformatics analysis of RNA-seq data from RCC patients and controls.
- Construction of an ARG-based prognostic model using Cox regression and machine learning.
- Single-cell RNA sequencing (scRNA-seq) to analyze tumor heterogeneity and experimental validation of MMP9's function.
Main Results:
- A novel ARG-based prognostic model demonstrated superior predictive performance (5-year AUC of 0.79).
- Distinct immune and metabolic landscapes were observed between high- and low-risk groups.
- MMP9 was identified as a key prognostic gene promoting anoikis resistance, migration, and invasion in RCC, with knockdown increasing anoikis by 59%.
Conclusions:
- Targeting ARGs, particularly MMP9, can enhance anoikis sensitivity in RCC.
- Reducing MMP9 expression significantly inhibits RCC cell migration and invasion.
- This approach presents a potential therapeutic strategy to combat RCC metastasis and improve patient outcomes.
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