Molecular Subtype Identification and Potential Drug Prediction Based on Anoikis-Related Genes Expression in
Zhixin Jiang1, Boyang Zhang2, Shichong Jia1
1Tianjin Eye Hospital, Nankai University Affiliated Eye Hospital, Clinical College of Ophthalmology, Tianjin Medical University, Tianjin Eye Institute, Tianjin Key Laboratory of Ophthalmology and Visual Science, Tianjin, China.
Purpose:
Anoikis is a special apoptosis accompanied by the loss of extracellular matrix (ECM) environment and the decomposition of ECM is an important process in the occurrence of keratoconus (KC). This study aims to describe the expression profile of anoikis-related genes (ARGs) in KC samples, identify differentially expressed genes (DEGs), characterize the biological functions and immune characteristics of different molecular subtypes of KC and predict potential drugs based on the construction of a co-expression network.
Methods:
First, we identified molecular subtypes by optimal clustering K based on the expression profile of ARGs in the KC dataset and analyzed the differences of functional and immune characteristics. Then a weighted gene co-expression network was constructed based on cluster analysis to obtain hub genes and protein-protein interaction network was constructed to analyze hub nodes and predict potential node-targeting drugs.
Results:
By comparing the expression profile between disease and normal samples, we found that there were significant differences in ARGs such as BCL2, CAV1, and CEACAM5. Consistent cluster analysis identified two definite clusters on the basis of ARGs expression difference. Kyoto Encyclopedia of Genes and Genomes and Gene Ontology enrichment analysis showed that DEGs were enriched significantly in pathways like ECM receptor interaction, chemokine signal, notch signal, focal adhesion, and functional sets like proteolysis, anoikis, regulation of natural killer and T-cell proliferation. CIBERSORT calculation showed that there were significant differences between the two subtypes on immune cell infiltration (monocytes and plasma) and immune molecules (CCL11, CCL14, HLA-A, HLA-B, and so on). Then, co-expression network was constructed based on cluster phenotype, 5202 genes were selected as hub genes, and 321 HubDEGs were obtained after intersection with significant DEGs. Seven hub nodes, EIF4G1, KHSRP, PABPC1, POLR2A, PTBP1, RPS19, and SMARCA4, were identified and matched drugs or small molecular compounds. Insulin and dexamethasone were identified as potential target drugs.
Conclusions:
We revealed the differential expression of ARGs in KC samples, and identified two distinct subtypes that showed significant differences in biological function and immune infiltration. The identification of hub gene nodes elucidated their therapeutic value on predicted potential drugs.
Insights
This study reveals distinct molecular subtypes in keratoconus (KC) based on anoikis-related genes (ARGs), identifying key genes and potential drug targets like insulin and dexamethasone for therapeutic development.
Area of Science:
- Ophthalmology
- Molecular Biology
- Immunology
Background:
- Anoikis, a form of apoptosis triggered by extracellular matrix (ECM) detachment, and ECM decomposition are implicated in keratoconus (KC) pathogenesis.
- Understanding the molecular mechanisms underlying KC, particularly the role of anoikis-related genes (ARGs), is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the expression profile of ARGs in KC samples.
- To identify differentially expressed genes (DEGs) and characterize molecular subtypes of KC.
- To predict potential therapeutic drugs by constructing a co-expression network.
Main Methods:
- Identified molecular subtypes using K-means clustering based on ARG expression.
- Performed Kyoto Encyclopedia of Genes and Genomes and Gene Ontology enrichment analyses for DEGs.
- Constructed a weighted gene co-expression network and protein-protein interaction network to identify hub genes and predict drugs.
Main Results:
- Found significant differences in ARGs (e.g., BCL2, CAV1, CEACAM5) between KC and normal samples.
- Identified two distinct KC molecular subtypes with significant differences in biological functions (e.g., ECM receptor interaction, proteolysis, anoikis) and immune cell infiltration.
- Identified seven hub genes and potential drugs, including insulin and dexamethasone.
Conclusions:
- Revealed differential ARG expression and two distinct KC subtypes with varying biological functions and immune characteristics.
- Highlighted the therapeutic potential of identified hub genes and predicted drugs for keratoconus treatment.
