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AEG-1 as a Novel Therapeutic Target in Colon Cancer: A Study from Silencing AEG-1 in BALB/c Mice to Large Data
Sushmitha Sriramulu1, Sarubala Malayaperumal1, Antara Banerjee1
1Department of Medical Biotechnology, Faculty of Allied Health Sciences, Chettinad Academy of Research and Education (CARE), Chettinad Hospital and Research Institute (CHRI), Kelambakkam, Chennai 603103, India.
Background:
Astrocyte elevated gene-1 (AEG-1) is overexpressed in various malignancies. Exostosin-1 (EXT-1), a tumor suppressor, is an intermediate for malignant tumors. Understanding the mechanism behind the interaction between AEG-1 and EXT-1 may provide insights into colon cancer metastasis.
Methods:
AOM/DSS was used to induce tumor in BALB/c mice. Using an in vivo-jetPEI transfection reagent, transient transfection of AEG-1 and EXT-1 siRNAs were achieved. Histological scoring, immunohistochemical staining, and gene expression studies were performed from excised tissues. Data from the Cancer Genomic Atlas and GEO databases were obtained to identify the expression status of AEG-1 and itsassociation with the survival.
Results:
In BALB/c mice, the AOM+DSS treated mice developed necrotic, inflammatory and dysplastic changes in the colon with definite clinical symptoms such as loss of goblet cells, colon shortening, and collagen deposition. Administration of AEG-1 siRNA resulted in a substantial decrease in the disease activity index. Mice treated with EXT-1 siRNA showed diffusely reduced goblet cells. In vivo investigations revealed that PTCH-1 activity was influenced by upstream gene AEG-1, which in turn may affect EXT-1 activity. Data from The Cancer Genomic Atlas and GEO databases confirmed the upregulation of AEG-1 and downregulation of EXT-1 in cancer patients.
Conclusions:
This study revealed that AEG-1 silencing might alter EXT-1 expression indirectly through PTCH-1, influencing cell-ECM interactions, and decreasing dysplastic changes, proliferation and invasion.
Insights
Astrocyte elevated gene-1 (AEG-1) silencing may inhibit colon cancer metastasis by indirectly altering Exostosin-1 (EXT-1) expression via PTCH-1. This suggests a novel therapeutic target for colon cancer.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Astrocyte elevated gene-1 (AEG-1) is frequently overexpressed in various cancers.
- Exostosin-1 (EXT-1), a known tumor suppressor, plays a role in malignant tumor progression.
- Investigating the AEG-1 and EXT-1 interaction is crucial for understanding colon cancer metastasis.
Purpose of the Study:
- To elucidate the mechanistic link between AEG-1 and EXT-1 in colon cancer.
- To evaluate the therapeutic potential of targeting AEG-1 and EXT-1 in a mouse model of colon cancer.
- To correlate AEG-1 and EXT-1 expression with patient survival data.
Main Methods:
- Colon tumor induction in BALB/c mice using AOM/DSS.
- In vivo transfection of AEG-1 and EXT-1 siRNAs.
- Histological, immunohistochemical, and gene expression analyses of excised tissues.
- Analysis of The Cancer Genomic Atlas and GEO databases for expression patterns and survival associations.
Main Results:
- AOM/DSS treatment induced significant colonic pathological changes.
- AEG-1 siRNA administration reduced disease activity index.
- EXT-1 siRNA treatment led to reduced goblet cells.
- AEG-1 influenced PTCH-1 activity, potentially affecting EXT-1.
- Database analysis confirmed AEG-1 upregulation and EXT-1 downregulation in human colon cancer.
Conclusions:
- AEG-1 silencing may indirectly modulate EXT-1 expression through PTCH-1.
- This interaction influences cell-extracellular matrix interactions, reducing colon cancer progression.
- Targeting AEG-1 offers a potential strategy to decrease colon cancer dysplastic changes, proliferation, and invasion.
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