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MicroRNA profiling of carcinogen-induced rat colon tumors and the influence of dietary spinach
Mansi A Parasramka1, W Mohaiza Dashwood, Rong Wang
1Linus Pauling Institute, Oregon State University, Corvallis, OR 97331, USA.
Scope:
MicroRNA (miRNA) profiles are altered in chronic conditions such as cardiovascular disease, diabetes, neurological disorders, and cancer. A systems biology approach was used to examine, for the first time, miRNAs altered in rat colon tumors induced by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), a heterocyclic amine carcinogen from cooked meat.
Methods And Results:
Among the most highly dysregulated miRNAs were those belonging to the let-7 family. Subsequent computational modeling and target validation identified c-Myc and miRNA-binding proteins Lin28A/Lin28B (Lin28) as key players, along with Sox2, Nanog, and Oct-3/4. These targets of altered miRNAs in colon cancers have been implicated in tumor recurrence and reduced patient survival, in addition to their role as pluripotency factors. In parallel with these findings, the tumor-suppressive effects of dietary spinach given postinitiation correlated with elevated levels of let-7 family members and partial normalization of c-myc, Sox2, Nanog, Oct-3/4, HmgA2, Dnmt3b, and P53 expression.
Conclusion:
We conclude that the let-7/c-Myc/Lin28 axis is dysregulated in heterocyclic amine-induced colon carcinogenesis, and that the tumor suppressive effects of dietary spinach are associated with partial normalization of this pathway.
Insights
Altered microRNA (miRNA) profiles in PhIP-induced colon tumors reveal a dysregulated let-7/c-Myc/Lin28 axis. Dietary spinach partially normalizes this pathway, suggesting a therapeutic role in colon cancer prevention.
Area of Science:
- Oncology
- Molecular Biology
- Nutritional Science
Background:
- MicroRNA (miRNA) profiles are significantly altered in various chronic conditions, including cancer.
- Heterocyclic amines, such as PhIP found in cooked meat, are known carcinogens that can induce colon tumors.
- Understanding miRNA dysregulation in carcinogenesis is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate miRNA alterations in PhIP-induced rat colon tumors using a systems biology approach.
- To identify key molecular players and pathways involved in heterocyclic amine-induced colon carcinogenesis.
- To explore the potential tumor-suppressive effects of dietary spinach in this model.
Main Methods:
- Induction of colon tumors in rats using the heterocyclic amine PhIP.
- Application of a systems biology approach to analyze miRNA profiles.
- Computational modeling and target validation to identify key regulatory proteins and pathways.
- Assessment of gene expression changes in response to dietary spinach intervention.
Main Results:
- The let-7 miRNA family was found to be highly dysregulated in PhIP-induced colon tumors.
- The let-7/c-Myc/Lin28 axis was identified as a key dysregulated pathway, involving pluripotency factors Sox2, Nanog, and Oct-3/4.
- Dietary spinach administration post-tumor initiation showed tumor-suppressive effects.
- Spinach consumption led to elevated let-7 levels and partial normalization of c-myc, Sox2, Nanog, Oct-3/4, and other target genes.
Conclusions:
- The let-7/c-Myc/Lin28 axis is critically dysregulated in PhIP-induced colon carcinogenesis.
- Dietary spinach exerts tumor-suppressive effects by partially normalizing this critical pathway.
- These findings highlight the role of specific miRNA pathways in colon cancer development and the potential of dietary interventions.
