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Lessons from miR-143/145: the importance of cell-type localization of miRNAs
Oliver A Kent1, Matthew N McCall2, Toby C Cornish3
1Princess Margaret Cancer Center, University Health Network, 101 College Street, Room 8-703, Toronto Medical Discovery Tower, University of Toronto, Toronto, ON M5G 1L7, Canada.
Abstract:
miR-143 and miR-145 are co-expressed microRNAs (miRNAs) that have been extensively studied as potential tumor suppressors. These miRNAs are highly expressed in the colon and are consistently reported as being downregulated in colorectal and other cancers. Through regulation of multiple targets, they elicit potent effects on cancer cell growth and tumorigenesis. Importantly, a recent discovery demonstrates that miR-143 and miR-145 are not expressed in colonic epithelial cells; rather, these two miRNAs are highly expressed in mesenchymal cells such as fibroblasts and smooth muscle cells. The expression patterns of miR-143 and miR-145 and other miRNAs were initially determined from tissue level data without consideration that multiple different cell types, each with their own unique miRNA expression patterns, make up each tissue. Herein, we discuss the early reports on the identification of dysregulated miR-143 and miR-145 expression in colorectal cancer and how lack of consideration of cellular composition of normal tissue led to the misconception that these miRNAs are downregulated in cancer. We evaluate mechanistic data from miR-143/145 studies in context of their cell type-restricted expression pattern and the potential of these miRNAs to be considered tumor suppressors. Further, we examine other examples of miRNAs being investigated in inappropriate cell types modulating pathways in a non-biological fashion. Our review highlights the importance of determining the cellular expression pattern of each miRNA, so that downstream studies are conducted in the appropriate cell type.
Insights
Early studies misidentified miR-143 and miR-145 as downregulated tumor suppressors in colorectal cancer. These microRNAs (miRNAs) are actually expressed in mesenchymal cells, not colon cells, necessitating re-evaluation of their roles.
Area of Science:
- Molecular Biology
- Cancer Research
- Genetics
Background:
- MicroRNAs (miRNAs) miR-143 and miR-145 were initially thought to be downregulated tumor suppressors in colorectal cancer.
- These miRNAs were reported as highly expressed in the colon and downregulated in various cancers, impacting tumorigenesis.
- Early expression analyses relied on tissue-level data, overlooking the cellular heterogeneity within tissues.
Purpose of the Study:
- To re-evaluate the role of miR-143 and miR-145 in colorectal cancer based on their specific cellular expression patterns.
- To address the misconception arising from tissue-level miRNA expression analysis.
- To highlight the importance of cell-type specific miRNA analysis in cancer research.
Main Methods:
- Review of early reports on miR-143 and miR-145 expression in colorectal cancer.
- Analysis of mechanistic data in the context of cell type-restricted miRNA expression.
- Examination of other miRNA studies potentially affected by similar cellular composition issues.
Main Results:
- miR-143 and miR-145 are not expressed in colonic epithelial cells but are highly expressed in mesenchymal cells (fibroblasts, smooth muscle cells).
- The perceived downregulation in cancer was an artifact of analyzing mixed cell populations.
- Mechanistic studies using these miRNAs in inappropriate cell types may lead to non-biological pathway modulation.
Conclusions:
- The role of miR-143 and miR-145 as tumor suppressors needs re-evaluation due to their mesenchymal cell-specific expression.
- Tissue-level expression data can be misleading; cell-type specific analysis is crucial for accurate miRNA function determination.
- Future miRNA research must prioritize understanding cellular expression patterns to ensure biologically relevant findings.
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