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Published on: March 14, 2019
Overexpression of miR-194 Reverses HMGA2-driven Signatures in Colorectal Cancer
Hsin-Yi Chang1,2, Shu-Ping Ye1, Shiow-Lin Pan1
1The Ph.D. Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
Abstract:
Colorectal cancer (CRC) is one of the leading causes of cancer death worldwide with increasing incidence and mortality in developed countries. Oncogenes and microRNAs regulate key signaling pathways in CRC and are known to be deregulated. Oncogenic transcriptional regulator high-mobility group AT-hook 2 (HMGA2) participates in the transformation of several cancers including CRC and exhibits strong correlation with poor prognosis and distal metastasis. Evidence of HMGA2 and its co-regulated miRs contributing to tumor progression remains to be clarified.
Methods:
We performed gene-set enrichment analysis on the expression profiles of 70 CRC patients and revealed HMGA2 correlated genes that are targeted by several miRs including miR-194. To eliminate the oncogenic effects in HMGA2-driven CRC, we re-expressed miR-194 and found that miR-194 functions as a tumor suppressor by reducing cell proliferation and tumor growth in vitro and in vivo.
Results:
As a direct upstream inhibitory regulator of miR-194, overexpression of HMGA2 reduced miR-194 expression and biological activity, whereas re-expressing miR-194 in cells with high levels of HMGA2 impaired the effects of HMGA2, compromising cell survival, the epithelial-mesenchymal transition process, and drug resistance.
Conclusion:
Our findings demonstrate that novel molecular correlations can be discovered by revisiting transcriptome profiles. We uncover that miR-194 is as important as HMGA2, and both coordinately regulate the oncogenesis of CRC with inverted behaviors, revealing alternative molecular therapeutics for CRC patients with high HMGA2 expression.
Insights
High-mobility group AT-hook 2 (HMGA2) drives colorectal cancer (CRC) by suppressing miR-194. Restoring miR-194 inhibits HMGA2's oncogenic effects, offering new therapeutic strategies for CRC.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Colorectal cancer (CRC) presents a significant global health challenge with rising incidence and mortality.
- Oncogenes and microRNAs are key regulators of CRC signaling pathways, often exhibiting deregulation.
- High-mobility group AT-hook 2 (HMGA2) is an oncogenic regulator implicated in CRC progression and poor prognosis.
Purpose of the Study:
- To investigate the molecular interplay between HMGA2 and microRNAs (miRs) in colorectal cancer.
- To elucidate the role of miR-194 in HMGA2-driven CRC progression.
- To explore potential therapeutic strategies targeting the HMGA2-miR-194 axis in CRC.
Main Methods:
- Gene-set enrichment analysis of 70 CRC patient expression profiles.
- In vitro and in vivo experiments involving HMGA2 and miR-194 manipulation.
- Assessment of cell proliferation, tumor growth, epithelial-mesenchymal transition, and drug resistance.
Main Results:
- HMGA2 expression inversely correlates with miR-194 levels in CRC.
- Re-expression of miR-194 suppresses HMGA2-driven CRC cell proliferation and tumor growth.
- miR-194 re-expression counteracts HMGA2 effects on cell survival, epithelial-mesenchymal transition, and drug resistance.
Conclusions:
- HMGA2 and miR-194 are crucial, inversely acting regulators of CRC oncogenesis.
- Novel molecular correlations in CRC can be identified through transcriptome analysis.
- Targeting the HMGA2-miR-194 axis offers a promising therapeutic avenue for CRC patients with high HMGA2 expression.
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