Nikhil Prasad Fact checked by:Thailand Medical News Team May 30, 2024 6 months, 1 week, 5 days, 22 hours, 51 minutes ago
Cancer News: Metformin, widely known as a primary treatment for type 2 diabetes, has recently emerged as a promising agent in cancer prevention, particularly for colorectal cancer (CRC). This
Cancer News report delves into the molecular mechanisms through which metformin exerts its anti-tumor effects in CRC cells. By identifying specific microRNAs (miRNAs) influenced by metformin, this study provides valuable insights into how metformin disrupts CRC cell growth, impacting both metabolism and cell proliferation.
Metformin Targets Colorectal Cancer Cell Growth Via miRNA Regulation
Background: Metformin’s Dual Role
Metformin is primarily prescribed to manage blood sugar levels in type 2 diabetes patients by altering cellular metabolism. Interestingly, epidemiological studies have shown that metformin users have a lower incidence of various cancers, including CRC. However, the specific anti-tumor mechanisms of metformin in CRC remain incompletely understood. This research aims to uncover these mechanisms by exploring the miRNAs and their target genes affected by metformin treatment.
Methods: Investigating Metformin’s Molecular Impact
The study analyzed changes in miRNAs and the coding transcriptome in CRC cells treated with a sublethal dose of metformin. Using small RNA sequencing and total RNA sequencing, researchers identified differentially expressed miRNAs and mRNAs. They further validated potential miRNA–target gene pairs to understand the interactions and pathways involved.
Results: Metformin’s Molecular Footprint – miRNA and mRNA Changes
After treating CRC cells with metformin for 72 hours, researchers identified 104 differentially expressed miRNAs and 1221 differentially expressed mRNAs. Interaction networks between these miRNAs and their putative target mRNAs revealed that many differentially expressed genes were implicated in key metabolic and signaling processes, such as the PI3K-Akt and MAPK/ERK pathways.
Key Findings
miR-2110 and miR-132-3p Target PIK3R3: Metformin induced miR-2110 and miR-132-3p, which target the PIK3R3 gene, regulating CRC cell proliferation, cell cycle progression, and the PI3K-Akt signaling pathway.
miR-222-3p and miR-589-3p Target STMN1: These miRNAs directly target STMN1, inhibiting CRC cell proliferation and cell cycle progression.
Metformin’s Anti-Cancer Mechanisms
-Metformin and the PI3K-Akt Pathway
The PI3K-Akt signaling pathway is crucial for cell survival, growth, and metabolism. Dysregulation of this pathway is commonly associated with cancer. The study confirmed that miR-2110 and miR-132-3p, induced by metformin, directly target and downregulate PIK3R3, a key regulator of the PI3K-Akt pathway. This downregulation leads to decreased phosphorylation of downstream effectors such as p70 S6 kinase, ultimately inhibiting cell proliferation and inducing cell cycle arrest.<
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-Metformin and the MAPK/ERK Pathway
The MAPK/ERK pathway is another critical signaling cascade involved in cell proliferation, differentiation, and survival. Metformin treatment led to significant upregulation of miR-222-3p and miR-589-3p, which target and downregulate STMN1. This suppression of STMN1 disrupts microtubule dynamics during mitotic spindle formation, further inhibiting CRC cell growth and inducing cell cycle arrest at the G1 phase.
Validation Across CRC Cell Lines
The study’s findings were validated across various CRC cell lines, confirming the generalizability of the identified mechanisms. These validations underscore the robustness of the data and suggest that the anti-proliferative effects of metformin are not limited to a single cellular context but are applicable across different genetic backgrounds.
Limitations and Future Directions
One notable limitation of the study is the use of high-glucose medium, which does not fully replicate the physiological nutrient environment of tumors in vivo. Future studies should aim to replicate these findings using media that more closely mimic physiological conditions. Additionally, further research is required to explore the broader implications of these miRNA-mediated regulatory mechanisms in other types of cancer.
Conclusion: Metformin as a Multi-Targeted Cancer Therapy
This study highlights metformin’s potential as a multi-targeted therapy for CRC by revealing its ability to induce specific miRNAs that regulate key signaling pathways. By upregulating miR-2110 and miR-132-3p to target PIK3R3 and miR-222-3p and miR-589-3p to target STMN1, metformin effectively disrupts cell proliferation and induces cell cycle arrest. These findings not only enhance our understanding of metformin’s anti-cancer mechanisms but also open new avenues for developing RNA-based therapeutics in CRC treatment.
With these insights, the study underscores the potential of metformin as a therapeutic agent in cancer treatment, offering a new perspective on its application beyond diabetes management.
The study findings by the researchers from Flinders University-Australia, South Australia Health and Medical Research Institute, Adelaide-Australia and Flinders Medical Centre-Australia were published in the peer reviewed journal: Cancers.
https://www.mdpi.com/2072-6694/16/11/2055
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