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Restricting Colorectal Cancer Cell Metabolism with Metformin: An Integrated Transcriptomics Study
Ayla Orang1, Shashikanth Marri1, Ross A McKinnon1
1Flinders Health and Medical Research Institute, Flinders University, Bedford Park, SA 5042, Australia.
Background:
Metformin is a first-line therapy for type 2 diabetes as it disrupts cellular metabolism. Despite the association between metformin and lower cancer incidence, the anti-tumour activity of the drug in colorectal cancer (CRC) is incompletely understood. This study identifies underlying molecular mechanisms by which metformin slows colorectal cancer cell proliferation by investigating metformin-associated microRNA (miRNA) and target gene pairs implicated in signalling pathways.
Methods:
The present study analysed changes in miRNAs and the coding transcriptome in CRC cells treated with a sublethal dose of metformin, followed by the contextual validation of potential miRNA-target gene pairs.
Results:
Analyses of small RNA and transcriptome sequencing data revealed 104 miRNAs and 1221 mRNAs to be differentially expressed in CRC cells treated with metformin for 72 h. Interaction networks between differentially expressed miRNAs and putative target mRNAs were identified. Differentially expressed genes were mainly implicated in metabolism and signalling processes, such as the PI3K-Akt and MAPK/ERK pathways. Further validation of potential miRNA-target mRNA pairs revealed that metformin induced miR-2110 and miR-132-3p to target PIK3R3 and, consequently, regulate CRC cell proliferation, cell cycle progression and the PI3K-Akt signalling pathway. Metformin also induced miR-222-3p and miR-589-3p, which directly target STMN1 to inhibit CRC cell proliferation and cell cycle progression.
Conclusions:
This study identified novel changes in the coding transcriptome and small non-coding RNAs associated with metformin treatment of CRC cells. Integration of these datasets highlighted underlying mechanisms by which metformin impedes cell proliferation in CRC. Importantly, it identified the post-transcriptional regulation of specific genes that impact both metabolism and cell proliferation.
Insights
Metformin slows colorectal cancer cell proliferation by altering microRNAs (miRNAs) and gene expression. This study identifies specific miRNAs and genes involved in key metabolic and signaling pathways, revealing new anti-cancer mechanisms.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Metformin is a first-line type 2 diabetes drug impacting cellular metabolism.
- Its association with reduced cancer incidence is known, but anti-tumour mechanisms in colorectal cancer (CRC) require further elucidation.
- Understanding metformin's molecular effects in CRC is crucial for potential therapeutic applications.
Purpose of the Study:
- To identify molecular mechanisms by which metformin inhibits colorectal cancer cell proliferation.
- To investigate metformin-associated microRNA (miRNA) and target gene interactions in CRC.
- To explore the role of these interactions in key cellular signalling pathways.
Main Methods:
- Small RNA and transcriptome sequencing were performed on CRC cells treated with metformin.
- Differential expression analysis identified altered miRNAs and messenger RNAs (mRNAs).
- miRNA-target gene interactions were predicted and validated to understand pathway regulation.
Main Results:
- Metformin treatment altered 104 miRNAs and 1221 mRNAs in CRC cells.
- Key pathways affected include PI3K-Akt and MAPK/ERK, involved in metabolism and signalling.
- Specific miRNAs (miR-2110, miR-132-3p, miR-222-3p, miR-589-3p) were identified to target PIK3R3 and STMN1, regulating cell proliferation and cell cycle.
Conclusions:
- Novel changes in coding transcriptome and small non-coding RNAs were identified with metformin treatment in CRC.
- Metformin impedes CRC cell proliferation through post-transcriptional regulation of genes impacting metabolism and cell cycle.
- This study elucidates specific molecular targets and pathways through which metformin exerts anti-cancer effects in colorectal cancer.
