Metformin's Modulatory Effects on miRNAs Function in Cancer Stem Cells-A Systematic Review

Cancer stem cells (CSCs) have been reported in various hematopoietic and solid tumors, therefore, are considered to promote cancer progression, metastasis, recurrence and drug resistance. However, regulation of CSCs at the molecular level is not fully understood. microRNAs (miRNAs) have been identified as key regulators of CSCs by modulating their major functions: self-renewal capacity, invasion, migration and proliferation. Various studies suggest that metformin, an anti-diabetic drug, has an anti-tumor activity but its precise mechanism of action has not been understood. The present article was written in accordance to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. We systematically reviewed evidence for metformin's ability to eradicate CSCs through modulating the expression of miRNAs in various solid tumors. PubMed and MEDLINE were searched from January 1990 to January 2020 for in vitro studies. Two authors independently selected and reviewed articles according to predefined eligibility criteria and assessed risk of bias of included studies. Four papers met the inclusion criteria and presented low risk bias. All of the included studies reported a suppression of CSCs' major function after metformin dosage. Moreover, it was showed that metformin anti-tumor mechanism of action is based on regulation of miRNAs expression. Metformin inhibited cell survival, clonogenicity, wound-healing capacity, sphere formation and promotes chemosensitivity of tumor cells. Due to the small number of publications, aforementioned evidences are limited but may be consider as background for clinical studies.