Glucose insult elicits hyperactivation of cancer stem cells through miR-424–cdc42–prdm14 signalling axis

Abstract

Background:Meta-analysis shows that women with diabetes have a 20% increased risk of breast cancer and also an increased risk for distant metastasis and mortality. The molecular mechanisms for distant metastasis and mortality in breast cancer patients with diabetes are not very well understood.Methods:We compared the effect of physiological (5 mM) and diabetic (10 mM) levels of glucose on malignant breast epithelial cell invasion and stemness capabilities. We performed microRNA array to determine the dysregulated microRNAs in hyperglycaemic conditions and performed functional and molecular analysis of the gene targets.Results:Hyperglycaemia leads to hyperactivation of cancer stem cell pool and enhances invasive ability of breast cancer cells. MiR-424 seems to be a key regulator of cancer cell stemness and invasion. Knockdown of miR-424 in cancer cells under euglycaemic conditions leads to enhanced invasion and stem cell activity, whereas ectopic expression of miR-424 in cancer cells under hyperglycaemic conditions results in suppressed invasion and stem cell activity. Cdc42, a target of miR-424, influences cancer stem cell activity by positively regulating prdm14 through activation of pak1 (p-21-activated kinase 1) and stat5.Conclusions:Our findings establish miR-424→cdc42→prdm14 axis as a key molecular signalling cascade that might influence breast cancer progression in diabetic patients through hyperactivation of cancer stem cells.

Focus on Cdc42 in Breast Cancer: New Insights, Target Therapy Development and Non-Coding RNAs

“…The ectopic expression of miR-424, which always occurs in breast cancer patients under hyperglycemic conditions, leads to Cdc42 activation. Activated Cdc42 stimulates PAK1/STAT5 signaling and then activates the downstream transcriptional regulator prdm14, which maintains CSCs pluripotency and inhibits differentiation [183,184].…”

Cdc42: A Novel Regulator of Insulin Secretion and Diabetes-Associated Diseases

“…On this basis, some key factors, such as glucose transport carriers, glycolytic and glutamine pathways are suggested playing a significant role in this change [137]. It is demonstrated that hyperglycemia promotes invasion and cancer stem cell (CSC) activity through miR-424-Cdc42-prdm14 signalling axis in MDA-MB-231 cells [138]. In hyperglycemia, impaired inhibitory regulation of miR-424 on Cdc42 leads to the activation of prdm14 (PR-domain containing 14) which maintains pluripotency and represses differentiation [138,139].…”

P21-Activated Kinase 1: Emerging biological functions and potential therapeutic targets in Cancer

“…The activation of PGM further helps cancer cells glucose and energy homeostasis 65 . Another study found that hyperglycaemic will lead to the activation of CDC42-PAK1 signaling, which may increase the oncogenic of breast cancer cells 66 . In conclusion, the effects of PAK1 on immunity and metabolism can regulate the progression of cancer in a variety of situations.…”