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Glucose insult elicits hyperactivation of cancer stem cells through miR-424-cdc42-prdm14 signalling axis
- Source :
- British Journal of Cancer
- Publication Year :
- 2017
-
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.
- Subjects :
- 0301 basic medicine
cancer stem cells
Cancer Research
medicine.medical_specialty
Breast Neoplasms
03 medical and health sciences
Mice
0302 clinical medicine
Breast cancer
Cancer stem cell
breast cancer metastasis
Internal medicine
Cell Line, Tumor
microRNA
medicine
Animals
Humans
Neoplasm Invasiveness
cdc42 GTP-Binding Protein
prdm14
Molecular Diagnostics
STAT5
biology
diabetes
Kinase
business.industry
cdc42
RNA-Binding Proteins
medicine.disease
DNA-Binding Proteins
Repressor Proteins
MicroRNAs
030104 developmental biology
Endocrinology
Glucose
Oncology
Cell culture
030220 oncology & carcinogenesis
Hyperglycemia
Cancer cell
biology.protein
Cancer research
Neoplastic Stem Cells
Female
Stem cell
business
hyperglycaemia
Signal Transduction
Transcription Factors
Subjects
Details
- ISSN :
- 15321827
- Volume :
- 117
- Issue :
- 11
- Database :
- OpenAIRE
- Journal :
- British journal of cancer
- Accession number :
- edsair.doi.dedup.....7c8921bdfeaed3aaf220f17f076bc934