Obesity and cancer – a microRNA story

Obesity is a risk factor for several cancer types, suggesting shared molecular mechanisms. We have identified cancer-relevant microRNAs that respond to metabolic hormone signaling in culture or metabolic changes in human subjects. These include the pleiotropic miR-10b and the less known, non-canonical miR-4443.

Our recently published study showed that miR-10b is more strongly downregulated in the primary breast tumors of obese patients, suggesting that the metabolic state of the organism can lead to a significant difference in the molecular pathology of cancer. In ductal but not lobular tumors, significant inverse correlations were observed between the tumor levels of miR-10b and miR-30c and the mRNA levels of cancer-relevant target genes SRSF1, PIEZO1, MAPRE1, CDKN2A, TP-53 and TRA2B, as well as tumor grade. Suppression of miR-10b levels in BT-549 cells increased cell proliferation and invasive capacity, while exogenous miR-10b mimic decreased invasion. Manipulation of miR-10b levels also inversely affected the mRNA levels of miR-10b targets BCL2L11, PIEZO1 and NCOR2.

We previously reported that in cultured colon cancer cells, miR-4443 was upregulated by leptin and insulin in a MEK1/2-dependent manner. MiR-4443 overexpression decreased invasion and proliferation, and directly downregulated pro-metastatic NCOA1 and TRAF4. Insulin and/or leptin resistance (e.g. in obesity) may neutralize this tumor-suppressive pathway, increasing cancer risk. Supporting this notion, the miR-4443 locus is frequently deleted in cancers. Our new data show that miR-4443 is a non-canonical microRNA with a yet unknown biogenesis pathway.

Understanding the roles of metabolically controlled microRNAs may help improve risk assessment, diagnosis and treatment of metabolism-dependent cancers.