Abstract
Cancer cell survival and metastasis are dependent on metabolic reprogramming that is capable of increasing resistance to oxidative and energetic stress. Targeting these two processes can be crucial for cancer progression. Herein, we describe the role of microRNA‐661 (miR661) as epigenetic regulator of colon cancer (CC) cell metabolism. MicroR661 induces a global increase in reactive oxygen species, specifically in mitochondrial superoxide anions, which appears to be mediated by decreased carbohydrate metabolism and pentose phosphate pathway, and by a higher dependency on mitochondrial respiration. MicroR661 overexpression in non‐metastatic human CC cells induces an epithelial‐to‐mesenchymal transition phenotype, and a reduced tolerance to metabolic stress. This seems to be a general effect of miR661 in CC, since metastatic CC cell metabolism is also compromised upon miR661 overexpression. We propose hexose‐6‐phosphate dehydrogenase and pyruvate kinase M2 as two key players related to the observed metabolic reprogramming. Finally, the clinical relevance of miR661 expression levels in stage‐II and III CC patients is discussed. In conclusion, we propose miR661 as a potential modulator of redox and metabolic homeostasis in CC.
Highlights
Tumor cells reprogram their energetic metabolism to support rapid and uncontrolled growth
It is well known that oncogenic transformation alters cellular metabolism to facilitate cell proliferation, but less is known about the metabolic changes that promote epithelial to mesenchymal transition (EMT) and the EMT-associated metabolic reprogramming
The ability to manage and overcome the associated metabolic stress is crucial for cancer cell survival and metastasis (Jeon et al, 2012)
Summary
Tumor cells reprogram their energetic metabolism to support rapid and uncontrolled growth. MiR661 modulates colon cancer metabolism polarity and cell-to-cell adhesions, gaining a mesenchymal morphology with migration and invasion capabilities These properties promote metastasis and the development of several neoplasias (Gupta and Massague, 2006), including colorectal cancer, one of the most common cancers worldwide and the second most common malignant tumor in Europe, killing 230 000 people each year (http://www.europacolon.com). Reddy et al (2009) reported that miR661 inhibited the expression of metastatic tumor antigen 1 (MTA1) in invasive breast cancer cells and reintroduction of this miR was able to inhibit motility, invasiveness, and tumorigenesis This controversy disappears when one takes into account that, in the first work, Snail drives the EMT phenotype and miR661 is an associated player, whereas in the second work, miR661, by targeting MTA1, induces the opposite effect. We propose miR661 as a potential modulator of redox and metabolic homeostasis in CC
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