Abstract
Let-7 microRNAs (miRNAs) are highly conserved well-established promoters of terminal differentiation that are expressed in healthy adult tissues and frequently repressed in cancer cells. The tumor suppressive role of let-7 in a variety of cancers in vitro and in vivo has been widely documented and prompted these miRNAs to be candidate genes for miRNA replacement therapy. In this study we described a new role of let-7a in reprogramming cancer metabolism, recently identified as a new hallmark of cancer. We show that let-7a down-regulates key anabolic enzymes and increases both oxidative phosphorylation and glycolysis in triple-negative breast cancer and metastatic melanoma cell lines. Strikingly, the accelerated glycolysis coexists with drastically reduced cancer features. Moreover, let-7a causes mitochondrial ROS production concomitant with the up-regulation of oxidative stress responsive genes. To exploit these increased ROS levels for therapeutic purposes, we combined let-7a transfection with the chemotherapeutic drug doxorubicin. In both cancer types let-7a increased cell sensitivity to doxorubicin. Pre-treatment with N-acetyl cysteine (NAC) totally abolished this effect, indicating that the increased doxorubicin sensitivity of let-7a cells depends on the redox pathway. We thus have demonstrated that let-7a plays a prominent role in regulating energy metabolism in cancer cells, further expanding its therapeutic potential.
Highlights
MicroRNAs are evolutionarily conserved small (18-25 nucleotides) non-coding RNAs that modulate gene expression by targeting mRNAs of protein-coding genes
All of them fall into two major biosynthetic pathways: nucleotide (G6PD, TYMS, IMPDH2) and lipid (FASN, AASDHPPT, stearoyl-CoA desaturase (SCD)) biosynthesis
We did not detect any reduction neither in NADPH level, nor in GSH (Fig. S8) in let-7a transfected cells, suggesting that alternative cellular sources may replenish the NADPH pool [31]. Both TYMS and IMPDH2 are up-regulated by the MYC oncoprotein [32, 33], which is a target of let-7, suggesting an indirect regulatory mechanism
Summary
MicroRNAs (miRNAs) are evolutionarily conserved small (18-25 nucleotides) non-coding RNAs that modulate gene expression by targeting mRNAs of protein-coding genes. Further research on let-7 revealed a highly conserved miRNA family present in vertebrates, ascidians, hemichordates, molluscs, annelids and arthropods [2]. The let-7 family consists of 12 members, all sharing a common seed sequence. Let-7 miRNAs are involved in many physiological, as well as pathological processes, with a primary role in the induction of terminal differentiation and maintenance of this differentiated state throughout lifespan. Many known let-7 target genes, such as MYC, CCND1, RAS, LIN28 and HMGA2 are oncogenes involved in cell cycle progression and stemness. Ectopic expression of let-7 www.impactjournals.com/oncotarget reduces chemoresistance and invasiveness of cancer cells and suppresses tumor growth of human lung cancers in vivo [6]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
