microRNAs in cancer management Yi W Kong, PhD, David Ferland-McCollough, PhD, Thomas J Jackson, Dr Martin Bushell, DPhil  The Lancet Oncology  Volume 13, Issue 6, Pages e249-e258 (June 2012) DOI: 10.1016/S1470-2045(12)70073-6 Copyright © 2012 Elsevier Ltd Terms and Conditions

Figure 1 Regulation of tumorigenesis by miRNAs Tumorigenesis can be regulated by miRNAs at different levels. Upregulation of oncogenic miRNAs reduces expression of tumour-suppressor protein, but downregulation of tumour-suppressing miRNAs results in an increased production of oncogenic protein. Loss-of-function mutations in tumour-suppressing miRNAs and mutation of the target section of oncogene mRNA can cause tumorigenesis, because expression of oncogenic proteins is no longer regulated. Loss-of-function mutations in oncogenic miRNAs and mutations in tumour-suppressor mRNA would increase expression of tumour-suppressor proteins and hence reduce tumorigenesis. miRNA=microRNA. The Lancet Oncology 2012 13, e249-e258DOI: (10.1016/S1470-2045(12)70073-6) Copyright © 2012 Elsevier Ltd Terms and Conditions

Figure 2 Oncogenic and tumour-suppressing miRNAs in the DNA damage response DNA damage can lead to the upregulation of the miR-34 family through the activation of the P38 MAP-kinase and P53 pathways. The tumour suppressor miR-34 blocks MYC translation, thus inhibiting MYC-dependent transcription of oncogenes such as the oncogenic miR-17-92 miRNA cluster. P53 also enables miRNA processing through interactions with the primary miRNA processing enzyme Drosha. miRNA=microRNA. The Lancet Oncology 2012 13, e249-e258DOI: (10.1016/S1470-2045(12)70073-6) Copyright © 2012 Elsevier Ltd Terms and Conditions

Figure 3 Regulation of cancer progression at different stages by microRNAs The Lancet Oncology 2012 13, e249-e258DOI: (10.1016/S1470-2045(12)70073-6) Copyright © 2012 Elsevier Ltd Terms and Conditions

Figure 4 miRNA-based treatment In miRNA reduction treatment (A), single-stranded LNA molecules (anti-miRNAs) bind to miRNAs complementarily, preventing the miRNAs from binding to target mRNAs. In miRNA replacement treatment (B), tumour suppressive miRNAs that are lost during carcinogenesis are reintroduced by use of a miRNA mimic. These double-stranded miRNA mimics can either be modified on the complementary strand or encapsulated in nanoparticles to increase their stability. The delivery of LNA and miRNA mimics can be improved with nanoparticles conjugated to antibodies or cancer-specific ligands. LNA=locked nucleic acid. The Lancet Oncology 2012 13, e249-e258DOI: (10.1016/S1470-2045(12)70073-6) Copyright © 2012 Elsevier Ltd Terms and Conditions