The microcosmos of cancer

Abstract

The discovery of microRNAs (miRNAs) almost two decades ago established a new paradigm of gene regulation. During the past ten years these tiny non-coding RNAs have been linked to virtually all known physiological and pathological processes, including cancer. In the same way as certain key protein-coding genes, miRNAs can be deregulated in cancer, in which they can function as a group to mark differentiation states or individually as bona fide oncogenes or tumour suppressors. Importantly, miRNA biology can be harnessed experimentally to investigate cancer phenotypes or used therapeutically as a target for drugs or as the drug itself.

Figure 1. Mechanisms of miRNA perturbation in cancer

Cancer cells present global downregulation of miRNAs, loss of tumour-suppressor miRNAs and specific accumulation of oncogenic miRNAs. The alteration in miRNA expression patterns leads to the accumulation of oncogenes and downregulation of tumour-suppressor genes, which leads to the promotion of cancer development. a, The expression and function of oncogenic miRNAs is increased by genomic amplification, activating mutations, loss of epigenetic silencing and transcriptional activation. By contrast, tumour-suppressor miRNAs are lost by genomic deletion, inactivating mutations, epigenetic silencing or transcriptional repression. b, After transcription, global levels of miRNAs can be reduced by impaired miRNA biogenesis. Inactivating mutations and reduced expression have been described for almost all the members of the miRNA processing machinery. If there is a downreguation of DROSHA this can lead to a decrease in the cropping of primary miRNA (pri-miRNA) to precursor miRNA (pre-miRNA). In the case of XPO5 mutation, pre-miRNAs are prevented from being exported to the cytoplasm. Mutation of TARBP2 or downregulation of DICER1 results in a decrease in mature miRNA levels. Pol II, RNA polymerase II; RISC, RNA-induced silencing complex.

Figure 2. Contribution of miRNAs to cancer pathways

a, Tumour-suppressor miRNAs, which repress oncogenes in healthy cells, are lost in cancer cells, leading to oncogene upregulation, whereas oncogenic miRNAs inhibit tumour-suppressor genes, giving rise to cancer. b, The presence of different target genes in different cell lines can modify the function of an miRNA, both in healthy cells and cancer cells, which can lead to the development of cancer or a different outcome. c, Two miRNAs can function together to regulate one or several pathways, which reinforces those pathways and can result in the development of cancer. d, The oncogene MYC can either repress tumour-suppressor miRNAs (in blue) or activate oncogenic miRNAs (in red) and can therefore orchestrate several different pathways. MYC can repress let-7, directly, or indirectly, through LIN28 activation. Conversely, let-7 can also repress MYC, which closes the regulatory circle. e, Tumour suppressor p53 can regulate several tumour suppressor miRNAs (blue), activating different antitumoral pathways. The regulation of MDM2 by some of these miRNAs leads to interesting feedforward loops. At the same time, p53 can be negatively regulated by oncogenic miRNAs (in red). In addition, p53 is involved in the biogenesis of several tumour suppressor miRNAs.

Figure 3. In vivo miRNA expression or inhibition ‘á la carte’

a, Tetracycline (Tet)-mediated miRNA inactivation or activation by doxycycline administration using Tet-OFF, in which a tissue-specific promoter (TSP) is combined with a transactivator (tTA) to turn on expression of oncogenic miRNA (purple) and induce tumorigenesis (purple star) and subsequent tumour regression, revealing dependence on the oncogenic miRNA, or Tet-ON systems in which a reverse transactivator (rtTA) switches on oncogenic miRNA when the drug is applied. Drug withdrawal leads to tumour regression. b, Tet-mediated miRNA activation or inactivation by doxycycline administration using Tet-OFF or Tet-ON systems. miRNAs (green) can be inhibited by miRNA sponges (dark blue), with the same effects as miRNA expression, leading to tumorigenesis and subsequent tumour regression, which indicates a dependence on tumour-suppressor loss.

Figure 4. Proposed scheme for the treatment of liver cancer with combined chemotherapy and miRNA-based therapy

a, miRNA expression profiles of potential patients could be assessed by measuring circulating miRNAs in patient serum or tumoral miRNAs from a biopsy. For example, miR-21 expression and miR-26 loss could be detected in serum and tumour samples. b, This profile could be used for early detection of cancer, accurate diagnosis and prognosis, and choosing the best therapeutic strategy. The best available chemotherapeutic option could be combined with miRNA-based therapy. c, The oncomiRs detected in miRNA profiling and those present in the tumour, such as miR-21, could be inhibited by using different strategies, such as locked nucleic acid constructs. By contrast, the expression of tumour-suppressor miRNAs downregulated in the tumour could be restored and miR-26 levels could be increased with miRNA mimics. d, After treatment, the patient could be checked for relapse by periodically studying circulating miRNAs from serum in a non-invasive manner. The presence of miR-21 could indicate a potential relapse, and treatment would resume (black arrows).