MicroRNAs in Cancer

Mis-regulation of genes that control cell proliferation and cell fate determination often contribute to cancer development. In C. elegans let-7 mutants, stem cells frequently fail to terminally differentiate, and instead elect to divide again, a hallmark of cancer [7]. In C. elegans, let-7 directly regulates RAS, and another gene, lin-41, which is homologous to the cancer gene PML, mutated in almost all cases of promylocytic leukemia. let-7 is conserved in humans [1], where we linked it to cancer [2, 8]. Work from my group showed for the first time that miRNAs can regulate cellular oncogene mRNAs, e.g. the let-7 miRNA, expressed at low levels in cancer stem cells [9], regulates a number of oncogenes, including RAS [2] and MYC [10]. We also showed that loss of the let-7 miRNA in mouse lungs dramatically enhances the tumorigenicity of activated RAS alleles [5], providing the first in vivo evidence that miRNAs can act as tumor suppressors and hence as plausible drugs in cancer treatment. We showed that let-7 delivered to mice with lung cancer, can reduce the cancer phenotype, either delivered intranasally or intravenously [3, 5, 6]. We found similar results for miR-34 [6]. Thus we are focusing on the role of let-7 and miR-34 in regulating proto-oncogene expression during cancer, initially in lung and breast cancer.

This work led to an intense investigation of miRNAs as oncogenes and tumor suppressors. We and others have shown that additional miRNAs regulate processes important for cell growth, division, survival and migration, all processes that go awry in cancer. Several key miRNAs are encoded by genes that are amplified, deleted or mis-expressed in cancer [2, 11]. For example, we showed for the first time that over-expression of a single miRNA, miR-21 in this case, in a mouse model leads to cancer and that these cancers depend on miR-21 for their survival [4]. This work showed for the first time that not only are some miRNAs oncogenes (oncomiRs), but that tumors depend on these oncomiRs for their survival, making them excellent targets for therapy. Hence miRNAs are emerging as important targeted therapies and therapeutic targets. We teamed up with a biomedical engineer to solve the delivery problem for lymphocytes and delivered anti-miR molecules to successfully turn off an oncogenic miRNA [12].

Future work: Therapeutics that target drug resistant sub-populations or sensitize these to current therapies are lacking. Novel ideas based on a better understanding of cancer are required. MiRNAs are important master controllers of stem cells [13] and the cell survival and proliferation pathways that are critically important in cancer development and tumor maintenance [14]. Work from my group has shown that miRNAs themselves are both effective targets [4] and therapeutics [3, 5, 6, 15] in cancer, thus we propose moving towards clinical trials molecules that target or mimic these important regulators as cancer therapeutics. The ultimate goal is that the innovations described here from both the diagnostic and therapeutic directions will ultimately be extended into clinical cancer trials.

Our most obvious current translational projects involve delivering miRNA mimics and anti-miRs to genetically engineered mouse models of lung, lymphoma and breast cancer, where our published and preliminary results show very promising efficacy with no short-term side effects.

Literature cited:

  1. Pasquinelli, A.E., et al., Conservation of the sequence and temporal expression of let-7 heterochronic regulatory RNA. Nature, 2000. 408(6808): p. 86-9.
  2. Johnson, S.M., et al., RAS is regulated by the let-7 microRNA family. Cell, 2005. 120(5): p. 635-47.
  3. Esquela-Kerscher, A., et al., The let-7 microRNA reduces tumor growth in mouse models of lung cancer. Cell Cycle, 2008. 7(6): p. 759-64.
  4. Medina, P.P., M. Nolde, and F.J. Slack, OncomiR addiction in an in vivo model of microRNA-21-induced pre-B-cell lymphoma. Nature, 2010. 467(7311): p. 86-90.
  5. Trang, P., et al., Regression of murine lung tumors by the let-7 microRNA. Oncogene, 2010. 29(11): p. 1580-7.
  6. Trang, P., et al., Systemic Delivery of Tumor Suppressor microRNA Mimics Using a Neutral Lipid Emulsion Inhibits Lung Tumors in Mice. Mol Ther, 2011. 19(6): p. 1116-22.
  7. Reinhart, B., et al., The 21 nucleotide let-7 RNA regulates C. elegans developmental timing. Nature, 2000. 403: p. 901-906.
  8. Takamizawa, J., et al., Reduced expression of the let-7 microRNAs in human lung cancers in association with shortened postoperative survival. Cancer Res, 2004. 64(11): p. 3753-6.
  9. Yu, F., et al., let-7 Regulates Self Renewal and Tumorigenicity of Breast Cancer Cells. Cell, 2007. 131: p. 1109-23.
  10. Kim, H.H., et al., HuR recruits let-7/RISC to repress c-Myc expression. Genes Dev, 2009. 23(15): p. 1743-8.
  11. Calin, G.A., et al., Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proc Natl Acad Sci U S A, 2004. 101(9): p. 2999-3004.
  12. Babar, I.A., et al., Nanoparticle-based therapy in an in vivo microRNA-155 (miR-155)-dependent mouse model of lymphoma. Proc Natl Acad Sci U S A, 2012.
  13. Slack, F.J., Stem cells: Big roles for small RNAs. Nature, 2010. 463(7281): p. 616.
  14. Esquela-Kerscher, A. and F.J. Slack, Oncomirs - microRNAs with a role in cancer. Nat Rev Cancer, 2006. 6(4): p. 259-69.
  15. Weidhaas, J.B., et al., MicroRNAs as potential agents to alter resistance to cytotoxic anticancer therapy. Cancer Res, 2007. 67(23): p. 11111-6.