Apoptosis and the target genes of microRNA-21

Abstract

MicroRNA-21 (miR-21) is frequently up-regulated in cancer and the majority of its reported targets are tumor suppressors. Through functional suppression, miR-21 is implicated in practically every walk of oncogenic life: the promotion of cell proliferation, invasion and metastasis, genome instability and mutation, inflammation, replicative immortalization, abnormal metabolism, angiogenesis, and evading apoptosis, immune destruction, and growth suppressors. In particular, miR-21 is strongly involved in apoptosis. In this article, we reviewed the experimentally validated targets of miR-21 and found that two thirds are linked to intrinsic and/or extrinsic pathways of cellular apoptosis. This suggests that miR-21 is an oncogene which plays a key role in resisting programmed cell death in cancer cells and that targeting apoptosis is a viable therapeutic option against cancers expressing miR-21.

Figure 1.. MicroRNA-21 (miR-21) target genes and the next-generation hallmarks of cancer.

The eight hallmarks and two enabling characteristics (genome instability and inflammation) of cancer were described by Hanahan et al.. Target genes shown in green are specific to apoptosis with other targets shown in purple. miR-21 is a negative regulator of p53 signaling, and NF-κB signaling is promoted by miR-21. p53 inactivation and NF-κB activation are implicated in deregulation of glucose flux and oxidative phosphorylation. It is notable that several targets contribute to more than one hallmark, and that virtually every hallmark involves at least one miR-21 target.

Figure 2.. Convergence of miR-21 target genes and the apoptosis pathway.

miR-21 targets are shown in green. A, the intrinsic apoptosis pathway. Signals within the cell induce Bax, a BH123 domain containing protein, to permeabilize the mitochondrial membrane, allowing the release of cytochrome C. Cytochrome C binds and activates Apaf1, which in turn activates the initiator Caspase 9 by cleavage and formation of the apoptosome (not shown). This allows cleavage and activation of the effector caspases 3, 6, and 7, leading to apoptosis. TAp63 acts in a compensatory role in p53-deficient cells to activate Pro-apoptotic genes in response to DNA damage. Fak is a scaffolding protein that activates the PI3K/Akt pathway to avoid apoptosis. Inhibition of this by Pten allows for anoikis. Spy1 expression is associated with the inhibition of DNA damage signal cascades that initiate apoptosis. hMsh2 is a member of the mismatch repair complex that can signal within the DNA damage-induced apoptosis pathway. High levels of TGFBR2 stimulate apoptosis, potentially through stimulation of the Mapk pathway. B, the extrinsic apoptosis pathway. Death ligands such as TNF or FasL bind their cell surface receptors, causing them to tri- or oligomerize, causing recruitment of the adaptor proteins Fadd or Tradd, leading to the formation of the death inducing signaling complex (DISC, not shown) comprised of the intiator caspases 8, 10, or 2. These can then activate the effector caspases 3, 6, and 7, causing apoptosis. These death ligands can also signal the mitochondrial apoptotic pathway by activating BH3 domain containing proteins such as Bid and Bad, which inhibit the anti-apoptotic protein Bcl2. Bcl2 then releases BH123 domain containing proteins such as Bax, allowing release of cytochrome C, formation of the apoptosome by Apaf1, and induction of the Caspase cascade through the initiator Caspase 9. TAp63 induces apoptosis by activating signaling via death receptors and mitochondria. Pten inhibits TNF activation of NF-κB, which in this context would ordinarily activate transcription of anti-apoptotic genes. Ligands specific to PPARα induce apoptosis through up-regulation of PP2A, which positively affects Bad levels. FasL is an apoptosis inhibitor that signals through Fas, a death receptor. Anp32A is a tumor suppressor that regulates apoptosis through activation of Caspase activity. Pellino-1 is involved in activating NF-κB which prevents apoptosis during the proliferation phase of hepatocytes after hepatectomy. Pdcd4 is involved in TLR4 signaling and signals apoptosis through IL-6 and NF-κB.