MicroRNA let-7: an emerging next-generation cancer therapeutic

Abstract

In recent years, various RNA-based technologies have been under evaluation as potential next-generation cancer therapeutics. Micrornas (miRNAS), known to regulate the cell cycle and development, are deregulated in various cancers. Thus, they might serve as good targets or candidates in an exploration of anticancer therapeutics. One attractive candidate for this purpose is let-7 ("lethal-7"). Let-7 is underexpressed in various cancers, and restoration of its normal expression is found to inhibit cancer growth by targeting various oncogenes and inhibiting key regulators of several mitogenic pathways. In vivo, let-7 administration was found effective against mouse-model lung and breast cancers, and our computational prediction supports the possible effectiveness of let-7 in estrogen receptor (ER)-positive metastatic breast cancer. Data also suggest that let-7 regulates apoptosis and cancer stem cell (CSC) differentiation and can therefore be tested as a potential therapeutic in cancer treatment. However, the exact role of let-7 in cancer is not yet fully understood. There is a need to understand the causative molecular basis of let-7 alterations in cancer and to develop proper delivery systems before proceeding to therapeutic applications. This article attempts to highlight certain critical aspects of let-7's therapeutic potential in cancer.

Keywords: Let-7; cancer therapy; future medicine; let-7 regulation; microrna.

FIGURE 1

The most-accepted model of microrna (mirna) biogenesis and its mechanism of action. For detail, see text. rna Pol ii = rna polymerase ii; Pri-mirna = primary transcripts of mirna; DGCR8 = DiGeorge syndrome critical region gene 8; Drosha = class 2 rnase iii enzyme; XPO5 = exportin 5; Dicer = formal symbol DICER1 (dicer 1, ribonuclease type iii); TRBP = now labelled TARBP2P [tar (hiv-1) rna binding protein 2 pseudogene]; Ago1–4 = Argonaute-1 to -4 [symbol EIF2C1, 2, 3, 4 (eukaryotic translation initiation factor 2C, 1–4)]; rnp = ribonucleoprotein; mrna = messenger rna.

FIGURE 2

Regulatory circuits of microrna (mirna) let-7. The loop consists of pluripotency promoting factors {LIN28 [lin-28 homolog (Caenorhabditis elegans)], OCT4 [now labelled POU5F1 (pou class 5 homeobox 1)], SOX2 [sry (sex determining region Y)–box 2], NANOG [Nanog homeobox], and TCL3 [now labelled TLX1 (T-cell leukemia homeobox 1)]}, oncofetal genes [HMGA2 (high mobility group at–hook 2) and imps (insulin-like growth factor 2 mrna-binding proteins)], and oncogene MYC. For detail, see text. Pri-let 7 = primary transcripts of let-7; LIN28B = lin-28 homolog B (C. elegans).

FIGURE 3

Let-7 targets various key components of mitogenic and tumorigenic pathways to exert its tumour suppressor activity. Pathways include cell cycle, cell division, cell proliferation, dna replication, angiogenesis, and apoptosis. PLAGL1, 2 = pleomorphic adenoma gene-like 1, 2; CKS1B = cdc28 protein kinase regulatory subunit 1B; SKP2 = S-phase kinase-associated protein 2 (p45); fgf, fgfr = fibroblast growth factor and fibroblast growth factor receptor; igf = insulin-like growth factor; il-s = interleukin S; tgfb = transforming growth factor β; GRB2 = growth factor receptor-bound protein 2; mapk = mitogen-activated protein kinase; CYP19A1 = cytochrome P450, family 19, subfamily A, polypeptide 1; ESR1 = estrogen receptor 1; MMP2, 8 = matrix metallopeptidases 2, 8; ITGB3 = integrin β3; ANG = angiogenin; RRM1, 2 = ribonucleotide reductases M1 and M2; CDC6 = cell division cycle 6 homolog (Saccharomyces cerevisiae); ORC1L = origin recognition complex, subunit 1-like (yeast); MCM2 = minichromosome maintenance complex component 2; RFC2–5 = replication factor C (activator 1) 2–5; GMNN = geminin, dna replication inhibitor; E2F5, 6, 8 = e2f transcription factors 5, 6, 8; CDK8 = cyclin-dependent kinase 8; CDC16 = cell division cycle 16 homolog (S. cerevisiae); AURKA = aurora kinase A; CDC25A = cell division cycle 25 homolog A (Schizosaccharomyces pombe); CCNA2 = cyclin A2; CDC20, 23 = cell division cycle 20 and 23 homologs (S. cerevisiae); CDCA1 = (now labelled NUF2) NDC80 kinetochore complex component, homolog (S. cerevisiae); CHEK1 = chk1 checkpoint homolog (S. pombe); BUB1, 1B = budding uninhibited by benzimidazoles 1 and 1 β homologs (yeast); CCNB1, D1, D2, E2, F, J = cyclins B1, D1, D2, E2, F, J; CDC2 = cell division cycle 2, G1 to S and G2 to M; CDK2, 4, 6 = cyclin-dependent kinases 2, 4, 6; mrna = messenger rna.