Genes frequently mutated in colorectal cancer and their
relationships with miRNAs. Genes frequently mutated in CRC
(highlighted in orange) regulate and are regulated by miRNAs. Oncogenic
miRNAs are depicted in blue, tumor-suppressive miRNAs in red, and miRNAs
with reported pleiotropic effects in purple. Direct relationships are
shown with solid lines, while indirect relationships are illustrated
with dotted lines. The Wnt pathway is augmented by miR-135b, miR-21 and
miR-155, and inhibited by miR-34a, miR-29b/c. Downstream of Wnt,
MYC transcriptionally activates the miR-17-92 locus, but represses
expression of miR-15, miR-26 and miR-30. KRAS augments expression of
miR-31. MYC and KRAS promote cell cycle progression (CC, circular
arrows). In the PI3K pathway, which is negatively regulated by PTEN,
miR-135b is augmented by PI3K inhibition of FoxO transcription factors
(FOXO1 and FOXO3A), which represses cell cycle progression. MiR-221,
miR-21 and miR-17/106 enhance activation of PI3K signaling by
repressing negative regulators of this pathway. MiRNAs also modulate
inflammatory pathways mediated by the transcription factors NFΚB
and STAT3 by directly inhibiting IL-6 (via Let-7 miRNAs, which are
inhibited by LIN28B) or the IL-6 receptor (via miR-34 and miR-125b).
MiR-221/222 and miR-29b/c can also augment this pathway
via indirect stimulatory effects on IL-6, NFΚB, and STAT3. The
TGF-β pathway, which is important for repressing cellular
proliferation and cell cycle progression is also antagonized by several
miRNAs, including miR-17/106, miR-135b, and miR-20a through
effects on TGFBR2 and SMAD4. The miRNA miR-93 can stimulate the
TGF-β pathway by repressing the inhibitory SMAD7, although the
effect of miR-93 is inhibitory of Wnt signaling through inhibition of
SMAD7, which can augment nuclear accumulation of β-catenin.
Lastly, several miRNAs have effects on EMT in CRC tumorigenesis, with
miR-15/16 and miR-34 (which are transcriptionally activated by
TP53) inhibiting this process, while miR-21 enhances EMT. References for
the effects of these miRNAs can be found in Table 1 or in the main text.
Official human gene symbols and full names: APC,
adenomatous polyposis coli or WNT signaling pathway regulator;
CTNNB1, β-catenin; MYC,
v-myc avian myelocytomatosis viral oncogene homolog;
KRAS, Kirsten rat sarcoma viral oncogene homolog or
proto-oncogene and GTPase; PI3K, phosphatidylinositol-4,5-bisphosphate
3-kinase (PIK3CA, PIK3CB,
PIK3CD, PIK3CG); PTEN, phosphatase
and tensin homolog; FoxO, forkhead box O1 and O3a
(FOXO1 and FOXO3A);
PDCD4, programmed cell death 4 (neoplastic
transformation inhibitor); LIN28B, lineage-28 homolog
B; NFΚB, nuclear factor kappa B (NFKB1,
NFKB2, REL, RELA,
RELB); IL6, interleukin 6;
IL6R, interleukin 6 receptor;
STAT3, signal transducer and activator of
transcription 3; TGFBR2, transforming growth factor
beta receptor 2; SMAD4, mothers against decapentaplegic
homolog family member 4; SMAD7, mothers against
decapentaplegic homolog family member 7; TP53, tumor
protein p53.