Biology Reference
In-Depth Information
downregulation of mature let-7 miRNA levels or loss of target regulation
through deletion of 3
0
UTR target sites, for example. Some or all of the let-7
family miRNAs are depleted in tumor compared to normal tissues for many
types of cancer (
Boyerinas
et al.
, 2010
). While reexpression of LIN28
explains some cases of decreased let-7 levels, other mechanisms for reducing
let-7 in cancer cells are yet to be determined. The HMGA2 gene is an
example of a let-7 target that escapes regulation in some types of tumors
through truncation of its 3
0
UTR, which removes the let-7 binding sites
(
Lee and Dutta, 2007; Mayr
et al.
, 2007; Shell
et al.
, 2007
). HMGA2
encodes a chromatin-associated nonhistone protein that is highly expressed
in embryonic tissues, and undetectable is most differentiated adult cells.
Chromosomal rearrangements can separate the HMGA2 3
0
UTR from its
open reading frame, allowing for unregulated expression of the protein (
Lee
and Dutta, 2007; Mayr
et al.
, 2007; Shell
et al.
, 2007
). The truncated
HMGA2 gene has been shown to promote oncogenesis, underscoring the
importance of regulation through its 3
0
UTR (
Mayr
et al.
, 2007
).
The first indication that let-7 may act as a tumor suppressor came with
the discovery that it has a conserved role in regulating the expression of
RAS (
Johnson
et al.
, 2005
). The three human RAS oncogenes each contain
multiple let-7 binding sites in their 3
0
UTRs. The RAS proteins are fre-
quently upregulated in lung tumors, where let-7 family miRNAs tend to be
downregulated (
Johnson
et al.
, 2005; Takamizawa
et al.
, 2004
). A direct
role for let-7 in regulating RAS and preventing lung tumor growth has been
demonstrated in cell culture and mouse model systems (
Esquela-Kerscher
et al.
, 2008; Johnson
et al.
, 2005, 2007; Kumar
et al.
, 2008; Takamizawa
et al.
, 2004
). In addition to RAS, several oncogenes, such as IMP and MYC,
have been identified as direct let-7 targets, further supporting its classifica-
tion as a tumor suppressor (
Boyerinas
et al.
, 2008; Kim
et al.
, 2009a
).
Although downregulation of let-7 family miRNAs has been associated
with many types of cancers, there are a few examples of increased let-7
expression in certain tumors (
Boyerinas
et al.
, 2010
). Thus, the role of let-7
as a tumor suppressor will likely depend on the cellular environment and
targets available for regulation.
4.3. Neuronal functions
The let-7 family miRNAs are highly expressed in neuronal cells across
species, suggesting important roles in neurologic development and function
(
Caygill and Johnston, 2008; Johnson
et al.
, 2003; Sempere
et al.
, 2004;
Smirnova
et al.
, 2005; Sokol
et al.
, 2008
). Consistent with increasing
expression of let-7 miRNAs during mammalian brain development, these
miRNAs repress neuronal proliferation and promote differentiation pro-
grams (
Nishino
et al.
, 2008; Rybak
et al.
, 2008; Schwamborn
et al.
, 2009;
