Biology Reference
In-Depth Information
inflammatory disease owing to hyperactivation of NF-
B(
Boldin
et al
.,
2011; Zhao
et al
., 2011
). This appears to be a consequence of the enhanced
expression of IRAK1 and TRAF6 (
Taganov
et al
., 2006
), and possibly
STAT1 (
Lu
et al
., 2010
), all proinflammatory signaling proteins that are
direct targets of miR-146a.
Many human disorders of hematological origin are phenotypically simi-
lar to inflammatory hematopoiesis, suggesting an overlap between the
molecular mechanisms that govern these distinctly pathological and physi-
ological processes. Although the studies to date have taken important first
steps, much remains to be determined regarding how miRNAs modulate
hematopoiesis during inflammation and how these pathways relate to
proper immune function versus hematological diseases.
k
5.2. Cancer
It is quite clear that miRNA expression is dysregulated in a variety of
different human leukemias and lymphomas, and that this dysregulation is
sufficient to cause cancer in some cases (
Bousquet
et al
., 2010
;
Calin and
Croce, 2006
;
Costinean
et al
., 2006
;
Garzon
et al
., 2008
;
O'Connell
et al
.,
2010a
). It is not surprising that many of the same miRNAs that regulate
hematopoiesis under physiological conditions are involved in disease states.
Some miRNAs function as onco-miRs, and their overexpression is suffi-
cient to cause precancerous neoplasms, or in some cases, frank malignancies.
Other miRNAs act to suppress cancer development, and loss of these
molecular safeguards can result in the onset of malignant disease.
Because miRNAs regulate many different stages of hematopoiesis,
malignancies involving perturbations in their levels can arise from cells at
unique points within the developmental series. For example, overexpres-
sion of miR-155 or miR-29a in HSCs causes an MPD or a frank leukemia,
respectively (
Han
et al
., 2010
;
O'Connell
et al
., 2008
). Alternatively, B cell
malignancies are triggered when miR-21 or miR-155 is overexpressed or
miR-15a/16-1 is deleted in B lymphocytes (
Costinean
et al
., 2006
;
Klein
et al
., 2010
;
Medina
et al
., 2010
).
As we begin to define the protein targets of specific cancer-related
miRNAs, our understanding of how this class of ncRNAs influences cancer
phenotypes continues to expand. For example, miR-155 has been shown to
repress certain negative regulators of inflammation and cellular activation
such as Ship1 and Socs1 (
Androulidaki
et al
., 2009
;
Costinean
et al
., 2009
;
Lu
et al
., 2009
;
O'Connell
et al
., 2009
). Upon inappropriate overexpression
of miR-155 stemming from chronic inflammation or mutations triggering
constant cellular activation, these and other targets will be continually
repressed. Consequently, the pathways they normally restrict will become
hyperactivated and over time will cause hyperproliferative disease.
