Biology Reference
In-Depth Information
shortening of 3
0
UTRs of proto-oncogenes in cancer cell lines has been
found to enable the mRNA to escape the repression by miRs and result in
oncogene activation (
Mayr and Bartel, 2009
). Together, these studies raise
the hypothesis that the miR pathway often functions in tumor suppression,
as suggested earlier in this review.
It is also interesting that let-7 miRs appear to be powerful tumor
suppressors in their ability to target multiple critical oncogenes including
RAS, c-Myc, Hmga2, and Lin28 (
Johnson
et al
., 2005; Mayr
et al
., 2007;
Roush and Slack, 2008; Viswanathan
et al
., 2009
). Several miRs that are
highly expressed in normal skin, including miR-200 and miR-205, have
also been implicated in epithelial cancers. Both miR-200 miRs and
miR-205 are highly expressed in normal skin, where they specifically target
the expression of the mRNAs encoding transcriptional repressors of
E-cadherin, ZEB1, and ZEB2 (
Christoffersen
et al
., 2007; Gregory
et al
.,
2008; Korpal
et al
., 2008; Park
et al
., 2008
). By doing so, miR-200 and
miR-205 promote the upregulated expression of the intercellular adhesion
protein E-cadherin. Conversely, downregulation of the miR-200 family or
miR-205 leads to the inhibition of E-cadherin, thereby promoting an
epithelial-mesenchymal transition (
Gregory
et al
., 2008; Korpal
et al
.,
2008; Park
et al
., 2008
). Consistent with these studies, miR-205 is often
significantly downregulated in human epithelial tumors when comparing to
the normal tissues (
Childs
et al
., 2009; Feber
et al
., 2008
). That said, there are
profiling studies of human epithelial cancers, where miR-200 family and/or
miR-205 were found to be upregulated (
Iorio
et al
., 2007; Tran
et al
., 2007;
Yu
et al
., 2008
). These apparently contrasting results suggest that miRs may
have different targets and roles in different cells.
The identification of cancer stem cells in numerous tumors including
those derived from brain, breast, prostate, colon, head and neck, pancreas,
and skin necessitates an investigation into the underlying molecular
mechanisms involved. Given the diversity of miR expression patterns and
functions, it is perhaps not surprising that miRs are critically involved in
cancer stem cells. For instance, in the tumor initiating cells of breast cancer,
let-7 is significantly downregulated to allow the expression of H-Ras and
Hmga2 (
Yu
et al
., 2007
). Forced expression of let-7 in the tumor initiating
cells inhibits self-renewal through the downregulation of H-Ras and pro-
motes differentiation by repressing Hmga2 (
Yu
et al
., 2007
). Similarly,
miR-34a, a miR transcriptionally activated by p53 (
He
et al
., 2007
), func-
tions to inhibit clonogenic expansion of prostate cancer stem cells and
metastasis by directly repressing CD44 (
Liu
et al
., 2011
). In breast cancer
stem cells, the miR-200 family members including miR-200b and
miR-200c have multiple functions in restricting tumor development,
including repressing self-renewal by repressing a key polycomb protein
complex 1 (PRC1) member, BMI1 (
Shimono
et al
., 2009; Wellner
et al
.,
2009
). These miRs also play important roles in EMTs (
Wellner
et al
., 2009
),
